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Dewhirst, Mark Wesley

Overview:

Mark W. Dewhirst, DVM, PhD is the Gustavo S. Montana Professor of Radiation Oncology and Vice Director for Basic Science in the Duke Cancer Institute. Dr. Dewhirst has research interests in tumor hypoxia, angiogenesis, hyperthermia and drug transport. He has spent 30 years studying causes of tumor hypoxia and the use of hyperthermia to treat cancer. In collaboration with Professor David Needham in the Pratt School of Engineering, he has developed a novel thermally sensitive drug carrying liposome that has been successfully translated to human clinical trials. He has utilized the thermal characteristics of this liposome to develop an MR imageable form that can accurately reflect drug concentrations in tumors, which then is related to the extent of anti-tumor effect in pre-clinical models. This property has been widely used by other investigators, world-wide, particularly in the area of high intensity focused ultrasound, where it would be possible to literally paint drug to a target zone and visualize this process in real time, during heating. For his work in this area, Dr. Dewhirst was named a Fellow in the AAAS. Dr. Dewhirst has well over 500 peer-reviewed publications, book chapters and reviews, with >20,000 citations and an H-index of 73. He has given named lectures at the University of Western Ontario, Thomas Jefferson University and the New Zealand Cancer Society. He was awarded the Failla Medal and Lecture at the Radiation Research Society in 2008, the Eugene Robinson award for excellence hyperthermia research in 1992 and a similar award from the European Society for Hyperthermic Oncology in 2009. He was named a fellow of ASTRO in 2009 and was awarded the prestigious Gold Medal from the same society in 2012. He is a Senior Editor of Cancer Research and Editor-in-Chief of the International Journal of Hyperthermia. He has mentored 24 graduate students, and many postdoctoral fellows, residents, junior faculty and medical students. He has been particularly skillful in assisting those he has mentored to obtain DOD and NIH fellowships, K awards and first R01 grants. His skill in mentoring has been recognized by the Duke Comprehensive Cancer Center, the Medical Physics Graduate Training programs and the School of Medicine, where he has received “Mentor of the Year” awards. In 2011 he was selected to become the first Associate Dean of Faculty Mentoring in the Duke School of Medicine. In this position, he is implementing a comprehensive program to enhance success in obtaining NIH funding. He graduated from the University of Arizona in 1971 with a degree in Chemistry and Colorado State University in 1975 and 1979 with DVM and PhD degrees, respectively.

Positions:

Gustavo S. Montana Professor of Radiation Oncology, in the School of Medicine

Radiation Oncology
School of Medicine

Professor of Radiation Oncology

Radiation Oncology
School of Medicine

Associate Dean for Faculty Mentoring

School of Medicine
School of Medicine

Professor in Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1979

Ph.D. — Colorado State University at Fort Collins

News:

Mark Dewhirst: Running from cancer?

April 20, 2016 — The Scientist

How exercise may aid cancer treatment

March 25, 2015 — The New York Times

The bubbles that could save lives

July 03, 2013 — Sydney Daily Telegraph

Grants:

Duke KURe Program

Administered By
Obstetrics and Gynecology, Urogynecology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
August 01, 2013
End Date
September 13, 2023

Duke CTSA (KL2)

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
May 02, 2018
End Date
April 30, 2023

Duke CTSA (TL1)

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
May 02, 2018
End Date
April 30, 2023

A Portable low-cost, Point of Investigation CapCell Scope to Image and Quantify the Major Axes of Metabolism and the Associated Vasculature in In vitro and In vivo Biological Models

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
April 01, 2019
End Date
December 31, 2022

Building Interdisciplinary Research Careers in Women's Health

Administered By
Obstetrics and Gynecology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 26, 2002
End Date
July 31, 2022

University Training Program in Biomolecular and Tissue Engineering

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1994
End Date
June 30, 2022

University Training Program in Biomolecular and Tissue Engineering

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1994
End Date
June 30, 2022

Role of RBC Reactive Oxygen Species and Their Vicious Cycle in Sickle Vasculopathy

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Advisor
Start Date
August 16, 2017
End Date
May 31, 2021

Characterization of Tumor Immunobiological Factors that Promote Lymphovascular Invasion and Dissemination in Locally Advanced Breast Cancer

Administered By
Surgery, Surgical Sciences
AwardedBy
Department of Defense
Role
Collaborator
Start Date
August 15, 2017
End Date
August 14, 2020

Proteomic Signatures of Space Radiation Induced Cardiovascular Degeneration

Administered By
Surgery, Surgical Sciences
Role
Co Investigator
Start Date
May 12, 2016
End Date
May 11, 2020

Systemic EGFRvIII-targeted bispecific antibody as immunotherapy for glioblastoma

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
March 01, 2015
End Date
February 28, 2019

Dissecting mechanism(s) by which ionizing radiation promotes clonal expansion of premalignant cells in the thymus

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
September 15, 2016
End Date
August 31, 2018

Duke CTSA (UL1)

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Program Director
Start Date
September 26, 2013
End Date
July 31, 2018

Optimization of radiofrequency ablation with electrically conductive particles

Administered By
Radiology, Interventional Radiology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
August 14, 2015
End Date
January 31, 2018

The role of ERRalpha/PGC-1 in disease pathogenesis

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
April 01, 2006
End Date
January 31, 2018

Luminescent Oxygen Nanosensors for Tumor Hypoxia Imaging

Administered By
Radiation Oncology
Role
Principal Investigator
Start Date
September 25, 2012
End Date
December 31, 2017

Effects of Exercise Training on Tumor Growth in Triple Negative Breast Cancer

Administered By
Radiation Oncology
AwardedBy
Memorial Sloan Kettering Cancer Center
Role
Principal Investigator
Start Date
August 20, 2014
End Date
August 19, 2017

A Quantitative Optical Sensor to Monitor Tumor Vascular Physiology

Administered By
Radiation Oncology
Role
Principal Investigator
Start Date
September 01, 2015
End Date
December 31, 2016

Janssen Research AGreement

Administered By
Radiation Oncology
Role
Principal Investigator
Start Date
November 27, 2014
End Date
December 31, 2016

HIF-1 driven therapeutic resistance mechanisms in chest wall recurrences of inflammatory breast cancer (IBC)

Administered By
Radiation Oncology
Role
Principal Investigator
Start Date
December 01, 2013
End Date
December 31, 2016

Targeting nuclear FGF receptor to improve chemotherapy response in triple-negative breast cancer

Administered By
Pathology
AwardedBy
Department of Defense
Role
Investigator
Start Date
September 30, 2013
End Date
September 29, 2016

Research Training In Neuro-Oncology

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1998
End Date
August 31, 2016

Thermally Triggered Multivalent Targeting of Tumors

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
April 01, 2007
End Date
June 30, 2016

BMX-001 as a Radio-Protector in Head and Neck Cancer Therapy

Administered By
Radiation Oncology
Role
Principal Investigator
Start Date
February 13, 2015
End Date
May 08, 2016

Thermally Targeted Drug Delivery by Elastin Biopolymers

Administered By
Pratt School of Engineering
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
August 01, 2002
End Date
April 30, 2016

Cancer Biology Training Grant

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Cancer Institute
Role
Mentor
Start Date
July 01, 1993
End Date
March 31, 2016

Radiation Therapy: Dissecting the Role of Stromal Cells in Tumor Control

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
August 01, 2013
End Date
January 03, 2016

Detection of Novel Alternative Splicing Biomarkers of Hypoxia in Breast and Lung Tumors

Administered By
Radiation Oncology
Role
Principal Investigator
Start Date
July 01, 2014
End Date
December 31, 2015

Heat and Radiation Effects on Tumor Microcirculation

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
January 01, 1985
End Date
September 30, 2015

Harnessing the power of light to see and treat breast cancer

Administered By
Biomedical Engineering
Role
Investigator
Start Date
September 18, 2009
End Date
September 17, 2015

Clinical Oncology Research Career Development Program

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 29, 2009
End Date
July 31, 2015

27-hydroxycholesterol as a link between obesity and breast cancer pathogenesis

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Co-Mentor
Start Date
January 01, 2013
End Date
August 31, 2014

Resveratrol, Carbohydrate Restriction and Prostate Cancer Progression

Administered By
Surgery, Urology
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
September 15, 2008
End Date
July 31, 2014

Truncated GLI1 In Glioblastoma

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
April 15, 2014
End Date
June 30, 2014

Modulation of the blood-tumor barrier through targeted suppression of claudin 5

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
August 16, 2011
End Date
August 02, 2013

Cross-disciplinary Training in Medical Physics

Administered By
Duke University Medical Physics Graduate Program
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 2007
End Date
June 30, 2013

The Use of Hyperthermia and Copper Chelation to Overcome Cisplatin Resistance

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 01, 2011
End Date
May 31, 2013

Inhibition of metastasis-initiating cells by chimeric polypeptide nanoparticles

Administered By
Pratt School of Engineering
AwardedBy
National Institutes of Health
Role
Co-Mentor
Start Date
September 01, 2010
End Date
December 31, 2012

Can Optical Spectroscopy Predict Early Treatment Response in Solid Tumors

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
May 07, 2010
End Date
September 07, 2012

NCI Howard Temin Award (K01) Transition

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
September 25, 2006
End Date
July 31, 2012

Molecular mechanisms of chemoresistance in breast cancer

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
May 01, 2010
End Date
April 30, 2012

Small Animal PET / CT Molecular Imaging

Administered By
Radiology, Nuclear Medicine
AwardedBy
National Institutes of Health
Role
Major User
Start Date
April 01, 2011
End Date
March 31, 2012

Investigation of Anti-Angiogenic Mechanisms Using Novel Imaging Techniques

Administered By
Biomedical Engineering
Role
Mentor
Start Date
February 01, 2009
End Date
February 29, 2012

The Role of PTEN in Endothelial Biology

Administered By
Medicine, Cardiology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
February 15, 2008
End Date
January 31, 2012

Image-Guided Radiation Therapy and Radiosurgery for Small Animals

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Major User
Start Date
September 01, 2009
End Date
August 31, 2011

Hyperthermia and Perfusion Effects in Cancer Therapy

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 26, 2005
End Date
June 30, 2011

Intravital point-scanning confocal microscope

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Major User
Start Date
May 06, 2010
End Date
May 05, 2011

Accurate Models for Predicting Radiation-Induced Injury

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
May 10, 2006
End Date
April 30, 2011

Role of XIAP in Therapeutic Resistance in Inflammatory Breast Cancer

Administered By
Surgery
Role
Co-Mentor
Start Date
July 01, 2008
End Date
August 31, 2010

Research Training In Neuro-Oncology

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 15, 2005
End Date
August 31, 2010

Functional Optical Coherence Tomography for Monitoring Drug Resistance in Cancer

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 28, 2009
End Date
June 30, 2010

Hyperthermia and Perfusion Effects in Cancer Therapy

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
June 01, 1987
End Date
June 30, 2010

Erythropoietin Receptors in Breast Cancer

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
March 01, 2004
End Date
February 28, 2010

Training in Biomolecular and Tissue Engineering

Administered By
Orthopaedics
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 20, 2003
End Date
June 30, 2009

Stem Cell-Like Glioma Cells in Angiogenesis

Administered By
Neurology, General & Community Neurology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
April 07, 2008
End Date
January 31, 2009

TGFbeta-PTEN Interactions in Glioma Biology & Therapy

Administered By
Neurology, General & Community Neurology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
August 01, 2006
End Date
September 30, 2008

13th International Congress of Radiation Research

Administered By
Radiation Oncology
AwardedBy
Department of Energy
Role
Principal Investigator
Start Date
June 01, 2007
End Date
May 31, 2008

13th International Congress of Radiation Research

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 2007
End Date
March 31, 2008

Biomarker Studies for Novel Anti-Cancer Agents

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
May 28, 2003
End Date
February 29, 2008

Noninvasive Monitoring Glutathione Metabolism in Tumors

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
March 17, 2006
End Date
November 30, 2007

Mechanism of hypoxia mediated radiation lung injury

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
August 01, 2003
End Date
July 31, 2007

Activation of Sickle Red Cell Adhesion

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
July 01, 2003
End Date
June 30, 2007

Imaging Alternative Splicing During Tumor Progression

Administered By
Molecular Genetics and Microbiology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
August 01, 2002
End Date
January 31, 2007

The Duke University Molecular Imaging Center

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Senior Investigator
Start Date
August 30, 2001
End Date
December 31, 2006

Mentored Clinical Research Scholar Program

Administered By
Medicine, Infectious Diseases
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 30, 2002
End Date
September 29, 2006

Hyperthemia-Mediated Gene Therapy Approach for Cancer

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
April 02, 1999
End Date
September 01, 2006

Cancer Immunotherapy Targeting Endothelial Antigens

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
July 01, 2003
End Date
August 31, 2006

The Role of Glucose Metabolism on Tumor PO2

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
June 06, 2003
End Date
June 30, 2006

The Role of Glucose and O2 Transport on Tumor PO2

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 2000
End Date
June 30, 2006

Antiestrogenic Effects on Tumor Angiogenesis

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Sponsor
Start Date
May 01, 2001
End Date
April 30, 2006

Measurement of Hypoxia in Non-Small Cell Lung Carcinoma

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
April 01, 2002
End Date
March 31, 2006

New Clinical Biomarker for Cancer--Wound Angiogenesis

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 2000
End Date
January 31, 2006

Cell Viability in Implantable Diffusion Chambers

Administered By
Surgery, Plastic, Maxillofacial, and Oral Surgery
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
August 15, 2000
End Date
July 31, 2005

Molecular mechanisms of nitrosative stress resistance

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
August 01, 1999
End Date
July 31, 2005

TIE2-Associated Molecular Targets in Tumor Vasculature

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
July 01, 2002
End Date
June 30, 2005

Upgrade of a Shared Instrumentation Resource in the PSOE: The Laser Scanning Confocal Microscope

Administered By
Biomedical Engineering
Role
Co-Principal Investigator
Start Date
May 31, 2002
End Date
June 30, 2005

Molecular Imaging Center Planning Grant

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
August 01, 2000
End Date
July 31, 2004

Heat and Radiation Effects on Tumor Microcirculation

Administered By
Radiation Oncology
AwardedBy
National Cancer Institute
Role
Principal Investigator
Start Date
January 01, 1985
End Date
April 30, 2004

Hyperglycemia and Oxygen Breathing in Head & Neck Cancer

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
April 01, 2000
End Date
March 31, 2004

Methods To Improve Camptothecan-Based Chemotherapy

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 30, 1998
End Date
August 31, 2001

Predicting Human Tumor Response by 31p MRS

Administered By
Radiology, Neuroradiology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
July 21, 1995
End Date
February 28, 2001

Impaired Leukocyte/Endothelium Interactions In Tumors

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 1997
End Date
June 30, 2000

Hyperthermia And Perfusion Effects In Cancer Therapy

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 01, 1997
End Date
July 31, 1999

Hyperthermia And Perfusion Effects In Cancer Therapy

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 29, 1995
End Date
July 31, 1999

Hyperthermia And Perfusion Effects In Cancer Therapy

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
June 01, 1987
End Date
July 31, 1999

Tek Kinase And Breast Tunor Angiogenesis

Administered By
Medicine, Cardiology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
June 01, 1995
End Date
May 31, 1999

Heat & Radiation Effects On Tumor Microcirculation

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 01, 1997
End Date
April 30, 1999

Effects Of Heat And Radiation On Tumor

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 01, 1996
End Date
April 30, 1999

Astatine And Iodine Radiolabeled Monoclonal Antibodies

Administered By
Radiology, Nuclear Medicine
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
April 01, 1994
End Date
March 31, 1999

Astatine And Iodine Radiolabeled Monoclonal Antibodies

Administered By
Radiology, Nuclear Medicine
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 01, 1993
End Date
January 31, 1999

Astatine And Iodine Radiolabeled Monoclonal Antibodies

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 01, 1985
End Date
January 31, 1999

Cancer Center Core Support Grant

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 01, 1976
End Date
December 31, 1998

Comprehensive Cancer Center Core Support Grant

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 01, 1976
End Date
December 31, 1998

Comprehensive Cancer Center Core Support Grant

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 01, 1976
End Date
December 31, 1998

Spore In Breast Cancer

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 30, 1995
End Date
August 31, 1998

Spore In Breast Cancer

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 30, 1995
End Date
August 31, 1998

Spore In Breast Cancer

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 30, 1995
End Date
August 31, 1998

Tek Kinase And Breast Tumor Angiogenesis

Administered By
Medicine, Cardiology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
June 01, 1995
End Date
May 31, 1998

Effects Of Heat And Radiation On Tumor Microcirculation

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 01, 1994
End Date
April 30, 1996

Effects Of Heat And Radiation On Tumor Microcirculation

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 01, 1993
End Date
April 30, 1996

Effects Of Heat And Radiation On Tumor Microcirculation

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
January 01, 1985
End Date
April 30, 1996

Hyperthermia And Perfusion Effects In Cancer Therapy

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
June 01, 1993
End Date
May 31, 1995

Hyperthermia & Perfusion Effects In Cancer Therapy

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
June 01, 1990
End Date
May 31, 1995

Heat And Radiation Effects In Tumor Microcirculation

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 01, 1992
End Date
April 30, 1993

Response Of Canine Tumors To Nonstandard Fractionation

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 1987
End Date
June 01, 1988

Heat And Readiation Effects In Tumor Microcirculation

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
January 01, 1986
End Date
December 01, 1987

Heat And Radiaition Effects In Tumor Microcirculation

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
December 01, 1984
End Date
December 01, 1985
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Awards:

AAAS Fellows. American Association for the Advancement of Science, The.

Type
National
Awarded By
American Association for the Advancement of Science, The
Date
January 01, 2010

Publications:

E-Cadherin Represses Anchorage-Independent Growth in Sarcomas through Both Signaling and Mechanical Mechanisms.

CDH1 (also known as E-cadherin), an epithelial-specific cell-cell adhesion molecule, plays multiple roles in maintaining adherens junctions, regulating migration and invasion, and mediating intracellular signaling. Downregulation of E-cadherin is a hallmark of epithelial-to-mesenchymal transition (EMT) and correlates with poor prognosis in multiple carcinomas. Conversely, upregulation of E-cadherin is prognostic for improved survival in sarcomas. Yet, despite the prognostic benefit of E-cadherin expression in sarcoma, the mechanistic significance of E-cadherin in sarcomas remains poorly understood. Here, by combining mathematical models with wet-bench experiments, we identify the core regulatory networks mediated by E-cadherin in sarcomas, and decipher their functional consequences. Unlike carcinomas, E-cadherin overexpression in sarcomas does not induce a mesenchymal-to-epithelial transition (MET). However, E-cadherin acts to reduce both anchorage-independent growth and spheroid formation of sarcoma cells. Ectopic E-cadherin expression acts to downregulate phosphorylated CREB1 (p-CREB) and the transcription factor, TBX2, to inhibit anchorage-independent growth. RNAi-mediated knockdown of TBX2 phenocopies the effect of E-cadherin on CREB levels and restores sensitivity to anchorage-independent growth in sarcoma cells. Beyond its signaling role, E-cadherin expression in sarcoma cells can also strengthen cell-cell adhesion and restricts spheroid growth through mechanical action. Together, our results demonstrate that E-cadherin inhibits sarcoma aggressiveness by preventing anchorage-independent growth. IMPLICATIONS: We highlight how E-cadherin can restrict aggressive behavior in sarcomas through both biochemical signaling and biomechanical effects.

Authors
Jolly, MK; Ware, KE; Xu, S; Gilja, S; Shetler, S; Yang, Y; Wang, X; Austin, RG; Runyambo, D; Hish, AJ; Bartholf DeWitt, S; George, JT; Kreulen, RT; Boss, M-K; Lazarides, AL; Kerr, DL; Gerber, DG; Sivaraj, D; Armstrong, AJ; Dewhirst, MW; Eward, WC; Levine, H; Somarelli, JA
MLA Citation
Jolly, Mohit Kumar, et al. “E-Cadherin Represses Anchorage-Independent Growth in Sarcomas through Both Signaling and Mechanical Mechanisms..” Mol Cancer Res, vol. 17, no. 6, June 2019, pp. 1391–402. Pubmed, doi:10.1158/1541-7786.MCR-18-0763.
PMID
30862685
Source
pubmed
Published In
Mol Cancer Res
Volume
17
Issue
6
Publish Date
2019
Start Page
1391
End Page
1402
DOI
10.1158/1541-7786.MCR-18-0763

Can Exercise-Induced Modulation of the Tumor Physiologic Microenvironment Improve Antitumor Immunity?

The immune system plays an important role in controlling cancer growth. However, cancers evolve to evade immune detection. Immune tolerance and active immune suppression results in unchecked cancer growth and progression. A major contributor to immune tolerance is the tumor physiologic microenvironment, which includes hypoxia, hypoglucosis, lactosis, and reduced pH. Preclinical and human studies suggest that exercise elicits mobilization of leukocytes into circulation (also known as "exercise-induced leukocytosis"), especially cytotoxic T cells and natural killer cells. However, the tumor physiologic microenvironment presents a significant barrier for these cells to enter the tumor and, once there, properly function. We hypothesize that the effect of exercise on the immune system's ability to control cancer growth is linked to how exercise affects the tumor physiologic microenvironment. Normalization of the microenvironment by exercise may promote more efficient innate and adaptive immunity within the tumor. This review summarizes the current literature supporting this hypothesis.

Authors
Zhang, X; Ashcraft, KA; Betof Warner, A; Nair, SK; Dewhirst, MW
MLA Citation
Zhang, Xiaojie, et al. “Can Exercise-Induced Modulation of the Tumor Physiologic Microenvironment Improve Antitumor Immunity?.” Cancer Res, vol. 79, no. 10, May 2019, pp. 2447–56. Pubmed, doi:10.1158/0008-5472.CAN-18-2468.
PMID
31068341
Source
pubmed
Published In
Cancer Res
Volume
79
Issue
10
Publish Date
2019
Start Page
2447
End Page
2456
DOI
10.1158/0008-5472.CAN-18-2468

Simultaneous in vivo optical quantification of key metabolic and vascular endpoints reveals tumor metabolic diversity in murine breast tumor models.

Therapeutically exploiting vascular and metabolic endpoints becomes critical to translational cancer studies because altered vascularity and deregulated metabolism are two important cancer hallmarks. The metabolic and vascular phenotypes of three sibling breast tumor lines with different metastatic potential are investigated in vivo with a newly developed quantitative spectroscopy system. All tumor lines have different metabolic and vascular characteristics compared to normal tissues, and there are strong positive correlations between metabolic (glucose uptake and mitochondrial membrane potential) and vascular (oxygen saturations and hemoglobin concentrations) parameters for metastatic (4T1) tumors but not for micrometastatic (4T07) and nonmetastatic (67NR) tumors. A longitudinal study shows that both vascular and metabolic endpoints of 4T1 tumors increased up to a specific tumor size threshold beyond which these parameters decreased. The synchronous changes between metabolic and vascular parameters, along with the strong positive correlations between these endpoints suggest that 4T1 tumors rely on strong oxidative phosphorylation in addition to glycolysis. This study illustrates the great potential of our optical technique to provide valuable dynamic information about the interplay between the metabolic and vascular status of tumors, with important implications for translational cancer investigations.

Authors
Zhu, C; Li, M; Vincent, T; Martin, HL; Crouch, BT; Martinez, AF; Madonna, MC; Palmer, GM; Dewhirst, MW; Ramanujam, N
MLA Citation
Zhu, Caigang, et al. “Simultaneous in vivo optical quantification of key metabolic and vascular endpoints reveals tumor metabolic diversity in murine breast tumor models..” J Biophotonics, vol. 12, no. 4, Apr. 2019. Pubmed, doi:10.1002/jbio.201800372.
PMID
30565420
Source
pubmed
Published In
J Biophotonics
Volume
12
Issue
4
Publish Date
2019
Start Page
e201800372
DOI
10.1002/jbio.201800372

Rationale for hypoxia assessment and amelioration for precision therapy and immunotherapy studies

Authors
Dewhirst, MW; Mowery, YM; Mitchell, JB; Cherukuri, MK; Secomb, TW
MLA Citation
Dewhirst, M. W., et al. “Rationale for hypoxia assessment and amelioration for precision therapy and immunotherapy studies.” Journal of Clinical Investigation, vol. 129, no. 2, Feb. 2019, pp. 489–91. Scopus, doi:10.1172/JCI12604.
Source
scopus
Published In
The Journal of Clinical Investigation
Volume
129
Issue
2
Publish Date
2019
Start Page
489
End Page
491
DOI
10.1172/JCI12604

Exercise as Adjunct Therapy in Cancer.

Data from observational studies indicate that both physical activity as well as exercise (ie, structured physical activity) is associated with reductions in the risk of recurrence and cancer mortality after a diagnosis of certain forms of cancer. Emerging evidence from preclinical studies indicates that physical activity/exercise paradigms regulate intratumoral vascular maturity and perfusion, hypoxia, and metabolism and augments the antitumor immune response. Such responses may, in turn, enhance response to standard anticancer treatments. For instance, exercise improves efficacy of chemotherapeutic agents, and there is rationale to believe that it will also improve radiotherapy response. This review overviews the current preclinical as well as clinical evidence supporting exercise modulation of therapeutic response and postulated biological mechanisms underpinning such effects. We also examine the implications for tumor response to radiation, chemotherapy, and immunotherapy.

Authors
Ashcraft, KA; Warner, AB; Jones, LW; Dewhirst, MW
MLA Citation
Ashcraft, Kathleen A., et al. “Exercise as Adjunct Therapy in Cancer..” Seminars in Radiation Oncology, vol. 29, no. 1, Jan. 2019, pp. 16–24. Epmc, doi:10.1016/j.semradonc.2018.10.001.
PMID
30573180
Source
epmc
Published In
Seminars in Radiation Oncology
Volume
29
Issue
1
Publish Date
2019
Start Page
16
End Page
24
DOI
10.1016/j.semradonc.2018.10.001

Clinical and Pre-clinical Methods for Quantifying Tumor Hypoxia.

Hypoxia, a prevalent characteristic of most solid malignant tumors, contributes to diminished therapeutic responses and more aggressive phenotypes. The term hypoxia has two definitions. One definition would be a physiologic state where the oxygen partial pressure is below the normal physiologic range. For most normal tissues, the normal physiologic range is between 10 and 20 mmHg. Hypoxic regions develop when there is an imbalance between oxygen supply and demand. The impact of hypoxia on cancer therapeutics is significant: hypoxic tissue is 3× less radiosensitive than normoxic tissue, the impaired blood flow found in hypoxic tumor regions influences chemotherapy delivery, and the immune system is dependent on oxygen for functionality. Despite the clinical implications of hypoxia, there is not a universal, ideal method for quantifying hypoxia, particularly cycling hypoxia because of its complexity and heterogeneity across tumor types and individuals. Most standard imaging techniques can be modified and applied to measuring hypoxia and quantifying its effects; however, the benefits and challenges of each imaging modality makes imaging hypoxia case-dependent. In this chapter, a comprehensive overview of the preclinical and clinical methods for quantifying hypoxia is presented along with the advantages and disadvantages of each.

Authors
Rickard, AG; Palmer, GM; Dewhirst, MW
MLA Citation
Rickard, Ashlyn G., et al. “Clinical and Pre-clinical Methods for Quantifying Tumor Hypoxia..” Adv Exp Med Biol, vol. 1136, 2019, pp. 19–41. Pubmed, doi:10.1007/978-3-030-12734-3_2.
PMID
31201714
Source
pubmed
Published In
Advances in Experimental Medicine and Biology
Volume
1136
Publish Date
2019
Start Page
19
End Page
41
DOI
10.1007/978-3-030-12734-3_2

A potential solution for eliminating hypoxia as a cause for radioresistance.

Authors
Dewhirst, MW
MLA Citation
Dewhirst, Mark W. “A potential solution for eliminating hypoxia as a cause for radioresistance..” Proc Natl Acad Sci U S A, vol. 115, no. 42, Oct. 2018, pp. 10548–50. Pubmed, doi:10.1073/pnas.1814212115.
PMID
30301796
Source
pubmed
Published In
Proc Natl Acad Sci U S A
Volume
115
Issue
42
Publish Date
2018
Start Page
10548
End Page
10550
DOI
10.1073/pnas.1814212115

Development and Preliminary Evaluation of a Murine Model of Chronic Radiation-Induced Proctitis.

PURPOSE: Radiotherapy (RT) is commonly used to treat most pelvic malignancies. While treatment is often effective, curative radiation doses to the rectum can result in chronic radiation-induced proctitis, which is characterized by diarrhea, tenesmus, and/or rectal bleeding, recently termed pelvic radiation disease. An animal model of chronic radiation-induced proctitis would be useful to test both preventative and therapeutic strategies to limit this morbidity but has been elusive because of the high rodent mortality associated with acute bowel RT injury. The objective of this research was to develop a novel mouse model of chronic radiation-induced proctitis using advanced technology. METHODS AND MATERIALS: Using an X-RAD 225-Cx (Precision X-Ray) small animal irradiator, multiple plan configurations were evaluated for planning treatment volume and organ-at-risk avoidance to deliver a 15 Gy 3D conformal treatment plan. The final plan was verified by high resolution 3D dosimetry (PRESAGE/optical-CT), and delivered using a single arc. Mice were monitored for mortality for 250 days, followed by histopathological correlates including mucicarmine, Masson's trichrome, and fecal pellet length. RESULTS: Six beam arrangements were considered: single and parallel-opposed fields with whole-pelvis coverage, and collimated fields in parallel-opposed, 3-field, 4-field, and arc geometries. A collimated arc plan offered superior planning treatment volume coverage and organ-at-risk avoidance compared to whole-pelvis irradiation. Treatment verification with PRESAGE 3D dosimetry (Heuris Inc) showed >99% of voxels passing gamma analysis with 2%/2 mm criteria. Our treatment resulted in no acute mortality and 40% mortality at 250 days. Histopathological analysis showed increased mucous production and fibrosis of the irradiated colon, but no change in fecal pellet length. CONCLUSIONS: Our model was able to target successfully lower colon and rectum with lower mortality than other published models. This permitted measurement of late effects that recapitulate some features of rectal damage in humans.

Authors
Ashcraft, KA; Miles, D; Sunday, ME; Choudhury, KR; Young, KH; Palmer, GM; Patel, P; Woska, EC; Zhang, R; Oldham, M; Dewhirst, MW; Koontz, BF
MLA Citation
Ashcraft, Kathleen A., et al. “Development and Preliminary Evaluation of a Murine Model of Chronic Radiation-Induced Proctitis..” Int J Radiat Oncol Biol Phys, vol. 101, no. 5, Aug. 2018, pp. 1194–201. Pubmed, doi:10.1016/j.ijrobp.2018.04.061.
PMID
30012529
Source
pubmed
Published In
Int J Radiat Oncol Biol Phys
Volume
101
Issue
5
Publish Date
2018
Start Page
1194
End Page
1201
DOI
10.1016/j.ijrobp.2018.04.061

Near-simultaneous quantification of glucose uptake, mitochondrial membrane potential, and vascular parameters in murine flank tumors using quantitative diffuse reflectance and fluorescence spectroscopy.

The shifting metabolic landscape of aggressive tumors, with fluctuating oxygenation conditions and temporal changes in glycolysis and mitochondrial metabolism, is a critical phenomenon to study in order to understand negative treatment outcomes. Recently, we have demonstrated near-simultaneous optical imaging of mitochondrial membrane potential (MMP) and glucose uptake in non-tumor window chambers, using the fluorescent probes tetramethylrhodamine ethyl ester (TMRE) and 2-N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG). Here, we demonstrate a complementary technique to perform near-simultaneous in vivo optical spectroscopy of tissue vascular parameters, glucose uptake, and MMP in a solid tumor model that is most often used for therapeutic studies. Our study demonstrates the potential of optical spectroscopy as an effective tool to quantify the vascular and metabolic characteristics of a tumor, which is an important step towards understanding the mechanisms underlying cancer progression, metastasis, and resistance to therapies.

Authors
Zhu, C; Martin, HL; Crouch, BT; Martinez, AF; Li, M; Palmer, GM; Dewhirst, MW; Ramanujam, N
MLA Citation
Zhu, Caigang, et al. “Near-simultaneous quantification of glucose uptake, mitochondrial membrane potential, and vascular parameters in murine flank tumors using quantitative diffuse reflectance and fluorescence spectroscopy..” Biomed Opt Express, vol. 9, no. 7, July 2018, pp. 3399–412. Pubmed, doi:10.1364/BOE.9.003399.
PMID
29984105
Source
pubmed
Published In
Biomedical Optics Express
Volume
9
Issue
7
Publish Date
2018
Start Page
3399
End Page
3412
DOI
10.1364/BOE.9.003399

Application of a Novel Murine Ear Vein Model to Evaluate the Effects of a Vascular Radioprotectant on Radiation-Induced Vascular Permeability and Leukocyte Adhesion.

Vascular injury after radiation exposure contributes to multiple types of tissue injury through a cascade of events. Some of the earliest consequences of radiation damage include increased vascular permeability and promotion of inflammation, which is partially manifested by increased leukocyte-endothelial (L/E) interactions. We describe herein a novel intravital imaging method to evaluate L/E interactions, as a function of shear stress, and vascular permeability at multiple time points after local irradiation to the ear. This model permitted analysis of quiescent vasculature that was not perturbed by any surgical manipulation prior to imaging. To evaluate the effects of radiation on vascular integrity, fluorescent dextran was injected intravenously and its extravasation in the extravascular space surrounding the ear vasculature was measured at days 3 and 7 after 6 Gy irradiation. The vascular permeability rate increased approximately twofold at both days 3 and 7 postirradiation ( P < 0.05). Leukocyte rolling, which is indicative of L/E interactions, was significantly increased in mice at 24 h postirradiation compared to that of nonirradiated mice. To assess our model, as a means for assessing vascular radioprotectants, we treated additional cohorts of mice with a thrombopoietin mimetic, TPOm (RWJ-800088). In addition to stimulating platelet formation, thrombopoietin can protect vasculature after several forms of injury. Thus, we hypothesized that TPOm would reduce vascular permeability and L/E adhesion after localized irradiation to the ear vasculature of mice. If TPOm reduced these consequences of radiation, it would validate the utility of our intravital imaging method. TPOm reduced radiation-induced vascular leakage to control levels at day 7. Furthermore, L/E cell interactions were also reduced in irradiated mice treated with TPOm, compared with mice receiving irradiation alone, particularly at high shear stress ( P = 0.03, Kruskal-Wallis). We conclude that the ear model is useful for monitoring quiescent normal tissue vascular injury after radiation exposure. Furthermore, the application of TPOm, for preventing early inflammatory response created by damage to vascular endothelium, suggests that this drug may prove useful in reducing toxicities from radiotherapy, which damage microvasculature that critically important to tissue function.

Authors
Ashcraft, KA; Choudhury, KR; Birer, SR; Hendargo, HC; Patel, P; Eichenbaum, G; Dewhirst, MW
MLA Citation
Ashcraft, Kathleen A., et al. “Application of a Novel Murine Ear Vein Model to Evaluate the Effects of a Vascular Radioprotectant on Radiation-Induced Vascular Permeability and Leukocyte Adhesion..” Radiat Res, vol. 190, no. 1, July 2018, pp. 12–21. Pubmed, doi:10.1667/RR14896.1.
PMID
29671690
Source
pubmed
Published In
Radiat Res
Volume
190
Issue
1
Publish Date
2018
Start Page
12
End Page
21
DOI
10.1667/RR14896.1

In Reply to Pratx and Kapp.

Authors
Oldham, M; Yoon, SW; Adamson, J; Zhang, X; Fecci, P; Dewhirst, M
MLA Citation
Oldham, Mark, et al. “In Reply to Pratx and Kapp..” Int J Radiat Oncol Biol Phys, vol. 101, no. 2, June 2018, pp. 495–96. Pubmed, doi:10.1016/j.ijrobp.2018.02.018.
PMID
29726370
Source
pubmed
Published In
Int J Radiat Oncol Biol Phys
Volume
101
Issue
2
Publish Date
2018
Start Page
495
End Page
496
DOI
10.1016/j.ijrobp.2018.02.018

Assessing effects of pressure on tumor and normal tissue physiology using an automated self-calibrated, pressure-sensing probe for diffuse reflectance spectroscopy.

Diffuse reflectance spectroscopy (DRS) represents a quantitative, noninvasive, nondestructive means of assessing vascular oxygenation, vascularity, and structural properties. However, it is known that such measurements can be influenced by the effects of pressure, which is a major concern for reproducible and operator-independent assessment of tissues. Second, regular calibration is a necessary component of quantitative DRS to account for factors such as lamp decay and fiber bending. Without a means of reliably controlling for these factors, the accuracy of any such assessments will be reduced, and potentially biased. To address these issues, a self-calibrating, pressure-controlled DRS system is described and applied to both a patient-derived xenograft glioma model, as well as a set of healthy volunteers for assessments of oral mucosal tissues. It was shown that pressure had a significant effect on the derived optical parameters, and that the effects on the optical parameters were magnified with increasing time and pressure levels. These findings indicate that not only is it critical to integrate a pressure sensor into a DRS device, but that it is also important to do so in an automated way to trigger a measurement as soon as possible after probe contact is made to minimize the perturbation to the tissue site.

Authors
Palmer, GM; Zhang, H; Lee, C-T; Mikati, H; Herbert, JA; Krieger, M; von Windheim, J; Koester, D; Stevenson, D; Rocke, DJ; Esclamado, R; Erkanli, A; Ramanujam, N; Dewhirst, MW; Lee, WT
MLA Citation
Palmer, Gregory M., et al. “Assessing effects of pressure on tumor and normal tissue physiology using an automated self-calibrated, pressure-sensing probe for diffuse reflectance spectroscopy..” J Biomed Opt, vol. 23, no. 5, May 2018, pp. 1–8. Pubmed, doi:10.1117/1.JBO.23.5.057004.
PMID
29766688
Source
pubmed
Published In
Journal of Biomedical Optics
Volume
23
Issue
5
Publish Date
2018
Start Page
1
End Page
8
DOI
10.1117/1.JBO.23.5.057004

Technological Advances, Biologic Rationales, and the Associated Success of Chemotherapy With Hyperthermia in Improved Outcomes in Patients With Sarcoma.

Authors
Dewhirst, MW; Kirsch, D
MLA Citation
Dewhirst, Mark W., and David Kirsch. “Technological Advances, Biologic Rationales, and the Associated Success of Chemotherapy With Hyperthermia in Improved Outcomes in Patients With Sarcoma..” Jama Oncol, vol. 4, no. 4, Apr. 2018, pp. 493–94. Pubmed, doi:10.1001/jamaoncol.2017.4941.
PMID
29450459
Source
pubmed
Published In
Jama Oncol
Volume
4
Issue
4
Publish Date
2018
Start Page
493
End Page
494
DOI
10.1001/jamaoncol.2017.4941

Metaboloptics: Visualization of the tumor functional landscape via metabolic and vascular imaging.

Many cancers adeptly modulate metabolism to thrive in fluctuating oxygen conditions; however, current tools fail to image metabolic and vascular endpoints at spatial resolutions needed to visualize these adaptations in vivo. We demonstrate a high-resolution intravital microscopy technique to quantify glucose uptake, mitochondrial membrane potential (MMP), and SO2 to characterize the in vivo phentoypes of three distinct murine breast cancer lines. Tetramethyl rhodamine, ethyl ester (TMRE) was thoroughly validated to report on MMP in normal and tumor-bearing mice. Imaging MMP or glucose uptake together with vascular endpoints revealed that metastatic 4T1 tumors maintained increased glucose uptake across all SO2 ("Warburg effect"), and also showed increased MMP relative to normal tissue. Non-metastatic 67NR and 4T07 tumor lines both displayed increased MMP, but comparable glucose uptake, relative to normal tissue. The 4T1 peritumoral areas also showed a significant glycolytic shift relative to the tumor regions. During a hypoxic stress test, 4T1 tumors showed significant increases in MMP with corresponding significant drops in SO2, indicative of intensified mitochondrial metabolism. Conversely, 4T07 and 67NR tumors shifted toward glycolysis during hypoxia. Our findings underscore the importance of imaging metabolic endpoints within the context of a living microenvironment to gain insight into a tumor's adaptive behavior.

Authors
Martinez, AF; McCachren, SS; Lee, M; Murphy, HA; Zhu, C; Crouch, BT; Martin, HL; Erkanli, A; Rajaram, N; Ashcraft, KA; Fontanella, AN; Dewhirst, MW; Ramanujam, N
MLA Citation
Martinez, Amy F., et al. “Metaboloptics: Visualization of the tumor functional landscape via metabolic and vascular imaging..” Sci Rep, vol. 8, no. 1, Mar. 2018. Pubmed, doi:10.1038/s41598-018-22480-w.
PMID
29520098
Source
pubmed
Published In
Scientific Reports
Volume
8
Issue
1
Publish Date
2018
Start Page
4171
DOI
10.1038/s41598-018-22480-w

Enhancing Radiation Therapy Through Cherenkov Light-Activated Phototherapy.

PURPOSE: This work investigates a new approach to enhance radiotherapy through a photo therapeutic agent activated by Cherenkov light produced from the megavoltage photon beam. The process is termed Radiotherapy Enhanced with Cherenkov photo-Activation (RECA). RECA is compatible with various photo-therapeutics, but here we focus on use with psoralen, an ultraviolet activated therapeutic with extensive history of application in superficial and extracorporeal settings. RECA has potential to extend the scope of psoralen treatments beyond superficial to deep seated lesions. METHODS AND MATERIALS: In vitro studies in B16 melanoma and 4T1 murine breast cancer cells were performed to investigate the potential of RT plus RECA versus RT alone for increasing cytotoxicity (local control) and increasing surface expression of major histocompatibility complex I (MHC I). The latter represents potential for immune response amplification (increased antigen presentation), which has been observed in other psoralen therapies. Cytotoxicity assays included luminescence and clonogenics. The MHC I assays were performed using flow cytometry. In addition, Cherenkov light intensity measurements were performed to investigate the possibility of increasing the Cherenkov light intensity per unit dose from clinical megavoltage beams, to maximize psoralen activation. RESULTS: Luminescence assays showed that RECA treatment (2 Gy at 6 MV) increased cytotoxicity by up to 20% and 9.5% for 4T1 and B16 cells, respectively, compared with radiation and psoralen alone (ie, Cherenkov light was blocked). Similarly, flow cytometry revealed median MHC I expression was significantly higher in RECA-treated cells, compared with those receiving radiation and psoralen alone (approximately 450% and 250% at 3 Gy and 6 Gy, respectively, P < .0001). Clonogenic assays of B16 cells at doses of 6 Gy and 12 Gy showed decreases in tumor cell viability of 7% (P = .017) and 36% (P = .006), respectively, when Cherenkov was present. CONCLUSION: This work demonstrates for the first time the potential for photo-activation of psoralen directly in situ, from Cherenkov light generated by a clinical megavoltage treatment beam.

Authors
Yoon, SW; Tsvankin, V; Shrock, Z; Meng, B; Zhang, X; Dewhirst, M; Fecci, P; Adamson, J; Oldham, M
MLA Citation
Yoon, Suk W., et al. “Enhancing Radiation Therapy Through Cherenkov Light-Activated Phototherapy..” Int J Radiat Oncol Biol Phys, vol. 100, no. 3, Mar. 2018, pp. 794–801. Pubmed, doi:10.1016/j.ijrobp.2017.11.013.
Website
https://hdl.handle.net/10161/16475
PMID
29413289
Source
pubmed
Published In
Int J Radiat Oncol Biol Phys
Volume
100
Issue
3
Publish Date
2018
Start Page
794
End Page
801
DOI
10.1016/j.ijrobp.2017.11.013

Concurrent tracking of anatomy and metabolism.

Authors
Dewhirst, M
MLA Citation
Dewhirst, Mark. “Concurrent tracking of anatomy and metabolism..” Nat Biomed Eng, vol. 2, no. 2, Feb. 2018, pp. 54–55. Pubmed, doi:10.1038/s41551-018-0196-z.
PMID
31015623
Source
pubmed
Published In
Nature Biomedical Engineering
Volume
2
Issue
2
Publish Date
2018
Start Page
54
End Page
55
DOI
10.1038/s41551-018-0196-z

Nanoparticle formulation improves doxorubicin efficacy by enhancing host antitumor immunity.

Strategies that enhance the host antitumor immune response promise to revolutionize cancer therapy. Optimally mobilizing the immune system will likely require a multi-pronged approach to overcome the resistance developed by tumors to therapy. Recently, it has become recognized that doxorubicin can contribute to re-establishing host antitumor immunity through the generation of immunogenic cell death. However, the potential for delivery strategies to further enhance the immunological effects of doxorubicin has not been adequately examined. We report herein that Chimeric Polypeptide Doxorubicin (CP-Dox), a nanoparticle formulation of doxorubicin, enhances antitumor immunity. Compared to free doxorubicin, a single intravenous (IV) administration of CP-Dox at the maximum tolerated dose increases the infiltration of leukocytes into the tumor, slowing tumor growth and preventing metastasis in poorly immunogenic 4T1 mammary carcinoma. We demonstrate that the full efficacy of CP-Dox is dependent on CD8+ T cells and IFN-γ. CP-dox treatment also repolarized intratumoral myeloid cells towards an antitumor phenotype. These findings demonstrate that a nanoparticle drug is distinct from the free drug in its ability to productively stimulate antitumor immunity. Our study strongly argues for the use of antitumor immunotherapies combined with nanoparticle-packaged chemotherapy.

Authors
Mastria, EM; Cai, LY; Kan, MJ; Li, X; Schaal, JL; Fiering, S; Gunn, MD; Dewhirst, MW; Nair, SK; Chilkoti, A
MLA Citation
Mastria, Eric M., et al. “Nanoparticle formulation improves doxorubicin efficacy by enhancing host antitumor immunity..” J Control Release, vol. 269, Jan. 2018, pp. 364–73. Pubmed, doi:10.1016/j.jconrel.2017.11.021.
PMID
29146246
Source
pubmed
Published In
J Control Release
Volume
269
Publish Date
2018
Start Page
364
End Page
373
DOI
10.1016/j.jconrel.2017.11.021

Non-invasive, simultaneous quantification of vascular oxygenation, glucose uptake and mitochondria membrane potential in a flank tumor model

© OSA 2018. For the first time, we performed simultaneous in vivo spectroscopy of tissue hemoglobin, 2-NBDG, and TMRE in a preclinical model, to successfully capture vascular and metabolic parameters in vivo in solid tumors.

Authors
Zhu, C; Martin, HL; Li, M; Crouch, B; Martinez, AF; Palmer, GM; Dewhirst, MW; Ramanujam, N
MLA Citation
Zhu, C., et al. “Non-invasive, simultaneous quantification of vascular oxygenation, glucose uptake and mitochondria membrane potential in a flank tumor model.” Optics Infobase Conference Papers, vol. Part F91-TRANSLATIONAL 2018, 2018. Scopus, doi:10.1364/TRANSLATIONAL.2018.CF2B.2.
Source
scopus
Published In
Optics Infobase Conference Papers
Volume
Part F91-TRANSLATIONAL 2018
Publish Date
2018
DOI
10.1364/TRANSLATIONAL.2018.CF2B.2

Distinct Angiogenic Changes during Carcinogenesis Defined by Novel Label-Free Dark-Field Imaging in a Hamster Cheek Pouch Model.

There remain gaps in knowledge concerning how vascular morphology evolves during carcinogenesis. In this study, we imaged neovascularization by label-free dark-field microscopy of a 7,12-Dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch model of oral squamous cell carcinoma (SCC). Wavelength-dependent imaging revealed distinct vascular features at different imaging depths and vessel sizes. Vascular tortuosity increased significantly in high-risk lesions, whereas diameter decreased significantly in hyperplastic and SCC lesions. Large vessels preserved the same trends seen in the original images, whereas small vessels displayed different trends, with length and diameter increasing during carcinogenesis. On the basis of these data, we developed and validated a classification algorithm incorporating vascular features from different vessel masks. Receiver operator curves generated from the classification results demonstrated high accuracies in discriminating normal and hyperplasia from high-grade lesions (AUC > 0.94). Overall, these results provided automated imaging of vasculature in the earliest stages of carcinogenesis from which one can extract robust endpoints. The optical toolbox described here is simple, low-cost and portable, and can be used in a variety of health care and research settings for cancer prevention and pharmacology research. Cancer Res; 77(24); 7109-19. ©2017 AACR.

Authors
Hu, F; Martin, H; Martinez, A; Everitt, J; Erkanli, A; Lee, WT; Dewhirst, M; Ramanujam, N
MLA Citation
Hu, Fangyao, et al. “Distinct Angiogenic Changes during Carcinogenesis Defined by Novel Label-Free Dark-Field Imaging in a Hamster Cheek Pouch Model..” Cancer Res, vol. 77, no. 24, Dec. 2017, pp. 7109–19. Pubmed, doi:10.1158/0008-5472.CAN-17-1058.
PMID
29021136
Source
pubmed
Published In
Cancer Res
Volume
77
Issue
24
Publish Date
2017
Start Page
7109
End Page
7119
DOI
10.1158/0008-5472.CAN-17-1058

Transport of drugs from blood vessels to tumour tissue.

The effectiveness of anticancer drugs in treating a solid tumour is dependent on delivery of the drug to virtually all cancer cells in the tumour. The distribution of drug in tumour tissue depends on the plasma pharmacokinetics, the structure and function of the tumour vasculature and the transport properties of the drug as it moves through microvessel walls and in the extravascular tissue. The aim of this Review is to provide a broad, balanced perspective on the current understanding of drug transport to tumour cells and on the progress in developing methods to enhance drug delivery. First, the fundamental processes of solute transport in blood and tissue by convection and diffusion are reviewed, including the dependence of penetration distance from vessels into tissue on solute binding or uptake in tissue. The effects of the abnormal characteristics of tumour vasculature and extravascular tissue on these transport properties are then discussed. Finally, methods for overcoming limitations in drug transport and thereby achieving improved therapeutic results are surveyed.

Authors
Dewhirst, MW; Secomb, TW
MLA Citation
Dewhirst, Mark W., and Timothy W. Secomb. “Transport of drugs from blood vessels to tumour tissue..” Nat Rev Cancer, vol. 17, no. 12, Dec. 2017, pp. 738–50. Pubmed, doi:10.1038/nrc.2017.93.
PMID
29123246
Source
pubmed
Published In
Nat Rev Cancer
Volume
17
Issue
12
Publish Date
2017
Start Page
738
End Page
750
DOI
10.1038/nrc.2017.93

Differential response to exercise in claudin-low breast cancer.

Exposure to exercise following a breast cancer diagnosis is associated with reductions in the risk of recurrence. However, it is not known whether breast cancers within the same molecular-intrinsic subtype respond differently to exercise. Syngeneic mouse models of claudin-low breast cancer (i.e., EO771, 4TO7, and C3(1)SV40Tag-p16-luc) were allocated to a uniform endurance exercise treatment dose (forced treadmill exercise) or sham-exercise (stationary treadmill). Compared to sham-controls, endurance exercise treatment differentially affected tumor growth rate: 1- slowed (EO771), 2- accelerated (C3(1)SV40Tag-p16-luc), or 3- was not affected (4TO7). Differential sensitivity of the three tumor lines to exercise was paralleled by effects on intratumoral Ki-67, Hif1-α, and metabolic programming. Inhibition of Hif1-α synthesis by the cardiac glycoside, digoxin, completely abrogated exercise-accelerated tumor growth in C3(1)SV40Tag-p16-luc. These results suggest that intratumoral Hif1-α expression is an important determinant of claudin-low breast cancer adaptation to exercise treatment.

Authors
Glass, OK; Bowie, M; Fuller, J; Darr, D; Usary, J; Boss, K; Choudhury, KR; Liu, X; Zhang, Z; Locasale, JW; Williams, C; Dewhirst, MW; Jones, LW; Seewaldt, V
MLA Citation
Glass, Oliver K., et al. “Differential response to exercise in claudin-low breast cancer..” Oncotarget, vol. 8, no. 60, Nov. 2017, pp. 100989–1004. Pubmed, doi:10.18632/oncotarget.21054.
Website
http://hdl.handle.net/10161/15836
PMID
29254140
Source
pubmed
Published In
Oncotarget
Volume
8
Issue
60
Publish Date
2017
Start Page
100989
End Page
101004
DOI
10.18632/oncotarget.21054

Endothelial cell-surface tissue transglutaminase inhibits neutrophil adhesion by binding and releasing nitric oxide.

Nitric oxide (NO) produced by endothelial cells in response to cytokines displays anti-inflammatory activity by preventing the adherence, migration and activation of neutrophils. The molecular mechanism by which NO operates at the blood-endothelium interface to exert anti-inflammatory properties is largely unknown. Here we show that on endothelial surfaces, NO is associated with the sulfhydryl-rich protein tissue transglutaminase (TG2), thereby endowing the membrane surfaces with anti-inflammatory properties. We find that tumor necrosis factor-α-stimulated neutrophil adherence is opposed by TG2 molecules that are bound to the endothelial surface. Alkylation of cysteine residues in TG2 or inhibition of endothelial NO synthesis renders the surface-bound TG2 inactive, whereas specific, high affinity binding of S-nitrosylated TG2 (SNO-TG2) to endothelial surfaces restores the anti-inflammatory properties of the endothelium, and reconstitutes the activity of endothelial-derived NO. We also show that SNO-TG2 is present in healthy tissues and that it forms on the membranes of shear-activated endothelial cells. Thus, the anti-inflammatory mechanism that prevents neutrophils from adhering to endothelial cells is identified with TG2 S-nitrosylation at the endothelial cell-blood interface.

Authors
Lai, T-S; Lindberg, RA; Zhou, H-L; Haroon, ZA; Dewhirst, MW; Hausladen, A; Juang, Y-L; Stamler, JS; Greenberg, CS
MLA Citation
Lai, Thung-S., et al. “Endothelial cell-surface tissue transglutaminase inhibits neutrophil adhesion by binding and releasing nitric oxide..” Sci Rep, vol. 7, no. 1, Nov. 2017. Pubmed, doi:10.1038/s41598-017-16342-0.
PMID
29170410
Source
pubmed
Published In
Scientific Reports
Volume
7
Issue
1
Publish Date
2017
Start Page
16163
DOI
10.1038/s41598-017-16342-0

Multidisciplinary Mentoring Programs to Enhance Junior Faculty Research Grant Success.

PROBLEM: Junior faculty face challenges in establishing independent research careers. Declining funding combined with a shift to multidisciplinary, collaborative science necessitates new mentorship models and enhanced institutional support. APPROACH: Two multidisciplinary mentorship programs to promote grant success for junior faculty were established at the Duke University School of Medicine beginning in 2011. These four-month programs-the Path to Independence Program (PtIP) for National Institutes of Health (NIH) R applicants and the K Club for NIH K applicants-use multiple senior faculty mentors and professional grant-writing staff to provide a 20-hour joint curriculum comprising a series of lectures, hands-on workshops, career development counseling, peer groups, and an internal study section. In March 2016, the authors analyzed the success rate for all NIH grants submitted by participants since program enrollment. In a 2015 postprogram survey, participants rated their feelings of support and competency across six skill factors. OUTCOMES: From October 2011 to March 2016, the programs engaged 265 senior faculty mentors, 145 PtIP participants, and 138 K Club participants. Success rates for NIH grant applications were 28% (61 awards/220 decisions) for PtIP participants-an increase over the 2010 Duke University junior faculty baseline of 11%-and 64% (38/59) for K Club participants. Respondents reported significantly increased feelings of support and self-ratings for each competency post program. NEXT STEPS: The authors plan to expand the breadth of both the mentorship pool and faculty served. Broad implementation of similar programs elsewhere could bolster success, satisfaction, and retention of junior faculty investigators.

Authors
Freel, SA; Smith, PC; Burns, EN; Downer, JB; Brown, AJ; Dewhirst, MW
MLA Citation
Freel, Stephanie A., et al. “Multidisciplinary Mentoring Programs to Enhance Junior Faculty Research Grant Success..” Acad Med, vol. 92, no. 10, Oct. 2017, pp. 1410–15. Pubmed, doi:10.1097/ACM.0000000000001620.
PMID
28272113
Source
pubmed
Published In
Acad Med
Volume
92
Issue
10
Publish Date
2017
Start Page
1410
End Page
1415
DOI
10.1097/ACM.0000000000001620

NIR-emissive PEG-b-TCL micelles for breast tumor imaging and minimally invasive pharmacokinetic analysis.

Motivated by the goal of developing a fully biodegradable optical contrast agent with translational clinical potential, a nanoparticle delivery vehicle was generated from the self-assembly of poly(ethylene-glycol)-block-poly(trimethylene carbonate-co-caprolactone) (PEG-b-TCL) copolymers. Cryogenic transmission electron microscopy verified that PEG-b-TCL-based micelles were formed at low solution temperatures (∼38 °C). Detailed spectroscopic experiments validated facile loading of large quantities of the high emission dipole strength, tris(porphyrin)-based fluorophore PZn3 within their cores, and the micelles displayed negligible in vitro and in vivo toxicities in model systems. The pharmacokinetics and biodistribution of PZn3-loaded PEG-b-TCL-based micelles injected intravenously were determined via ex vivo near-infrared (NIR) imaging of PZn3 emission in microcapillary tubes containing minute quantities of blood, to establish a novel method for minimally invasive pharmacokinetic monitoring. The in vivo circulatory half-life of the PEG-b-TCL-based micelles was found to be ∼19.6 h. Additionally, longitudinal in vivo imaging of orthotopically transplanted breast tumors enabled determination of micelle biodistribution that correlated to ex vivo imaging results, demonstrating accumulation predominantly within the tumors and livers of mice. The PEG-b-TCL-based micelles quickly extravasated within 4T1 orthotopic mammary carcinomas, exhibiting peak accumulation at ∼48 h following intravenous tail-vein injection. In summary, PEG-b-TCL-based micelles demonstrated favorable characteristics for further development as in vivo optical contrast agents for minimally invasive imaging of breast tumors.

Authors
Hofmann, CL; O'Sullivan, MC; Detappe, A; Yu, Y; Yang, X; Qi, W; Landon, CD; Therien, MJ; Dewhirst, MW; Ghoroghchian, PP; Palmer, GM
MLA Citation
Hofmann, Christina L., et al. “NIR-emissive PEG-b-TCL micelles for breast tumor imaging and minimally invasive pharmacokinetic analysis..” Nanoscale, vol. 9, no. 36, Sept. 2017, pp. 13465–76. Pubmed, doi:10.1039/c7nr02363d.
PMID
28861570
Source
pubmed
Published In
Nanoscale
Volume
9
Issue
36
Publish Date
2017
Start Page
13465
End Page
13476
DOI
10.1039/c7nr02363d

GBM radiosensitizers: dead in the water…or just the beginning?

The finding that most GBMs recur either near or within the primary site after radiotherapy has fueled great interest in the development of radiosensitizers to enhance local control. Unfortunately, decades of clinical trials testing a wide range of novel therapeutic approaches have failed to yield any clinically viable radiosensitizers. However, many of  the previous radiosensitizing strategies were not based on clear pre-clinical evidence, and in many cases blood-barrier penetration was not considered. Furthermore, DNA repair inhibitors have only recenly arrived in the clinic, and likely represent potent agents for glioma radiosensitization. Here, we present recent progress in the use of small molecule DNA damage response inhibitors as GBM radiosensitizers. In addition, we discuss the latest progress in targeting hypoxia and oxidative stress for GBM radiosensitization.

Authors
Bindra, RS; Chalmers, AJ; Evans, S; Dewhirst, M
MLA Citation
Bindra, Ranjit S., et al. “GBM radiosensitizers: dead in the water…or just the beginning?.” J Neurooncol, vol. 134, no. 3, Sept. 2017, pp. 513–21. Pubmed, doi:10.1007/s11060-017-2427-7.
PMID
28762004
Source
pubmed
Published In
J Neurooncol
Volume
134
Issue
3
Publish Date
2017
Start Page
513
End Page
521
DOI
10.1007/s11060-017-2427-7

Development of enhanced ethanol ablation as an alternative to surgery in treatment of superficial solid tumors.

While surgery is at the foundation of cancer treatment, its access is limited in low-income countries. Here, we describe development of a low-cost alternative therapy based on intratumoral ethanol injection suitable for resource-limited settings. Although ethanol-based tumor ablation is successful in treating hepatocellular carcinomas, the necessity for multiple treatments, injection of large fluid volumes, and decreased efficacy in treatment of non-capsulated tumors limit its applicability. To address these limitations, we investigated an enhanced ethanol ablation strategy to retain ethanol within the tumor through the addition of ethyl cellulose. This increases the viscosity of injected ethanol and forms an ethanol-based gel-phase upon exposure to the aqueous tumor environment. This technique was first optimized to maximize distribution volume, using tissue-simulating phantoms. Then, chemically-induced epithelial tumors in the hamster cheek pouch were treated. As controls, pure ethanol injections of either four times or one-fourth the tumor volume induced complete regression of 33% and 0% of tumors, respectively. In contrast, ethyl cellulose-ethanol injections of one-fourth the tumor volume induced complete regression in 100% of tumors. These results contribute to proof-of-concept for enhanced ethanol ablation as a novel and effective alternative to surgery for tumor treatment, with relevance to resource-limited settings.

Authors
Morhard, R; Nief, C; Barrero Castedo, C; Hu, F; Madonna, M; Mueller, JL; Dewhirst, MW; Katz, DF; Ramanujam, N
MLA Citation
Morhard, Robert, et al. “Development of enhanced ethanol ablation as an alternative to surgery in treatment of superficial solid tumors..” Sci Rep, vol. 7, no. 1, Aug. 2017. Pubmed, doi:10.1038/s41598-017-09371-2.
PMID
28821832
Source
pubmed
Published In
Scientific Reports
Volume
7
Issue
1
Publish Date
2017
Start Page
8750
DOI
10.1038/s41598-017-09371-2

Noninvasive measurement of tissue blood oxygenation with Cerenkov imaging during therapeutic radiation delivery.

Tumor tissue oxygenation significantly affects the outcome of radiotherapy. Real-time monitoring of tumor hypoxia is highly desirable for effective radiotherapy, and is the basis for improved treatment because hypoxic tumor cells are more resistant to radiation damage than fully oxygenated cells. We propose to use Cerenkov imaging to monitor tumor hypoxia by means of tissue blood oxygenation without the need for any exogenous contrast agent. Using a rodent hypoxia model, we demonstrate that Cerenkov imaging can be used as a noninvasive and noncontact method to measure tissue blood oxygenation level during radiation delivery. The data from Cerenkov imaging were validated using near infrared spectrometry methods. The results demonstrate the feasibility of using Cerenkov imaging to monitor tumor hypoxia during therapeutic radiation delivery.

Authors
Zhang, X; Lam, SK; Palmer, G; Das, S; Oldham, M; Dewhirst, M
MLA Citation
Zhang, Xiaofeng, et al. “Noninvasive measurement of tissue blood oxygenation with Cerenkov imaging during therapeutic radiation delivery..” Opt Lett, vol. 42, no. 16, Aug. 2017, pp. 3101–04. Pubmed, doi:10.1364/OL.42.003101.
Website
http://hdl.handle.net/10161/15411
PMID
28809883
Source
pubmed
Published In
Opt Lett
Volume
42
Issue
16
Publish Date
2017
Start Page
3101
End Page
3104
DOI
10.1364/OL.42.003101

Subtype-Specific Radiation Response and Therapeutic Effect of FAS Death Receptor Modulation in Human Breast Cancer.

Breast cancer is the most common malignancy diagnosed among women and represents a heterogeneous group of subtypes. Radiation therapy is a critical component of treatment for breast cancer patients. However, little is known about radiation response among these intrinsic subtypes. In previous studies, we identified a significant induction of FAS after irradiation in biologically favorable breast cancer patients and breast cancer cell lines. Here, we expanded our study and investigated radiation response in a mouse model of breast cancer. MCF7 (luminal), HCC1954 (HER2+) or SUM159 (basal) cells were implanted orthotopically into the dorsal mammary fat pad of nude mice. These mice were then treated with different doses of radiation to assess tumor growth control. We further investigated the therapeutic effect of FAS modulation by silencing FAS in radiation-responsive tumors and injecting FAS agonist antibody into radiation-resistant tumors. Exposure to radiation inhibited MCF7, and to a lesser extent HCC1954 tumor growth in a dose-dependent manner. In contrast, SUM159 tumors were resistant to radiation. The estimated TCD50 values were 19.3 Gy for MCF7 and 44.9 Gy for SUM159. Radiation induced FAS expression in MCF7 tumors, but not SUM159 tumors. We found that silencing of FAS did not negatively impact radiation response in MCF7 tumors, possibly due to compensation by other apoptotic pathways. On the other hand, FAS activating antibody in combination with radiation treatment delayed SUM159 and HCC1954 tumor growth. However, it did not reach statistical significance compared to radiation treatment alone. Our results suggest that there is intrinsic variation in radiation response among breast cancer subtypes. FAS activation concurrent with radiation slows tumor growth in the radiation-resistant subtypes, but the effect was not significant. Alternative subtype-specific modulators of radiation response are under investigation.

Authors
Lee, C-T; Zhou, Y; Roy-Choudhury, K; Siamakpour-Reihani, S; Young, K; Hoang, P; Kirkpatrick, JP; Chi, J-TA; Dewhirst, MW; Horton, JK
MLA Citation
Lee, Chen-Ting, et al. “Subtype-Specific Radiation Response and Therapeutic Effect of FAS Death Receptor Modulation in Human Breast Cancer..” Radiat Res, vol. 188, no. 2, Aug. 2017, pp. 169–80. Pubmed, doi:10.1667/RR14664.1.
PMID
28598289
Source
pubmed
Published In
Radiat Res
Volume
188
Issue
2
Publish Date
2017
Start Page
169
End Page
180
DOI
10.1667/RR14664.1

Potential for a novel manganese porphyrin compound as adjuvant canine lymphoma therapy.

PURPOSE: Manganese porphyrins are redox-active drugs and superoxide dismutase mimics, which have been shown to chemosensitize lymphoma, a cancer which frequently occurs in dogs. This study aimed to identify critical information regarding the pharmacokinetics and toxicity of Mn(III) meso-tetrakis (N-n-butoxyetylpyridium-2-yl) porphyrin, (MnTnBuOE-2-PyP5+, MnBuOE) in dogs as a prelude to a clinical trial in canine lymphoma patients. METHODS: A single-dose pharmacokinetic (PK) study in normal dogs was performed to determine the plasma half-life (t 1/2) of MnBuOE. A dose reduction study was performed to establish the maximum tolerated dose (MTD) of MnBuOE. The safety and PK of a multi-dosing protocol was assessed. RESULTS: Peak plasma drug concentration occurred 30 min post-injection. The t 1/2 was defined as 7 h. MnBuOE induced an anaphylactic reaction and prolonged tachycardia. The MTD was defined as 0.25 mg/kg. The dogs were given MTD 3×/week for 2-3 weeks. The highest recorded tissue drug levels were in the lymph nodes (4-6 μM), followed by kidney and liver (2.5, 2.0 uM, respectively). CONCLUSIONS: We obtained critical information regarding the PK and toxicity of MnBuOE in dogs. The acute drug reaction and tachycardia post-injection have not been described in other species and may be specific to canines. The high tissue drug levels in lymph nodes have not been previously reported. MnBuOE accumulation in lymph nodes has important implications for the utility of adjuvant MnBuOE to treat lymphoma. With MnBuOE lymph node accumulation, reduction in the dose and/or administration frequency could be possible, leading to reduced toxicity.

Authors
Boss, MK; Dewhirst, MW; Sampaio, RS; Bennett, A; Tovmasyan, A; Berman, KG; Beaven, AW; Rizzieri, DA; Batinic-Haberle, I; Hauck, ML; Spasojevic, I
MLA Citation
Boss, M. K., et al. “Potential for a novel manganese porphyrin compound as adjuvant canine lymphoma therapy..” Cancer Chemother Pharmacol, vol. 80, no. 2, Aug. 2017, pp. 421–31. Pubmed, doi:10.1007/s00280-017-3372-z.
PMID
28685347
Source
pubmed
Published In
Cancer Chemother Pharmacol
Volume
80
Issue
2
Publish Date
2017
Start Page
421
End Page
431
DOI
10.1007/s00280-017-3372-z

Inhibition of the Continuum of Radiation-Induced Normal Tissue Injury by a Redox-Active Mn Porphyrin.

Normal tissue damage after head and neck radiotherapy involves a continuum of pathologic events to the mucosa, tongue and salivary glands. We examined the radioprotective effects of MnBuOE, a redox-active manganese porphyrin, at three stages of normal tissue damage: immediate (leukocyte endothelial cell [L/E] interactions), early (mucositis) and late (xerostomia and fibrosis) after treatment. In this study, mice received 0 or 9 Gy irradiation to the oral cavity and salivary glands ± MnBuOE treatment. Changes in leukocyte-endothelial cell interactions were measured 24 h postirradiation. At 11 days postirradiation, mucositis was assessed with a cathepsin-sensitive near-infrared optical probe. Stimulated saliva production was quantified at 11 weeks postirradiation. Finally, histological analyses were conducted to assess the extent of long-term effects in salivary glands at 12 weeks postirradiation. MnBuOE reduced oral mucositis, xerostomia and salivary gland fibrosis after irradiation. Additionally, although we have previously shown that MnBuOE does not interfere with tumor control at high doses when administered with radiation alone, most head and neck cancer patients will be treated with the combinations of radiotherapy and cisplatin. Therefore, we also evaluated whether MnBuOE would protect tumors against radiation and cisplatin using tumor growth delay as an endpoint. Using a range of radiation doses, we saw no evidence that MnBuOE protected tumors from radiation and cisplatin. We conclude that MnBuOE radioprotects normal tissue at both early and late time points, without compromising anti-tumor effects of radiation and cisplatin.

Authors
Birer, SR; Lee, C-T; Choudhury, KR; Young, KH; Spasojevic, I; Batinic-Haberle, I; Crapo, JD; Dewhirst, MW; Ashcraft, KA
MLA Citation
Birer, Samuel R., et al. “Inhibition of the Continuum of Radiation-Induced Normal Tissue Injury by a Redox-Active Mn Porphyrin..” Radiat Res, vol. 188, no. 1, July 2017, pp. 94–104. Pubmed, doi:10.1667/RR14757.1.S1.
PMID
28517962
Source
pubmed
Published In
Radiat Res
Volume
188
Issue
1
Publish Date
2017
Start Page
94
End Page
104
DOI
10.1667/RR14757.1.S1

Inflammatory breast cancer tumor emboli express high levels of anti-apoptotic proteins: use of a quantitative high content and high-throughput 3D IBC spheroid assay to identify targeting strategies.

Inflammatory breast cancer (IBC) is one of the most lethal breast cancer variants; with existing therapy, 5-yr survival rate is only 35%. Current barriers to successful treatment of IBC include frequent infiltration and the presence of tumor cell clusters, termed tumor emboli, within the breast parenchyma and lymphatics. Prior studies have identified the role of anti-apoptotic signaling, in particular hyperactivation of NFκB and its target genes, in IBC pathobiology and therapeutic resistance. The objectives of this study were to: (1) determine if IBC tumor emboli express anti-apoptotic proteins and (2) develop a high content, multiparametric assay to assess the morphology of the IBC 3D spheroids and to optimize a high throughput format to screen for compounds that can inhibit the formation of the IBC tumor clusters/embolic structures. Immunohistochemical analysis of IBC patient tumor samples with documented tumor emboli revealed high NFκB (p65) staining along with expression of XIAP, a potent anti-apoptotic protein known to interact with NFκB signaling in enhancing survival of malignant cells. Subsequently, the high content assay developed allowed for simultaneous imaging and morphometric analysis, including count and viability of spheroids derived from SUM149, rSUM149 and SUM190 cells and its application to evaluate XIAP and NFκB inhibitory agents. We demonstrate the efficacy of the off-patent drug disulfiram when chelated with copper, which we had previously reported to inhibit NFκB signaling, was highly effective in disrupting both IBC spheroids and emboli grown in vitro. Taken together, these results identify a high-throughput approach to target tumor spheroid formation for drug discovery. Finally, disulfiram is a safe and approved drug for management of alcohol abuse, warranting its evaluation for repurposing in IBC therapy.

Authors
Arora, J; Sauer, SJ; Tarpley, M; Vermeulen, P; Rypens, C; Van Laere, S; Williams, KP; Devi, GR; Dewhirst, MW
MLA Citation
Arora, Jay, et al. “Inflammatory breast cancer tumor emboli express high levels of anti-apoptotic proteins: use of a quantitative high content and high-throughput 3D IBC spheroid assay to identify targeting strategies..” Oncotarget, vol. 8, no. 16, Apr. 2017, pp. 25848–63. Pubmed, doi:10.18632/oncotarget.15667.
PMID
28460441
Source
pubmed
Published In
Oncotarget
Volume
8
Issue
16
Publish Date
2017
Start Page
25848
End Page
25863
DOI
10.18632/oncotarget.15667

Evidence for Feedback Regulation Following Cholesterol Lowering Therapy in a Prostate Cancer Xenograft Model.

BACKGROUND: Epidemiologic data suggest cholesterol-lowering drugs may prevent the progression of prostate cancer, but not the incidence of the disease. However, the association of combination therapy in cholesterol reduction on prostate or any cancer is unclear. In this study, we compared the effects of the cholesterol lowering drugs simvastatin and ezetimibe alone or in combination on the growth of LAPC-4 prostate cancer in vivo xenografts. METHODS: Proliferation assays were conducted by MTS solution and assessed by Student's t-test. 90 male nude mice were placed on a high-cholesterol Western-diet for 7 days then injected subcutaneously with 1 × 105 LAPC-4 cells. Two weeks post-injection, mice were randomized to control, 11 mg/kg/day simvastatin, 30 mg/kg ezetimibe, or the combination and sacrificed 42 days post-randomization. We used a generalized linear model with the predictor variables of treatment, time, and treatment by time (i.e., interaction term) with tumor volume as the outcome variable. Total serum and tumor cholesterol were measured. Tumoral RNA was extracted and cDNA synthesized from 1 ug of total RNA for quantitative real-time PCR. RESULTS: Simvastatin directly reduced in vitro prostate cell proliferation in a dose-dependent, cell line-specific manner, but ezetimibe had no effect. In vivo, low continuous dosing of ezetimibe, delivered by food, or simvastatin, delivered via an osmotic pump had no effect on tumor growth compared to control mice. In contrast, dual treatment of simvastatin and ezetimibe accelerated tumor growth. Ezetimibe significantly lowered serum cholesterol by 15%, while simvastatin had no effect. Ezetimibe treatment resulted in higher tumor cholesterol. A sixfold induction of low density lipoprotein receptor mRNA was observed in ezetimibe and the combination with simvastatin versus control tumors. CONCLUSIONS: Systemic cholesterol lowering by ezetimibe did not slow tumor growth, nor did the cholesterol independent effects of simvastatin and the combined treatment increased tumor growth. Despite lower serum cholesterol, tumors from ezetimibe treated mice had higher levels of cholesterol. This study suggests that induction of low density lipoprotein receptor is a possible mechanism of resistance that prostate tumors use to counteract the therapeutic effects of lowering serum cholesterol. Prostate 77:446-457, 2017. © 2016 Wiley Periodicals, Inc.

Authors
Masko, EM; Alfaqih, MA; Solomon, KR; Barry, WT; Newgard, CB; Muehlbauer, MJ; Valilis, NA; Phillips, TE; Poulton, SH; Freedland, AR; Sun, S; Dambal, SK; Sanders, SE; Macias, E; Freeman, MR; Dewhirst, MW; Pizzo, SV; Freedland, SJ
MLA Citation
Masko, Elizabeth M., et al. “Evidence for Feedback Regulation Following Cholesterol Lowering Therapy in a Prostate Cancer Xenograft Model..” Prostate, vol. 77, no. 5, Apr. 2017, pp. 446–57. Pubmed, doi:10.1002/pros.23282.
PMID
27900797
Source
pubmed
Published In
Prostate
Volume
77
Issue
5
Publish Date
2017
Start Page
446
End Page
457
DOI
10.1002/pros.23282

Encapsulating a Hydrophilic Chemotherapeutic into Rod-like Nanoparticles of a Genetically Encoded Asymmetric Triblock Polypeptide Improves its Efficacy.

Encapsulating hydrophilic chemotherapeutics into the core of polymeric nanoparticles can improve their therapeutic efficacy by increasing their plasma half-life, tumor accumulation and intracellular uptake, and by protecting them from premature degradation. To achieve these goals, we designed a recombinant asymmetric triblock polypeptide (ATBP) that self-assembles into rod-shaped nanoparticles, and which can be used to conjugate diverse hydrophilic molecules, including chemotherapeutics, into their core. These ATBPs consist of three segments: a biodegradable elastin-like polypeptide, a hydrophobic Tyrosine-rich segment, and a short Cysteine-rich segment, that spontaneously self-assemble into rod-shaped micelles. Covalent conjugation of a structurally diverse set of hydrophilic small molecules, including a hydrophilic chemotherapeutic -gemcitabine- to the Cysteine residues also leads to formation of nanoparticles over a range of ATBP concentrations. Gemcitabine-loaded ATBP nanoparticles have significantly better tumor regression compared to free drug in a murine cancer model. This simple strategy of encapsulation of hydrophilic small molecules by conjugation to an ATBP can be used to effectively deliver a range of water-soluble drugs and imaging agents in vivo.

Authors
Bhattacharyya, J; Weitzhandler, I; Ho, SB; McDaniel, JR; Li, X; Tang, L; Liu, J; Dewhirst, M; Chilkoti, A
MLA Citation
Bhattacharyya, Jayanta, et al. “Encapsulating a Hydrophilic Chemotherapeutic into Rod-like Nanoparticles of a Genetically Encoded Asymmetric Triblock Polypeptide Improves its Efficacy..” Adv Funct Mater, vol. 27, no. 12, Mar. 2017. Pubmed, doi:10.1002/adfm.201605421.
PMID
30319320
Source
pubmed
Published In
Advanced Functional Materials
Volume
27
Issue
12
Publish Date
2017
DOI
10.1002/adfm.201605421

Oxygen and Perfusion Kinetics in Response to Fractionated Radiation Therapy in FaDu Head and Neck Cancer Xenografts Are Related to Treatment Outcome.

PURPOSE: To test whether oxygenation kinetics correlate with the likelihood for local tumor control after fractionated radiation therapy. METHODS AND MATERIALS: We used diffuse reflectance spectroscopy to noninvasively measure tumor vascular oxygenation and total hemoglobin concentration associated with radiation therapy of 5 daily fractions (7.5, 9, or 13.5 Gy/d) in FaDu xenografts. Spectroscopy measurements were obtained immediately before each daily radiation fraction and during the week after radiation therapy. Oxygen saturation and total hemoglobin concentration were computed using an inverse Monte Carlo model. RESULTS: First, oxygenation kinetics during and after radiation therapy, but before tumor volumes changed, were associated with local tumor control. Locally controlled tumors exhibited significantly faster increases in oxygenation after radiation therapy (days 12-15) compared with tumors that recurred locally. Second, within the group of tumors that recurred, faster increases in oxygenation during radiation therapy (day 3-5 interval) were correlated with earlier recurrence times. An area of 0.74 under the receiver operating characteristic curve was achieved when classifying the local control tumors from all irradiated tumors using the oxygen kinetics with a logistic regression model. Third, the rate of increase in oxygenation was radiation dose dependent. Radiation doses ≤9.5 Gy/d did not initiate an increase in oxygenation, whereas 13.5 Gy/d triggered significant increases in oxygenation during and after radiation therapy. CONCLUSIONS: Additional confirmation is required in other tumor models, but these results suggest that monitoring tumor oxygenation kinetics could aid in the prediction of local tumor control after radiation therapy.

Authors
Hu, F; Vishwanath, K; Salama, JK; Erkanli, A; Peterson, B; Oleson, JR; Lee, WT; Brizel, DM; Ramanujam, N; Dewhirst, MW
MLA Citation
Hu, Fangyao, et al. “Oxygen and Perfusion Kinetics in Response to Fractionated Radiation Therapy in FaDu Head and Neck Cancer Xenografts Are Related to Treatment Outcome..” Int J Radiat Oncol Biol Phys, vol. 96, no. 2, Oct. 2016, pp. 462–69. Pubmed, doi:10.1016/j.ijrobp.2016.06.007.
PMID
27598811
Source
pubmed
Published In
Int J Radiat Oncol Biol Phys
Volume
96
Issue
2
Publish Date
2016
Start Page
462
End Page
469
DOI
10.1016/j.ijrobp.2016.06.007

Discovery of Manassantin A Protein Targets Using Large-Scale Protein Folding and Stability Measurements.

Manassantin A is a natural product that has been shown to have anticancer activity in cell-based assays, but has a largely unknown mode-of-action. Described here is the use of two different energetics-based approaches to identify protein targets of manassantin A. Using the stability of proteins from rates of oxidation technique with an isobaric mass tagging strategy (iTRAQ-SPROX) and the pulse proteolysis technique with a stable isotope labeling with amino acids in cell culture strategy (SILAC-PP), over 1000 proteins in a MDA-MB-231 cell lysate grown under hypoxic conditions were assayed for manassantin A interactions (both direct and indirect). A total of 28 protein hits were identified with manassantin A-induced thermodynamic stability changes. Two of the protein hits (filamin A and elongation factor 1α) were identified using both experimental approaches. The remaining 26 hit proteins were only assayed in either the iTRAQ-SPROX or the SILAC-PP experiment. The 28 potential protein targets of manassantin A identified here provide new experimental avenues along which to explore the molecular basis of manassantin A's mode of action. The current work also represents the first application iTRAQ-SPROX and SILAC-PP to the large-scale analysis of protein-ligand binding interactions involving a potential anticancer drug with an unknown mode-of-action.

Authors
Geer Wallace, MA; Kwon, D-Y; Weitzel, DH; Lee, C-T; Stephenson, TN; Chi, J-T; Mook, RA; Dewhirst, MW; Hong, J; Fitzgerald, MC
MLA Citation
Geer Wallace, M. Ariel, et al. “Discovery of Manassantin A Protein Targets Using Large-Scale Protein Folding and Stability Measurements..” J Proteome Res, vol. 15, no. 8, Aug. 2016, pp. 2688–96. Pubmed, doi:10.1021/acs.jproteome.6b00237.
PMID
27322910
Source
pubmed
Published In
J Proteome Res
Volume
15
Issue
8
Publish Date
2016
Start Page
2688
End Page
2696
DOI
10.1021/acs.jproteome.6b00237

Efficacy and Mechanisms of Aerobic Exercise on Cancer Initiation, Progression, and Metastasis: A Critical Systematic Review of In Vivo Preclinical Data.

A major objective of the emerging field of exercise-oncology research is to determine the efficacy of, and biological mechanisms by which, aerobic exercise affects cancer incidence, progression, and/or metastasis. There is a strong inverse association between self-reported exercise and the primary incidence of several forms of cancer; similarly, emerging data suggest that exercise exposure after a cancer diagnosis may improve outcomes for early-stage breast, colorectal, or prostate cancer. Arguably, critical next steps in the development of exercise as a candidate treatment in cancer control require preclinical studies to validate the biological efficacy of exercise, identify the optimal "dose", and pinpoint mechanisms of action. To evaluate the current evidence base, we conducted a critical systematic review of in vivo studies investigating the effects of exercise in cancer prevention and progression. Studies were evaluated on the basis of tumor outcomes (e.g., incidence, growth, latency, metastasis), dose-response, and mechanisms of action, when available. A total of 53 studies were identified and evaluated on tumor incidence (n = 24), tumor growth (n = 33), or metastasis (n = 10). We report that the current evidence base is plagued by considerable methodologic heterogeneity in all aspects of study design, endpoints, and efficacy. Such heterogeneity precludes meaningful comparisons and conclusions at present. To this end, we provide a framework of methodologic and data reporting standards to strengthen the field to guide the conduct of high-quality studies required to inform translational, mechanism-driven clinical trials. Cancer Res; 76(14); 4032-50. ©2016 AACR.

Authors
Ashcraft, KA; Peace, RM; Betof, AS; Dewhirst, MW; Jones, LW
MLA Citation
Ashcraft, Kathleen A., et al. “Efficacy and Mechanisms of Aerobic Exercise on Cancer Initiation, Progression, and Metastasis: A Critical Systematic Review of In Vivo Preclinical Data..” Cancer Res, vol. 76, no. 14, July 2016, pp. 4032–50. Pubmed, doi:10.1158/0008-5472.CAN-16-0887.
PMID
27381680
Source
pubmed
Published In
Cancer Res
Volume
76
Issue
14
Publish Date
2016
Start Page
4032
End Page
4050
DOI
10.1158/0008-5472.CAN-16-0887

Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials.

There is an urgent need to improve reproducibility and translatability of preclinical data to fully exploit opportunities for molecular therapeutics involving radiation and radiochemotherapy. For in vitro research, the clonogenic assay remains the current state-of-the-art of preclinical assays, whereas newer moderate and high-throughput assays offer the potential for rapid initial screening. Studies of radiation response modification by molecularly targeted agents can be improved using more physiologic 3D culture models. Elucidating effects on the cancer stem cells (CSC, and CSC-like) and developing biomarkers for defining targets and measuring responses are also important. In vivo studies are necessary to confirm in vitro findings, further define mechanism of action, and address immunomodulation and treatment-induced modification of the microenvironment. Newer in vivo models include genetically engineered and patient-derived xenograft mouse models and spontaneously occurring cancers in domesticated animals. Selection of appropriate endpoints is important for in vivo studies; for example, regrowth delay measures bulk tumor killing, whereas local tumor control assesses effects on CSCs. The reliability of individual assays requires standardization of procedures and cross-laboratory validation. Radiation modifiers must be tested as part of clinical standard of care, which includes radiochemotherapy for most tumors. Radiation models are compatible with but also differ from those used for drug screening. Furthermore, the mechanism of a drug as a chemotherapeutic agent may be different from its interaction with radiation and/or radiochemotherapy. This provides an opportunity to expand the use of molecular-targeted agents. Clin Cancer Res; 22(13); 3138-47. ©2016 AACR.

Authors
Coleman, CN; Higgins, GS; Brown, JM; Baumann, M; Kirsch, DG; Willers, H; Prasanna, PGS; Dewhirst, MW; Bernhard, EJ; Ahmed, MM
MLA Citation
Coleman, C. Norman, et al. “Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials..” Clin Cancer Res, vol. 22, no. 13, July 2016, pp. 3138–47. Pubmed, doi:10.1158/1078-0432.CCR-16-0069.
PMID
27154913
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
22
Issue
13
Publish Date
2016
Start Page
3138
End Page
3147
DOI
10.1158/1078-0432.CCR-16-0069

Implications of Increase in Vascular Permeability in Tumors by VEGF: A Commentary on the Pioneering Work of Harold Dvorak.

See related article by Senger et al., Cancer Res 1986;46:5629-32Visit the Cancer Research 75(th) Anniversary timeline.

Authors
Dewhirst, MW; Ashcraft, KA
MLA Citation
Dewhirst, Mark W., and Kathleen A. Ashcraft. “Implications of Increase in Vascular Permeability in Tumors by VEGF: A Commentary on the Pioneering Work of Harold Dvorak..” Cancer Res, vol. 76, no. 11, June 2016, pp. 3118–20. Pubmed, doi:10.1158/0008-5472.CAN-16-1292.
PMID
27251086
Source
pubmed
Published In
Cancer Res
Volume
76
Issue
11
Publish Date
2016
Start Page
3118
End Page
3120
DOI
10.1158/0008-5472.CAN-16-1292

Effects of hyperthermia in neutralising mechanisms of drug resistance in non-muscle-invasive bladder cancer.

Non-muscle-invasive bladder cancer is a challenging disease, even given its superficial nature. It is prone to multiple recurrences and progression to muscle-invasive cancer. These features of this disease contribute significantly to reduced quality of life as well as creating significant morbidity and even mortality. Randomised trials demonstrate that when hyperthermia is added to conventional mitomycin-C treatment that local control rates and progression-free survival are substantially improved. In this review we consider how hyperthermia can exert such beneficial effects. Some of the mechanisms presented are theoretical, while others are facts. It is hoped that this review will contribute rationale for further examination of mechanisms, because an understanding of such mechanisms may lead to even better chemotherapeutic approaches, as well as potential biomarkers for predicting and monitoring treatment success.

Authors
van der Heijden, AG; Dewhirst, MW
MLA Citation
van der Heijden, Antoine G., and Mark W. Dewhirst. “Effects of hyperthermia in neutralising mechanisms of drug resistance in non-muscle-invasive bladder cancer..” Int J Hyperthermia, vol. 32, no. 4, June 2016, pp. 434–45. Pubmed, doi:10.3109/02656736.2016.1155761.
PMID
27098923
Source
pubmed
Published In
Int J Hyperthermia
Volume
32
Issue
4
Publish Date
2016
Start Page
434
End Page
445
DOI
10.3109/02656736.2016.1155761

Neurobehavioral radiation mitigation to standard brain cancer therapy regimens by Mn(III) n-butoxyethylpyridylporphyrin-based redox modifier.

Combinations of radiotherapy (RT) and chemotherapy have shown efficacy toward brain tumors. However, therapy-induced oxidative stress can damage normal brain tissue, resulting in both progressive neurocognitive loss and diminished quality of life. We have recently shown that MnTnBuOE-2-PyP(5+) (Mn(III)meso-tetrakis(N-n-butoxyethylpyridinium -2-yl)porphyrin) rescued RT-induced white matter damage in cranially-irradiated mice. Radiotherapy is not used in isolation for treatment of brain tumors; temozolomide is the standard-of-care for adult glioblastoma, whereas cisplatin is often used for treatment of pediatric brain tumors. Therefore, we evaluated the brain radiation mitigation ability of MnTnBuOE-2-PyP(5+) after either temozolomide or cisplatin was used singly or in combination with 10 Gy RT. MnTnBuOE-2-PyP(5+) accumulated in brains at low nanomolar levels. Histological and neurobehavioral testing showed a drastic decrease (1) of axon density in the corpus callosum and (2) rotorod and running wheel performance in the RT only treatment group, respectively. MnTnBuOE-2-PyP(5+) completely rescued this phenotype in irradiated animals. In the temozolomide groups, temozolomide/ RT treatment resulted in further decreased rotorod responses over RT alone. Again, MnTnBuOE-2-PyP(5+) treatment rescued the negative effects of both temozolomide ± RT on rotorod performance. While the cisplatin-treated groups did not give similar results as the temozolomide groups, inclusion of MnTnBuOE-2-PyP(5+) did not negatively affect rotorod performance. Additionally, MnTnBuOE-2-PyP(5+) sensitized glioblastomas to either RT ± temozolomide in flank tumor models. Mice treated with both MnTnBuOE-2-PyP(5+) and radio-/chemo-therapy herein demonstrated brain radiation mitigation. MnTnBuOE-2-PyP(5+) may well serve as a normal tissue radio-/chemo-mitigator adjuvant therapy to standard brain cancer treatment regimens. Environ. Mol. Mutagen. 57:372-381, 2016. © 2016 Wiley Periodicals, Inc.

Authors
Weitzel, DH; Tovmasyan, A; Ashcraft, KA; Boico, A; Birer, SR; Roy Choudhury, K; Herndon, J; Rodriguiz, RM; Wetsel, WC; Peters, KB; Spasojevic, I; Batinic-Haberle, I; Dewhirst, MW
MLA Citation
Weitzel, Douglas H., et al. “Neurobehavioral radiation mitigation to standard brain cancer therapy regimens by Mn(III) n-butoxyethylpyridylporphyrin-based redox modifier..” Environ Mol Mutagen, vol. 57, no. 5, June 2016, pp. 372–81. Pubmed, doi:10.1002/em.22021.
PMID
27224425
Source
pubmed
Published In
Environ Mol Mutagen
Volume
57
Issue
5
Publish Date
2016
Start Page
372
End Page
381
DOI
10.1002/em.22021

ERRα-Regulated Lactate Metabolism Contributes to Resistance to Targeted Therapies in Breast Cancer.

Imaging studies in animals and in humans have indicated that the oxygenation and nutritional status of solid tumors is dynamic. Furthermore, the extremely low level of glucose within tumors, while reflecting its rapid uptake and metabolism, also suggests that cancer cells must rely on other energy sources in some circumstances. Here, we find that some breast cancer cells can switch to utilizing lactate as a primary source of energy, allowing them to survive glucose deprivation for extended periods, and that this activity confers resistance to PI3K/mTOR inhibitors. The nuclear receptor, estrogen-related receptor alpha (ERRα), was shown to regulate the expression of genes required for lactate utilization, and isotopomer analysis revealed that genetic or pharmacological inhibition of ERRα activity compromised lactate oxidation. Importantly, ERRα antagonists increased the in vitro and in vivo efficacy of PI3K/mTOR inhibitors, highlighting the potential clinical utility of this drug combination.

Authors
Park, S; Chang, C-Y; Safi, R; Liu, X; Baldi, R; Jasper, JS; Anderson, GR; Liu, T; Rathmell, JC; Dewhirst, MW; Wood, KC; Locasale, JW; McDonnell, DP
MLA Citation
Park, Sunghee, et al. “ERRα-Regulated Lactate Metabolism Contributes to Resistance to Targeted Therapies in Breast Cancer..” Cell Rep, vol. 15, no. 2, Apr. 2016, pp. 323–35. Pubmed, doi:10.1016/j.celrep.2016.03.026.
PMID
27050525
Source
pubmed
Published In
Cell Reports
Volume
15
Issue
2
Publish Date
2016
Start Page
323
End Page
335
DOI
10.1016/j.celrep.2016.03.026

Oxygen-Enhanced MRI Is a Major Advance in Tumor Hypoxia Imaging.

Authors
Dewhirst, MW; Birer, SR
MLA Citation
Dewhirst, Mark W., and Samuel R. Birer. “Oxygen-Enhanced MRI Is a Major Advance in Tumor Hypoxia Imaging..” Cancer Res, vol. 76, no. 4, Feb. 2016, pp. 769–72. Pubmed, doi:10.1158/0008-5472.CAN-15-2818.
PMID
26837768
Source
pubmed
Published In
Cancer Res
Volume
76
Issue
4
Publish Date
2016
Start Page
769
End Page
772
DOI
10.1158/0008-5472.CAN-15-2818

Perspectives from man's best friend: National Academy of Medicine's Workshop on Comparative Oncology.

Authors
LeBlanc, AK; Breen, M; Choyke, P; Dewhirst, M; Fan, TM; Gustafson, DL; Helman, LJ; Kastan, MB; Knapp, DW; Levin, WJ; London, C; Mason, N; Mazcko, C; Olson, PN; Page, R; Teicher, BA; Thamm, DH; Trent, JM; Vail, DM; Khanna, C
MLA Citation
LeBlanc, Amy K., et al. “Perspectives from man's best friend: National Academy of Medicine's Workshop on Comparative Oncology..” Sci Transl Med, vol. 8, no. 324, Feb. 2016. Pubmed, doi:10.1126/scitranslmed.aaf0746.
PMID
26843188
Source
pubmed
Published In
Sci Transl Med
Volume
8
Issue
324
Publish Date
2016
Start Page
324ps5
DOI
10.1126/scitranslmed.aaf0746

The future of biology in driving the field of hyperthermia.

In 2011 Hanahan and Weinberg updated their well-established paper 'The hallmarks of cancer'. The rationale for that review and its predecessor was to produce a conceptual framework for future research in cancer. The original Hallmarks included: cell signalling to enhance tumour cell proliferation, acquisition of ability to evade growth suppressors, developing mechanisms to resist cell death, enabling replicative immortality, initiating angiogenesis and activating processes to enable invasion and metastasis. In the more recent paper, Hanahan and Weinberg added important new features to this composite paradigm. The new features were: (1) altered metabolism, (2) evasion of immune destruction, (3) tumour promoting inflammation, and (4) the cellular microenvironment. These four new features are the main focus of this review. Hanahan and Weinberg did not specifically include the physiological microenvironment which is dominated by hypoxia and acidosis. In this review we will consider these features in addition to the cellular and metabolic components of the microenvironment. The purpose of this review is to present a vision of emerging fields of study in hyperthermia biology over the next decade and beyond. As such, we are focusing our attention on pre-clinical studies, primarily using mice. The application of hyperthermia in human patients has been thoroughly reviewed elsewhere.

Authors
Dewhirst, MW; Lee, C-T; Ashcraft, KA
MLA Citation
Dewhirst, Mark W., et al. “The future of biology in driving the field of hyperthermia..” Int J Hyperthermia, vol. 32, no. 1, 2016, pp. 4–13. Pubmed, doi:10.3109/02656736.2015.1091093.
PMID
26850697
Source
pubmed
Published In
Int J Hyperthermia
Volume
32
Issue
1
Publish Date
2016
Start Page
4
End Page
13
DOI
10.3109/02656736.2015.1091093

X-Ray Psoralen Activated Cancer Therapy (X-PACT).

This work investigates X-PACT (X-ray Psoralen Activated Cancer Therapy): a new approach for the treatment of solid cancer. X-PACT utilizes psoralen, a potent anti-cancer therapeutic with current application to proliferative disease and extracorporeal photopheresis (ECP) of cutaneous T Cell Lymphoma. An immunogenic role for light-activated psoralen has been reported, contributing to long-term clinical responses. Psoralen therapies have to-date been limited to superficial or extracorporeal scenarios due to the requirement for psoralen activation by UVA light, which has limited penetration in tissue. X-PACT solves this challenge by activating psoralen with UV light emitted from novel non-tethered phosphors (co-incubated with psoralen) that absorb x-rays and re-radiate (phosphoresce) at UV wavelengths. The efficacy of X-PACT was evaluated in both in-vitro and in-vivo settings. In-vitro studies utilized breast (4T1), glioma (CT2A) and sarcoma (KP-B) cell lines. Cells were exposed to X-PACT treatments where the concentrations of drug (psoralen and phosphor) and radiation parameters (energy, dose, and dose rate) were varied. Efficacy was evaluated primarily using flow cell cytometry in combination with complimentary assays, and the in-vivo mouse study. In an in-vitro study, we show that X-PACT induces significant tumor cell apoptosis and cytotoxicity, unlike psoralen or phosphor alone (p<0.0001). We also show that apoptosis increases as doses of phosphor, psoralen, or radiation increase. Finally, in an in-vivo pilot study of BALBc mice with syngeneic 4T1 tumors, we show that the rate of tumor growth is slower with X-PACT than with saline or AMT + X-ray (p<0.0001). Overall these studies demonstrate a potential therapeutic effect for X-PACT, and provide a foundation and rationale for future studies. In summary, X-PACT represents a novel treatment approach in which well-tolerated low doses of x-ray radiation are delivered to a specific tumor site to generate UVA light which in-turn unleashes both short- and potentially long-term antitumor activity of photo-active therapeutics like psoralen.

Authors
Oldham, M; Yoon, P; Fathi, Z; Beyer, WF; Adamson, J; Liu, L; Alcorta, D; Xia, W; Osada, T; Liu, C; Yang, XY; Dodd, RD; Herndon, JE; Meng, B; Kirsch, DG; Lyerly, HK; Dewhirst, MW; Fecci, P; Walder, H; Spector, NL
MLA Citation
Oldham, Mark, et al. “X-Ray Psoralen Activated Cancer Therapy (X-PACT)..” Plos One, vol. 11, no. 9, 2016. Pubmed, doi:10.1371/journal.pone.0162078.
Website
http://hdl.handle.net/10161/13034
PMID
27583569
Source
pubmed
Published In
Plos One
Volume
11
Issue
9
Publish Date
2016
Start Page
e0162078
DOI
10.1371/journal.pone.0162078

Anticancer therapeutic potential of Mn porphyrin/ascorbate system.

Ascorbate (Asc) as a single agent suppressed growth of several tumor cell lines in a mouse model. It has been tested in a Phase I Clinical Trial on pancreatic cancer patients where it exhibited no toxicity to normal tissue yet was of only marginal efficacy. The mechanism of its anticancer effect was attributed to the production of tumoricidal hydrogen peroxide (H2O2) during ascorbate oxidation catalyzed by endogenous metalloproteins. The amount of H2O2 could be maximized with exogenous catalyst that has optimized properties for such function and is localized within tumor. Herein we studied 14 Mn porphyrins (MnPs) which differ vastly with regards to their redox properties, charge, size/bulkiness and lipophilicity. Such properties affect the in vitro and in vivo ability of MnPs (i) to catalyze ascorbate oxidation resulting in the production of H2O2; (ii) to subsequently employ H2O2 in the catalysis of signaling proteins oxidations affecting cellular survival pathways; and (iii) to accumulate at site(s) of interest. The metal-centered reduction potential of MnPs studied, E1/2 of Mn(III)P/Mn(II)P redox couple, ranged from -200 to +350 mV vs NHE. Anionic and cationic, hydrophilic and lipophilic as well as short- and long-chained and bulky compounds were explored. Their ability to catalyze ascorbate oxidation, and in turn cytotoxic H2O2 production, was explored via spectrophotometric and electrochemical means. Bell-shape structure-activity relationship (SAR) was found between the initial rate for the catalysis of ascorbate oxidation, vo(Asc)ox and E1/2, identifying cationic Mn(III) N-substituted pyridylporphyrins with E1/2>0 mV vs NHE as efficient catalysts for ascorbate oxidation. The anticancer potential of MnPs/Asc system was subsequently tested in cellular (human MCF-7, MDA-MB-231 and mouse 4T1) and animal models of breast cancer. At the concentrations where ascorbate (1mM) and MnPs (1 or 5 µM) alone did not trigger any alteration in cell viability, combined treatment suppressed cell viability up to 95%. No toxicity was observed with normal human breast epithelial HBL-100 cells. Bell-shape relationship, essentially identical to vo(Asc)oxvs E1/2, was also demonstrated between MnP/Asc-controlled cytotoxicity and E1/2-controlled vo(Asc)ox. Magnetic resonance imaging studies were conducted to explore the impact of ascorbate on T1-relaxivity. The impact of MnP/Asc on intracellular thiols and on GSH/GSSG and Cys/CySS ratios in 4T1 cells was assessed and cellular reduction potentials were calculated. The data indicate a significant increase in cellular oxidative stress induced by MnP/Asc. Based on vo(Asc)oxvs E1/2 relationships and cellular toxicity, MnTE-2-PyP(5+) was identified as the best catalyst among MnPs studied. Asc and MnTE-2-PyP(5+) were thus tested in a 4T1 mammary mouse flank tumor model. The combination of ascorbate (4 g/kg) and MnTE-2-PyP(5+) (0.2mg/kg) showed significant suppression of tumor growth relative to either MnTE-2-PyP(5+) or ascorbate alone. About 7-fold higher accumulation of MnTE-2-PyP(5+) in tumor vs normal tissue was found to contribute largely to the anticancer effect.

Authors
Tovmasyan, A; Sampaio, RS; Boss, M-K; Bueno-Janice, JC; Bader, BH; Thomas, M; Reboucas, JS; Orr, M; Chandler, JD; Go, Y-M; Jones, DP; Venkatraman, TN; Haberle, S; Kyui, N; Lascola, CD; Dewhirst, MW; Spasojevic, I; Benov, L; Batinic-Haberle, I
MLA Citation
Tovmasyan, Artak, et al. “Anticancer therapeutic potential of Mn porphyrin/ascorbate system..” Free Radic Biol Med, vol. 89, Dec. 2015, pp. 1231–47. Pubmed, doi:10.1016/j.freeradbiomed.2015.10.416.
PMID
26496207
Source
pubmed
Published In
Free Radic Biol Med
Volume
89
Publish Date
2015
Start Page
1231
End Page
1247
DOI
10.1016/j.freeradbiomed.2015.10.416

Novel Manganese-Porphyrin Superoxide Dismutase-Mimetic Widens the Therapeutic Margin in a Preclinical Head and Neck Cancer Model.

PURPOSE: To test the effects of a novel Mn porphyrin oxidative stress modifier, Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin (MnBuOE), for its radioprotective and radiosensitizing properties in normal tissue versus tumor, respectively. METHODS AND MATERIALS: Murine oral mucosa and salivary glands were treated with a range of radiation doses with or without MnBuOE to establish the dose-effect curves for mucositis and xerostomia. Radiation injury was quantified by intravital near-infrared imaging of cathepsin activity, assessment of salivation, and histologic analysis. To evaluate effects of MnBuOE on the tumor radiation response, we administered the drug as an adjuvant to fractionated radiation of FaDu xenografts. Again, a range of radiation therapy (RT) doses was administered to establish the radiation dose-effect curve. The 50% tumor control dose values with or without MnBuOE and dose-modifying factor were determined. RESULTS: MnBuOE protected normal tissue by reducing RT-mediated mucositis, xerostomia, and fibrosis. The dose-modifying factor for protection against xerostomia was 0.77. In contrast, MnBuOE increased tumor local control rates compared with controls. The dose-modifying factor, based on the ratio of 50% tumor control dose values, was 1.3. Immunohistochemistry showed that MnBuOE-treated tumors exhibited a significant influx of M1 tumor-associated macrophages, which provides mechanistic insight into its radiosensitizing effects in tumors. CONCLUSIONS: MnBuOE widens the therapeutic margin by decreasing the dose of radiation required to control tumor, while increasing normal tissue resistance to RT-mediated injury. This is the first study to quantitatively demonstrate the magnitude of a single drug's ability to radioprotect normal tissue while radiosensitizing tumor.

Authors
Ashcraft, KA; Boss, M-K; Tovmasyan, A; Roy Choudhury, K; Fontanella, AN; Young, KH; Palmer, GM; Birer, SR; Landon, CD; Park, W; Das, SK; Weitner, T; Sheng, H; Warner, DS; Brizel, DM; Spasojevic, I; Batinic-Haberle, I; Dewhirst, MW
MLA Citation
Ashcraft, Kathleen A., et al. “Novel Manganese-Porphyrin Superoxide Dismutase-Mimetic Widens the Therapeutic Margin in a Preclinical Head and Neck Cancer Model..” Int J Radiat Oncol Biol Phys, vol. 93, no. 4, Nov. 2015, pp. 892–900. Pubmed, doi:10.1016/j.ijrobp.2015.07.2283.
PMID
26530759
Source
pubmed
Published In
Int J Radiat Oncol Biol Phys
Volume
93
Issue
4
Publish Date
2015
Start Page
892
End Page
900
DOI
10.1016/j.ijrobp.2015.07.2283

FAS Death Receptor: A Breast Cancer Subtype-Specific Radiation Response Biomarker and Potential Therapeutic Target.

Although a standardized approach to radiotherapy has been used to treat breast cancer, regardless of subtype (e.g., luminal, basal), recent clinical data suggest that radiation response may vary significantly among subtypes. We hypothesized that this clinical variability may be due, in part, to differences in cellular radiation response. In this study, we utilized RNA samples for microarray analysis from two sources: 1. Paired pre- and postirradiation breast tumor tissue from 32 early-stage breast cancer patients treated in our unique preoperative radiation Phase I trial; and 2. Sixteen biologically diverse breast tumor cell lines exposed to 0 and 5 Gy irradiation. The transcriptome response to radiation exposure was derived by comparing gene expression in samples before and after irradiation. Genes with the highest coefficient of variation were selected for further evaluation and validated at the RNA and protein level. Gene editing and agonistic antibody treatment were performed to assess the impact of gene modulation on radiation response. Gene expression in our cohort of luminal breast cancer patients was distinctly different before and after irradiation. Further, two distinct patterns of gene expression were observed in our biologically diverse group of breast cancer cell lines pre- versus postirradiation. Cell lines that showed significant change after irradiation were largely luminal subtype, while gene expression in the basal and HER2+ cell lines was minimally impacted. The 100 genes with the most significant response to radiation in patients were identified and analyzed for differential patterns of expression in the radiation-responsive versus nonresponsive cell lines. Fourteen genes were identified as significant, including FAS, a member of the tumor necrosis factor receptor family known to play a critical role in programed cell death. Modulation of FAS in breast cancer cell lines altered radiation response phenotype and enhanced radiation sensitivity in radioresistant basal cell lines. Our findings suggest that cell-type-specific, radiation-induced FAS contributes to subtype-specific breast cancer radiation response and that activation of FAS pathways may be exploited for biologically tailored radiotherapy.

Authors
Horton, JK; Siamakpour-Reihani, S; Lee, C-T; Zhou, Y; Chen, W; Geradts, J; Fels, DR; Hoang, P; Ashcraft, KA; Groth, J; Kung, H-N; Dewhirst, MW; Chi, J-TA
MLA Citation
Horton, Janet K., et al. “FAS Death Receptor: A Breast Cancer Subtype-Specific Radiation Response Biomarker and Potential Therapeutic Target..” Radiat Res, vol. 184, no. 5, Nov. 2015, pp. 456–69. Pubmed, doi:10.1667/RR14089.1.
PMID
26488758
Source
pubmed
Published In
Radiat Res
Volume
184
Issue
5
Publish Date
2015
Start Page
456
End Page
469
DOI
10.1667/RR14089.1

Synthesis and Biological Evaluation of Manassantin Analogues for Hypoxia-Inducible Factor 1α Inhibition.

To cope with hypoxia, tumor cells have developed a number of adaptive mechanisms mediated by hypoxia-inducible factor 1 (HIF-1) to promote angiogenesis and cell survival. Due to significant roles of HIF-1 in the initiation, progression, metastasis, and resistance to treatment of most solid tumors, a considerable amount of effort has been made to identify HIF-1 inhibitors for treatment of cancer. Isolated from Saururus cernuus, manassantins A (1) and B (2) are potent inhibitors of HIF-1 activity. To define the structural requirements of manassantins for HIF-1 inhibition, we prepared and evaluated a series of manassantin analogues. Our SAR studies examined key regions of manassantin's structure in order to understand the impact of these regions on biological activity and to define modifications that can lead to improved performance and drug-like properties. Our efforts identified several manassantin analogues with reduced structural complexity as potential lead compounds for further development. Analogues MA04, MA07, and MA11 down-regulated hypoxia-induced expression of the HIF-1α protein and reduced the levels of HIF-1 target genes, including cyclin-dependent kinase 6 (Cdk6) and vascular endothelial growth factor (VEGF). These findings provide an important framework to design potent and selective HIF-1α inhibitors, which is necessary to aid translation of manassantin-derived natural products to the clinic as novel therapeutics for cancers.

Authors
Kwon, D-Y; Lee, HE; Weitzel, DH; Park, K; Lee, SH; Lee, C-T; Stephenson, TN; Park, H; Fitzgerald, MC; Chi, J-T; Mook, RA; Dewhirst, MW; Lee, YM; Hong, J
MLA Citation
Kwon, Do-Yeon, et al. “Synthesis and Biological Evaluation of Manassantin Analogues for Hypoxia-Inducible Factor 1α Inhibition..” J Med Chem, vol. 58, no. 19, Oct. 2015, pp. 7659–71. Pubmed, doi:10.1021/acs.jmedchem.5b01220.
PMID
26394152
Source
pubmed
Published In
Journal of Medicinal Chemistry
Volume
58
Issue
19
Publish Date
2015
Start Page
7659
End Page
7671
DOI
10.1021/acs.jmedchem.5b01220

Prognostic significance of differential expression of angiogenic genes in women with high-grade serous ovarian carcinoma.

OBJECTIVES: To identify angiogenic biomarkers associated with tumor angiogenesis and clinical outcome in high-grade serous ovarian cancer (HGSC). METHODS: 51 HGSC samples were analyzed using Affymetrix HG-U133A microarray. Microvessel density (MVD) counts were determined using CD31 and CD105. Associations between mRNA expression levels and overall survival were assessed using rank score statistic. Effect size was estimated as a hazard ratio (HR) under a proportional hazard model. The Storey q-value method was used to account for multiple testing within the false-discovery rate (FDR) framework. Publicly available databases including TCGA and GSE were used for external confirmation. RESULTS: Thirty-one angiogenic-related genes were significantly associated with survival (q≤0.05). Of these 31 genes, 4 were also associated with outcome in the TCGA data: AKT1 (q=0.02; TCGA p=0.01, HR=0.8), CD44 (q=0.003; TCGA p=0.05, HR=0.9), EPHB2 (q=0.01; TCGA p=0.05, HR=1.2), and ERBB2 (q=0.02; TCGA p=0.05, HR=1.2). While 5 were associated with outcome in the GSE database: FLT1 (q=0.03; GSE26712 p=0.01, HR=3.1); PF4 (q=0.02; GSE26712 p=0.01, HR=3.0); NRP1 (q=0.02; GSE26712 p<0.04, HR>1.4); COL4A3 (q=0.04; GSE26712 p=0.03, HR=1.3); and ANGPTL3 (q=0.02; GSE14764 p=0.02, HR=1.5). High AKT1 and CD44 were associated with longer survival. In contrast, high expression of EPHB2, ERBB2, FLT1; PF4, NRP1, COL4A3, and ANGPTL3 were associated with shorter survival. CD105-MVD and CD31-MVD were not significantly associated with angiogenic gene expression. CONCLUSIONS: Thirty-one angiogenic-related genes were associated with survival in advanced HGSC and nine of these genes were confirmed in independent publicly available databases.

Authors
Siamakpour-Reihani, S; Owzar, K; Jiang, C; Turner, T; Deng, Y; Bean, SM; Horton, JK; Berchuck, A; Marks, JR; Dewhirst, MW; Alvarez Secord, A
MLA Citation
Siamakpour-Reihani, Sharareh, et al. “Prognostic significance of differential expression of angiogenic genes in women with high-grade serous ovarian carcinoma..” Gynecol Oncol, vol. 139, no. 1, Oct. 2015, pp. 23–29. Pubmed, doi:10.1016/j.ygyno.2015.08.001.
PMID
26260910
Source
pubmed
Published In
Gynecol Oncol
Volume
139
Issue
1
Publish Date
2015
Start Page
23
End Page
29
DOI
10.1016/j.ygyno.2015.08.001

Microdosimetric and Biological Effects of Photon Irradiation at Different Energies in Bone Marrow.

To ensure reliability and reproducibility of radiobiological data, it is necessary to standardize dosimetry practices across all research institutions. The photoelectric effect predominates over other interactions at low energy and in high atomic number materials such as bone, which can lead to increased dose deposition in soft tissue adjacent to mineral bone due to secondary radiation particles. This may produce radiation effects that deviate from higher energy photon irradiation that best model exposure from clinical radiotherapy or nuclear incidences. Past theoretical considerations have indicated that this process should affect radiation exposure of neighboring bone marrow (BM) and account for reported differences in relative biological effectiveness (RBE) for hematopoietic failure in rodents. The studies described herein definitively estimate spatial dose distribution and biological effectiveness within the BM compartment for (137)Cs gamma rays and 320 kVp X rays at two levels of filtration: 1 and 4 mm Cu half-value layer (HVL). In these studies, we performed: 1. Monte Carlo simulations on a 5 μm resolution model of mouse vertebrae and femur derived from micro-CT images; 2. In vitro biological experiments irradiating BM cells plated directly on the surface of a bone-equivalent material (BEM); and 3. An in vivo study on BM cell survival in irradiated live mice. Simulation results showed that the relative dose increased in proximity to bone at the lower radiation energies and produced averaged values of relative dose over the entire BM volume within imaged trabecular bone of 1.17, 1.08 and 1.01 for beam qualities of 1 mm Cu HVL, 4 mm Cu HVL and (137)Cs, respectively. In accordance with Monte Carlo simulations, in vitro irradiation of BM cells located on BEM and in vivo whole-body irradiation at a prescribed dose to soft tissue of 6 Gy produced relative cell killing of hematopoietic progenitors (CFU-C) that significantly increased for the 1 mm Cu HVL X rays compared to radiation exposures of higher photon energies. Thus, we propose that X rays of the highest possible kVp and filtration be used to investigate radiation effects on the hematopoietic system, as this will allow for better comparisons with high-energy photon exposures applied in radiotherapy or as anticipated in a nuclear event.

Authors
Belley, MD; Ashcraft, KA; Lee, C-T; Cornwall-Brady, MR; Chen, J-J; Gunasingha, R; Burkhart, M; Dewhirst, M; Yoshizumi, TT; Down, JD
MLA Citation
Belley, Matthew D., et al. “Microdosimetric and Biological Effects of Photon Irradiation at Different Energies in Bone Marrow..” Radiat Res, vol. 184, no. 4, Oct. 2015, pp. 378–91. Pubmed, doi:10.1667/RR14095.1.
PMID
26401594
Source
pubmed
Published In
Radiat Res
Volume
184
Issue
4
Publish Date
2015
Start Page
378
End Page
391
DOI
10.1667/RR14095.1

Abstract 3302: Subtype-specific radiation response in a mouse model of human breast cancer

Authors
Lee, C-T; Zhou, Y; Siamakpour-Reihani, S; Choudhury, KR; Dewhirst, MW; Horton, JK
MLA Citation
Lee, Chen-Ting, et al. “Abstract 3302: Subtype-specific radiation response in a mouse model of human breast cancer.” Tumor Biology, American Association for Cancer Research, 2015. Crossref, doi:10.1158/1538-7445.am2015-3302.
Source
crossref
Published In
Tumor Biology
Publish Date
2015
DOI
10.1158/1538-7445.am2015-3302

Preoperative Single-Fraction Partial Breast Radiation Therapy: A Novel Phase 1, Dose-Escalation Protocol With Radiation Response Biomarkers.

PURPOSE: Women with biologically favorable early-stage breast cancer are increasingly treated with accelerated partial breast radiation (PBI). However, treatment-related morbidities have been linked to the large postoperative treatment volumes required for external beam PBI. Relative to external beam delivery, alternative PBI techniques require equipment that is not universally available. To address these issues, we designed a phase 1 trial utilizing widely available technology to 1) evaluate the safety of a single radiation treatment delivered preoperatively to the small-volume, intact breast tumor and 2) identify imaging and genomic markers of radiation response. METHODS AND MATERIALS: Women aged ≥55 years with clinically node-negative, estrogen receptor-positive, and/or progesterone receptor-positive HER2-, T1 invasive carcinomas, or low- to intermediate-grade in situ disease ≤2 cm were enrolled (n=32). Intensity modulated radiation therapy was used to deliver 15 Gy (n=8), 18 Gy (n=8), or 21 Gy (n=16) to the tumor with a 1.5-cm margin. Lumpectomy was performed within 10 days. Paired pre- and postradiation magnetic resonance images and patient tumor samples were analyzed. RESULTS: No dose-limiting toxicity was observed. At a median follow-up of 23 months, there have been no recurrences. Physician-rated cosmetic outcomes were good/excellent, and chronic toxicities were grade 1 to 2 (fibrosis, hyperpigmentation) in patients receiving preoperative radiation only. Evidence of dose-dependent changes in vascular permeability, cell density, and expression of genes regulating immunity and cell death were seen in response to radiation. CONCLUSIONS: Preoperative single-dose radiation therapy to intact breast tumors is well tolerated. Radiation response is marked by early indicators of cell death in this biologically favorable patient cohort. This study represents a first step toward a novel partial breast radiation approach. Preoperative radiation should be tested in future clinical trials because it has the potential to challenge the current treatment paradigm and provide a path forward to identify radiation response biomarkers.

Authors
Horton, JK; Blitzblau, RC; Yoo, S; Geradts, J; Chang, Z; Baker, JA; Georgiade, GS; Chen, W; Siamakpour-Reihani, S; Wang, C; Broadwater, G; Groth, J; Palta, M; Dewhirst, M; Barry, WT; Duffy, EA; Chi, J-TA; Hwang, ES
MLA Citation
Horton, Janet K., et al. “Preoperative Single-Fraction Partial Breast Radiation Therapy: A Novel Phase 1, Dose-Escalation Protocol With Radiation Response Biomarkers..” Int J Radiat Oncol Biol Phys, vol. 92, no. 4, July 2015, pp. 846–55. Pubmed, doi:10.1016/j.ijrobp.2015.03.007.
PMID
26104938
Source
pubmed
Published In
Int J Radiat Oncol Biol Phys
Volume
92
Issue
4
Publish Date
2015
Start Page
846
End Page
855
DOI
10.1016/j.ijrobp.2015.03.007

Doxorubicin-conjugated polypeptide nanoparticles inhibit metastasis in two murine models of carcinoma.

Drug delivery vehicles are often assessed for their ability to control primary tumor growth, but the outcome of cancer treatment depends on controlling or inhibiting metastasis. Therefore, we studied the efficacy of our genetically encoded polypeptide nanoparticle for doxorubicin delivery (CP-Dox) in the syngeneic metastatic murine models 4T1 and Lewis lung carcinoma. We found that our nanoparticle formulation increased the half-life, maximum tolerated dose, and tumor accumulation of doxorubicin. When drug treatment was combined with primary tumor resection, greater than 60% of the mice were cured in both the 4T1 and Lewis lung carcinoma models compared to 20% treated with free drug. Mechanistic studies suggest that metastasis inhibition and survival increase were achieved by preventing the dissemination of viable tumor cells from the primary tumor.

Authors
Mastria, EM; Chen, M; McDaniel, JR; Li, X; Hyun, J; Dewhirst, MW; Chilkoti, A
MLA Citation
Mastria, Eric M., et al. “Doxorubicin-conjugated polypeptide nanoparticles inhibit metastasis in two murine models of carcinoma..” J Control Release, vol. 208, June 2015, pp. 52–58. Pubmed, doi:10.1016/j.jconrel.2015.01.033.
PMID
25637704
Source
pubmed
Published In
J Control Release
Volume
208
Publish Date
2015
Start Page
52
End Page
58
DOI
10.1016/j.jconrel.2015.01.033

Dynamic treatment effect (DTE) curves reveal the mode of action for standard and experimental cancer therapies.

We present a method for estimating the empirical dynamic treatment effect (DTE) curves from tumor growth delay (TGD) studies. This improves on current common methods of TGD analysis, such as T/C ratio and doubling times, by providing a more detailed treatment effect and overcomes their lack of reproducibility. The methodology doesn't presuppose any prior form for the treatment effect dynamics and is shown to give consistent estimates with missing data. The method is illustrated by application to real data from TGD studies involving three types of therapy. Firstly, we demonstrate that radiotherapy induces a sharp peak in inhibition in a FaDu model. The height, duration and timing of the peak increase linearly with radiation dose. Second, we demonstrate that a combination of temozolomide and an experimental therapy in a glioma PDX model yields an effect, similar to an additive version of the DTE curves for the mono-therapies, except that there is a 30 day delay in peak inhibition. In the third study, we consider the DTE of anti-angiogenic therapy in glioma. We show that resulting DTE curves are flat. We discuss how features of the DTE curves should be interpreted and potentially used to improve therapy.

Authors
Choudhury, KR; Keir, ST; Ashcraft, KA; Boss, M-K; Dewhirst, MW
MLA Citation
Choudhury, Kingshuk Roy, et al. “Dynamic treatment effect (DTE) curves reveal the mode of action for standard and experimental cancer therapies..” Oncotarget, vol. 6, no. 16, June 2015, pp. 14656–68. Pubmed, doi:10.18632/oncotarget.4141.
PMID
25986925
Source
pubmed
Published In
Oncotarget
Volume
6
Issue
16
Publish Date
2015
Start Page
14656
End Page
14668
DOI
10.18632/oncotarget.4141

Genomic profiling in locally advanced and inflammatory breast cancer and its link to DCE-MRI and overall survival.

PURPOSE: We have previously reported that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) perfusion patterns obtained from locally advanced breast cancer (LABC) patients prior to neoadjuvant therapy predicted pathologic clinical response. Genomic analyses were also independently conducted on the same patient population. This retrospective study was performed to test two hypotheses: (1) gene expression profiles are associated with DCE-MRI perfusion patterns, and (2) association between long-term overall survival data and gene expression profiles can lead to the identification of novel predictive biomarkers. METHODS: We utilised RNA microarray and DCE-MRI data from 47 LABC patients, including 13 inflammatory breast cancer (IBC) patients. Association between gene expression profile and DCE-MRI perfusion patterns (centrifugal and centripetal) was determined by Wilcoxon rank sum test. Association between gene expression level and survival was assessed using a Cox rank score test. Additional genomic analysis of the IBC subset was conducted, with a period of follow-up of up to 11 years. Associations between gene expression and overall survival were further assessed in The Cancer Genome Atlas Data Portal. RESULTS: Differences in gene expression profiles were seen between centrifugal and centripetal perfusion patterns in the sulphotransferase family, cytosolic, 1 A, phenol-preferring, members 1 and 2 (SULT1A1, SULT1A2), poly (ADP-ribose) polymerase, member 6 (PARP6), and metastasis tumour antigen1 (MTA1). In the IBC subset our analyses demonstrated that differential expression of 45 genes was associated with long-term survival. CONCLUSIONS: Here we have demonstrated an association between DCE-MRI perfusion patterns and gene expression profiles. In addition we have reported on candidate prognostic biomarkers in IBC patients, with some of the genes being significantly associated with survival in IBC and LABC.

Authors
Siamakpour-Reihani, S; Owzar, K; Jiang, C; Scarbrough, PM; Craciunescu, OI; Horton, JK; Dressman, HK; Blackwell, KL; Dewhirst, MW
MLA Citation
Siamakpour-Reihani, Sharareh, et al. “Genomic profiling in locally advanced and inflammatory breast cancer and its link to DCE-MRI and overall survival..” Int J Hyperthermia, vol. 31, no. 4, June 2015, pp. 386–95. Pubmed, doi:10.3109/02656736.2015.1016557.
PMID
25811737
Source
pubmed
Published In
Int J Hyperthermia
Volume
31
Issue
4
Publish Date
2015
Start Page
386
End Page
395
DOI
10.3109/02656736.2015.1016557

HIF-1 Alpha Regulates the Response of Primary Sarcomas to Radiation Therapy through a Cell Autonomous Mechanism.

Hypoxia is a major cause of radiation resistance, which may predispose to local recurrence after radiation therapy. While hypoxia increases tumor cell survival after radiation exposure because there is less oxygen to oxidize damaged DNA, it remains unclear whether signaling pathways triggered by hypoxia contribute to radiation resistance. For example, intratumoral hypoxia can increase hypoxia inducible factor 1 alpha (HIF-1α), which may regulate pathways that contribute to radiation sensitization or radiation resistance. To clarify the role of HIF-1α in regulating tumor response to radiation, we generated a novel genetically engineered mouse model of soft tissue sarcoma with an intact or deleted HIF-1α. Deletion of HIF-1α sensitized primary sarcomas to radiation exposure in vivo. Moreover, cell lines derived from primary sarcomas lacking HIF-1α, or in which HIF-1α was knocked down, had decreased clonogenic survival in vitro, demonstrating that HIF-1α can promote radiation resistance in a cell autonomous manner. In HIF-1α-intact and -deleted sarcoma cells, radiation-induced reactive oxygen species, DNA damage repair and activation of autophagy were similar. However, sarcoma cells lacking HIF-1α had impaired mitochondrial biogenesis and metabolic response after irradiation, which might contribute to radiation resistance. These results show that HIF-1α promotes radiation resistance in a cell autonomous manner.

Authors
Zhang, M; Qiu, Q; Li, Z; Sachdeva, M; Min, H; Cardona, DM; DeLaney, TF; Han, T; Ma, Y; Luo, L; Ilkayeva, OR; Lui, K; Nichols, AG; Newgard, CB; Kastan, MB; Rathmell, JC; Dewhirst, MW; Kirsch, DG
MLA Citation
Zhang, Minsi, et al. “HIF-1 Alpha Regulates the Response of Primary Sarcomas to Radiation Therapy through a Cell Autonomous Mechanism..” Radiat Res, vol. 183, no. 6, June 2015, pp. 594–609. Pubmed, doi:10.1667/RR14016.1.
PMID
25973951
Source
pubmed
Published In
Radiat Res
Volume
183
Issue
6
Publish Date
2015
Start Page
594
End Page
609
DOI
10.1667/RR14016.1

Modulation of murine breast tumor vascularity, hypoxia and chemotherapeutic response by exercise.

Exercise has been shown to improve postischemia perfusion of normal tissues; we investigated whether these effects extend to solid tumors. Estrogen receptor-negative (ER-, 4T1) and ER+ (E0771) tumor cells were implanted orthotopically into syngeneic mice (BALB/c, N = 11-12 per group) randomly assigned to exercise or sedentary control. Tumor growth, perfusion, hypoxia, and components of the angiogenic and apoptotic cascades were assessed by MRI, immunohistochemistry, western blotting, and quantitative polymerase chain reaction and analyzed with one-way and repeated measures analysis of variance and linear regression. All statistical tests were two-sided. Exercise statistically significantly reduced tumor growth and was associated with a 1.4-fold increase in apoptosis (sedentary vs exercise: 1544 cells/mm(2), 95% CI = 1223 to 1865 vs 2168 cells/mm(2), 95% CI = 1620 to 2717; P = .048), increased microvessel density (P = .004), vessel maturity (P = .006) and perfusion, and reduced intratumoral hypoxia (P = .012), compared with sedentary controls. We also tested whether exercise could improve chemotherapy (cyclophosphamide) efficacy. Exercise plus chemotherapy prolonged growth delay compared with chemotherapy alone (P < .001) in the orthotopic 4T1 model (n = 17 per group). Exercise is a potential novel adjuvant treatment of breast cancer.

Authors
Betof, AS; Lascola, CD; Weitzel, D; Landon, C; Scarbrough, PM; Devi, GR; Palmer, G; Jones, LW; Dewhirst, MW
MLA Citation
Betof, Allison S., et al. “Modulation of murine breast tumor vascularity, hypoxia and chemotherapeutic response by exercise..” J Natl Cancer Inst, vol. 107, no. 5, May 2015. Pubmed, doi:10.1093/jnci/djv040.
Website
http://hdl.handle.net/10161/12580
PMID
25780062
Source
pubmed
Published In
J Natl Cancer Inst
Volume
107
Issue
5
Publish Date
2015
DOI
10.1093/jnci/djv040

A tribute to Philip Marcus and the development of the clonogenic assay.

Philip Marcus (1927-2013), a prominent and celebrated virus and interferon researcher, was also influential to the field of radiobiology. His work as a graduate student led to the development of the first mammalian cell clonogenic assay. This tribute to Philip Marcus is written to memorialize this inventive scientist and share the stimulating story of how he and his mentors developed the clonogenic assay.

Authors
Boss, M-K; Dewhirst, M
MLA Citation
Boss, Mary-Keara, and Mark Dewhirst. “A tribute to Philip Marcus and the development of the clonogenic assay..” Radiat Res, vol. 183, no. 5, May 2015, pp. 497–500.
PMID
26000758
Source
pubmed
Published In
Radiat Res
Volume
183
Issue
5
Publish Date
2015
Start Page
497
End Page
500

Luminescent difluoroboron β-diketonate PEG-PLA oxygen nanosensors for tumor imaging

© 2015 Wiley-VCH Verlag GmbH & Co. KGaA. Surface modification of nanoparticles and biosensors is a dynamic, expanding area of research for targeted delivery in vivo. For more efficient delivery, surfaces are PEGylated to impart stealth properties, long circulation, and enable enhanced permeability and retention (EPR) in tumor tissues. Previously, BF2dbm(I)PLA was proven to be a good oxygen nanosensor material for tumor hypoxia imaging in vivo, though particles were applied directly to the tumor and surrounding region. Further surface modification is needed for this dual-emissive oxygen sensitive material for effective intravenous (IV) administration and passive and active delivery to tumors. In this paper, an efficient synthesis of a new dual-emissive material BF2dbm(I)PLA-mPEG is presented and in vitro stability studies are conducted. It is found that fabricated nanoparticles are stable for 24 weeks as a suspension, while after 25 weeks the nanoparticles swell and both dye and polymer degradation escalates. Preliminary studies show BF2dbm(I) PLA-mPEG nanoparticle accumulation in a window chamber mammary tumor 24 h after IV injection into mice (C57Bl/6 strain) enabling tumor oxygen imaging. (Graph Presented)

Authors
Samonina-Kosicka, J; Weitzel, DH; Hofmann, CL; Hendargo, H; Hanna, G; Dewhirst, MW; Palmer, GM; Fraser, CL
MLA Citation
Samonina-Kosicka, J., et al. “Luminescent difluoroboron β-diketonate PEG-PLA oxygen nanosensors for tumor imaging.” Macromolecular Rapid Communications, vol. 36, no. 7, Apr. 2015, pp. 694–99. Scopus, doi:10.1002/marc.201500022.
Source
scopus
Published In
Macromolecular Rapid Communications
Volume
36
Issue
7
Publish Date
2015
Start Page
694
End Page
699
DOI
10.1002/marc.201500022

Reply: Pharmacokinetic and Pharmacodynamic Modifiers of EF5 Uptake and Binding.

Authors
Chitneni, SK; Bida, GT; Zalutsky, MR; Dewhirst, MW
MLA Citation
Chitneni, Satish K., et al. “Reply: Pharmacokinetic and Pharmacodynamic Modifiers of EF5 Uptake and Binding..” J Nucl Med, vol. 56, no. 4, Apr. 2015, pp. 653–54. Pubmed, doi:10.2967/jnumed.115.154054.
PMID
25745087
Source
pubmed
Published In
Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
Volume
56
Issue
4
Publish Date
2015
Start Page
653
End Page
654
DOI
10.2967/jnumed.115.154054

Luminescent difluoroboron β-diketonate PEG-PLA oxygen nanosensors for tumor imaging.

Surface modification of nanoparticles and biosensors is a dynamic, expanding area of research for targeted delivery in vivo. For more efficient delivery, surfaces are PEGylated to impart stealth properties, long circulation, and enable enhanced permeability and retention (EPR) in tumor tissues. Previously, BF2 dbm(I)PLA was proven to be a good oxygen nanosensor material for tumor hypoxia imaging in vivo, though particles were applied directly to the tumor and surrounding region. Further surface modification is needed for this dual-emissive oxygen sensitive material for effective intravenous (IV) administration and passive and active delivery to tumors. In this paper, an efficient synthesis of a new dual-emissive material BF2 dbm(I)PLA-mPEG is presented and in vitro stability studies are conducted. It is found that fabricated nanoparticles are stable for 24 weeks as a suspension, while after 25 weeks the nanoparticles swell and both dye and polymer degradation escalates. Preliminary studies show BF2 dbm(I)PLA-mPEG nanoparticle accumulation in a window chamber mammary tumor 24 h after IV injection into mice (C57Bl/6 strain) enabling tumor oxygen imaging.

Authors
Samonina-Kosicka, J; Weitzel, DH; Hofmann, CL; Hendargo, H; Hanna, G; Dewhirst, MW; Palmer, GM; Fraser, CL
MLA Citation
Samonina-Kosicka, Jelena, et al. “Luminescent difluoroboron β-diketonate PEG-PLA oxygen nanosensors for tumor imaging..” Macromol Rapid Commun, vol. 36, no. 7, Apr. 2015, pp. 694–99. Pubmed, doi:10.1002/marc.201500022.
PMID
25753154
Source
pubmed
Published In
Macromol Rapid Commun
Volume
36
Issue
7
Publish Date
2015
Start Page
694
End Page
699
DOI
10.1002/marc.201500022

Common responses of tumors and wounds to hypoxia.

Hypoxia is a characteristic of tumors and wounds. Hypoxic cells develop 2 common strategies to face hypoxia: the glycolytic switch and the angiogenic switch. At the onset of hypoxia, alleviation of the Pasteur effect ensures short-term cell survival. Long-term hypoxic cell survival requires a further acceleration of the glycolytic flux under the control of hypoxia-inducible factor 1 that stimulates the expression of most glycolytic transporters and enzymes, uncouples glycolysis from the TCA cycle, and rewires glycolysis to lactic fermentation. Hypoxic cells also trigger angiogenesis, a process that aims to restore normal microenvironmental conditions. Transcription factors (hypoxia-inducible factor 1, nuclear factor κB, activator protein 1) and lactate cooperate to stimulate the expression of proangiogenic agents. Cancer cells differ from normal hypoxic cells by their proliferative agenda and by a high metabolic heterogeneity. These effects in tumor account for further molecular and metabolic changes and for a persistent stimulation of angiogenesis.

Authors
Payen, VL; Brisson, L; Dewhirst, MW; Sonveaux, P
MLA Citation
Payen, Valéry L., et al. “Common responses of tumors and wounds to hypoxia..” Cancer J, vol. 21, no. 2, Mar. 2015, pp. 75–87. Pubmed, doi:10.1097/PPO.0000000000000098.
PMID
25815847
Source
pubmed
Published In
Cancer J
Volume
21
Issue
2
Publish Date
2015
Start Page
75
End Page
87
DOI
10.1097/PPO.0000000000000098

From the guest editor: an integrated multidisciplinary view of tumor metabolism.

Authors
Dewhirst, MW
MLA Citation
Dewhirst, Mark W. “From the guest editor: an integrated multidisciplinary view of tumor metabolism..” Cancer J, vol. 21, no. 2, Mar. 2015, pp. 47–48. Pubmed, doi:10.1097/PPO.0000000000000108.
PMID
25815842
Source
pubmed
Published In
Cancer J
Volume
21
Issue
2
Publish Date
2015
Start Page
47
End Page
48
DOI
10.1097/PPO.0000000000000108

Targeting N-cadherin increases vascular permeability and differentially activates AKT in melanoma.

OBJECTIVE: We investigate the mechanism through which N-cadherin disruption alters the effectiveness of regional chemotherapy for locally advanced melanoma. BACKGROUND: N-cadherin antagonism during regional chemotherapy has demonstrated variable treatment effects. METHODS: Isolated limb infusion (ILI) with melphalan (LPAM) or temozolomide (TMZ) was performed on rats bearing melanoma xenografts after systemic administration of the N-cadherin antagonist, ADH-1, or saline. Permeability studies were performed using Evans blue dye as the infusate, and interstitial fluid pressure was measured. Immunohistochemistry of LPAM-DNA adducts and damage was performed as surrogates for LPAM and TMZ delivery. Tumor signaling was studied by Western blotting and reverse-phase protein array analysis. RESULTS: Systemic ADH-1 was associated with increased growth and activation of the PI3K (phosphatidylinositol-3 kinase)-AKT pathway in A375 but not DM443 xenografts. ADH-1 in combination with LPAM ILI improved antitumor responses compared with LPAM alone in both cell lines. Combination of ADH-1 with TMZ ILI did not improve tumor response in A375 tumors. ADH-1 increased vascular permeability without effecting tumor interstitial fluid pressure, leading to increased delivery of LPAM but not TMZ. CONCLUSIONS: ADH-1 improved responses to regional LPAM but had variable effects on tumors regionally treated with TMZ. N-cadherin-targeting agents may lead to differential effects on the AKT signaling axis that can augment growth of some tumors. The vascular targeting actions of N-cadherin antagonism may not augment some regionally delivered alkylating agents, leading to a net increase in tumor size with this type of combination treatment strategy.

Authors
Turley, RS; Tokuhisa, Y; Toshimitsu, H; Lidsky, ME; Padussis, JC; Fontanella, A; Deng, W; Augustine, CK; Beasley, GM; Davies, MA; Dewhirst, MW; Tyler, DS
MLA Citation
Turley, Ryan S., et al. “Targeting N-cadherin increases vascular permeability and differentially activates AKT in melanoma..” Ann Surg, vol. 261, no. 2, Feb. 2015, pp. 368–77. Pubmed, doi:10.1097/SLA.0000000000000635.
PMID
24646553
Source
pubmed
Published In
Ann Surg
Volume
261
Issue
2
Publish Date
2015
Start Page
368
End Page
377
DOI
10.1097/SLA.0000000000000635

Effects of high-dose microbeam irradiation on tumor microvascular function and angiogenesis.

Microbeam radiation therapy (MRT) is a form of cancer treatment in which a single large dose of radiation is spatially fractionated in-line or grid-like patterns. Preclinical studies have demonstrated that MRT is capable of eliciting high levels of tumor response while sparing normal tissue that is exposed to the same radiation field. Since a large fraction of the MRT-treated tumor is in the dose valley region that is not directly irradiated, tumor response may be driven by radiation bystander effects, which in turn elicit a microvascular response. Differential alterations in hemodynamics between the tumor and normal tissue may explain the therapeutic advantages of MRT. Direct observation of these dynamic responses presents a challenge for conventional ex vivo analysis. Furthermore, knowledge gleaned from in vitro studies of radiation bystander response has not been widely incorporated into in vivo models of tumor radiotherapy, and the biological contribution of the bystander effect within the tumor microenvironment is unknown. In this study, we employed noninvasive, serial observations of the tumor microenvironment to address the question of how tumor vasculature and HIF-1 expression are affected by microbeam radiotherapy. Tumors (approximately 4 mm in diameter) grown in a dorsal window chamber were irradiated in a single fraction using either a single, microplanar beam (300 micron wide swath) or a wide-field setup (whole-window chamber) to a total dose of 50 Gy. The tumors were optically observed daily for seven days postirradiation. Microvascular changes in the tumor and surrounding normal tissue differed greatly between the wide-field and microbeam treatments. We present evidence that these changes may be due to dissimilar spatial and temporal patterns of HIF-1 expression induced through radiation bystander effects.

Authors
Fontanella, AN; Boss, M-K; Hadsell, M; Zhang, J; Schroeder, T; Berman, KG; Dewhirst, MW; Chang, S; Palmer, GM
MLA Citation
Fontanella, Andrew N., et al. “Effects of high-dose microbeam irradiation on tumor microvascular function and angiogenesis..” Radiat Res, vol. 183, no. 2, Feb. 2015, pp. 147–58. Pubmed, doi:10.1667/RR13712.1.
PMID
25574586
Source
pubmed
Published In
Radiat Res
Volume
183
Issue
2
Publish Date
2015
Start Page
147
End Page
158
DOI
10.1667/RR13712.1

Akt phosphorylates and activates HSF-1 independent of heat shock, leading to Slug overexpression and epithelial-mesenchymal transition (EMT) of HER2-overexpressing breast cancer cells.

Epithelial-mesenchymal transition (EMT) is an essential step for tumor progression, although the mechanisms driving EMT are still not fully understood. In an effort to investigate these mechanisms, we observed that heregulin (HRG)-mediated activation of HER2, or HER2 overexpression, resulted in EMT, which is accompanied with increased expression of a known EMT regulator Slug, but not TWIST or Snail. We then investigated how HER2 induced Slug expression and found, for the first time, that there are four consensus HSF sequence-binding elements (HSEs), the binding sites for heat shock factor-1 (HSF-1), located in the Slug promoter. HSF-1 bound to and transactivated the Slug promoter independent of heat shock, leading to Slug expression in breast cancer cells. Mutation of the putative HSEs ablated Slug transcriptional activation induced by HRG or HSF-1 overexpression. Knockdown of HSF-1 expression by siRNA reduced Slug expression and HRG-induced EMT. The positive association between HSF-1 and Slug was confirmed by immunohistochemical staining of a cohort of 100 invasive breast carcinoma specimens. While investigating how HER2 activated HSF-1 independent of heat shock, we observed that HER2 activation resulted in concurrent phosphorylation of Akt and HSF-1. We then observed, also for the first time, that Akt directly interacted with HSF-1 and phosphorylated HSF-1 at S326. Inhibition of Akt using siRNA, dominant-negative Akt mutant, or small molecule inhibitors prevented HRG-induced HSF-1 activation and Slug expression. Conversely, constitutively active Akt induced HSF-1 phosphorylation and Slug expression. HSF-1 knockdown reduced the ability of Akt to induce Slug expression, indicating an essential role that HSF-1 plays in Akt-induced Slug upregulation. Altogether, our study uncovered the existence of a novel Akt-HSF-1 signaling axis that leads to Slug upregulation and EMT, and potentially contributes to progression of HER2-positive breast cancer.

Authors
Carpenter, RL; Paw, I; Dewhirst, MW; Lo, H-W
MLA Citation
Carpenter, R. L., et al. “Akt phosphorylates and activates HSF-1 independent of heat shock, leading to Slug overexpression and epithelial-mesenchymal transition (EMT) of HER2-overexpressing breast cancer cells..” Oncogene, vol. 34, no. 5, Jan. 2015, pp. 546–57. Pubmed, doi:10.1038/onc.2013.582.
PMID
24469056
Source
pubmed
Published In
Oncogene
Volume
34
Issue
5
Publish Date
2015
Start Page
546
End Page
557
DOI
10.1038/onc.2013.582

Targeting n-cadherin increases vascular permeability and differentially activates akt in melanoma

Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved. Objective: We investigate the mechanism through which N-cadherin disruption alters the effectiveness of regional chemotherapy for locally advanced melanoma. Background: N-cadherin antagonism during regional chemotherapy has demonstrated variable treatment effects. Methods: Isolated limb infusion (ILI) with melphalan (LPAM) or temozolomide (TMZ) was performed on rats bearing melanoma xenografts after systemic administration of the N-cadherin antagonist, ADH-1, or saline. Permeability studies were performed using Evans blue dye as the infusate, and interstitial fluid pressure was measured. Immunohistochemistry of LPAM-DNA adducts and damage was performed as surrogates for LPAM and TMZ delivery. Tumor signaling was studied by Western blotting and reverse-phase protein array analysis. Results: Systemic ADH-1 was associated with increased growth and activation of the PI3K (phosphatidylinositol-3 kinase)-AKT pathway in A375 but not DM443 xenografts. ADH-1 in combination with LPAM ILI improved antitumor responses compared with LPAM alone in both cell lines. Combination of ADH-1 with TMZ ILI did not improve tumor response in A375 tumors. ADH-1 increased vascular permeability without effecting tumor interstitial fluid pressure, leading to increased delivery of LPAM but not TMZ. Conclusions: ADH-1 improved responses to regional LPAM but had variable effects on tumors regionally treated with TMZ. N-cadherin-targeting agents may lead to differential effects on the AKT signaling axis that can augment growth of some tumors. The vascular targeting actions of N-cadherin antagonism may not augment some regionally delivered alkylating agents, leading to a net increase in tumor size with this type of combination treatment strategy.

Authors
Turley, RS; Tokuhisa, Y; Toshimitsu, H; Lidsky, ME; Padussis, JC; Fontanella, A; Deng, W; Augustine, CK; Beasley, GM; Davies, MA; Dewhirst, MW; Tyler, DS
MLA Citation
Turley, R. S., et al. “Targeting n-cadherin increases vascular permeability and differentially activates akt in melanoma.” Annals of Surgery, vol. 261, no. 2, Jan. 2015, pp. 368–77. Scopus, doi:10.1097/SLA.0000000000000635.
Source
scopus
Published In
Annals of Surgery
Volume
261
Issue
2
Publish Date
2015
Start Page
368
End Page
377
DOI
10.1097/SLA.0000000000000635

Evolution of Thermal Dosimetry for Application of Hyperthermia to Treat Cancer

The use of heat to treat cancer has been extensively studied in preclinical models and in human clinical trials. When combined with radiotherapy and chemotherapy, hyperthermia can yield synergistic interactions that increase likelihood that tumors will be controlled locally. Some evidence also exists that improvement in local tumor control. can lead to survival advantages. The achievement of therapeutic success with thermal therapies, however, requires a robust thermal dosimetry. This paper provides an overview of the evolution of thermometry and thermal dosimetry for both traditional hyperthermia and thermal ablation. Following the thermal dosimetry discussion, a brief review of key clinical trial results is discussed. © 2015 Elsevier Inc..

Authors
Dewhirst, MW; Abraham, J; Viglianti, B
MLA Citation
Dewhirst, M. W., et al. Evolution of Thermal Dosimetry for Application of Hyperthermia to Treat Cancer. Vol. 47, 2015, pp. 397–421. Scopus, doi:10.1016/bs.aiht.2015.09.001.
Source
scopus
Volume
47
Publish Date
2015
Start Page
397
End Page
421
DOI
10.1016/bs.aiht.2015.09.001

Radioprotection of the brain white matter by Mn(III) n-Butoxyethylpyridylporphyrin-based superoxide dismutase mimic MnTnBuOE-2-PyP5+.

Cranial irradiation is a standard therapy for primary and metastatic brain tumors. A major drawback of radiotherapy (RT), however, is long-term cognitive loss that affects quality of life. Radiation-induced oxidative stress in normal brain tissue is thought to contribute to cognitive decline. We evaluated the effectiveness of a novel mimic of superoxide dismutase enzyme (SOD), MnTnBuOE-2-PyP(5+)(Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin), to provide long-term neuroprotection following 8 Gy of whole brain irradiation. Long-term RT damage can only be assessed by brain imaging and neurocognitive studies. C57BL/6J mice were treated with MnTnBuOE-2-PyP(5+) before and after RT and evaluated three months later. At this time point, drug concentration in the brain was 25 nmol/L. Mice treated with MnTnBuOE-2-PyP(5+)/RT exhibited MRI evidence for myelin preservation in the corpus callosum compared with saline/RT treatment. Corpus callosum histology demonstrated a significant loss of axons in the saline/RT group that was rescued in the MnTnBuOE-2-PyP(5+)/RT group. In addition, the saline/RT groups exhibited deficits in motor proficiency as assessed by the rotorod test and running wheel tests. These deficits were ameliorated in groups treated with MnTnBuOE-2-PyP(5+)/RT. Our data demonstrate that MnTnBuOE-2-PyP(5+) is neuroprotective for oxidative stress damage caused by radiation exposure. In addition, glioblastoma cells were not protected by MnTnBuOE-2-PyP(5+) combination with radiation in vitro. Likewise, the combination of MnTnBuOE-2-PyP(5+) with radiation inhibited tumor growth more than RT alone in flank tumors. In summary, MnTnBuOE-2-PyP(5+) has dual activity as a neuroprotector and a tumor radiosensitizer. Thus, it is an attractive candidate for adjuvant therapy with RT in future studies with patients with brain cancer.

Authors
Weitzel, DH; Tovmasyan, A; Ashcraft, KA; Rajic, Z; Weitner, T; Liu, C; Li, W; Buckley, AF; Prasad, MR; Young, KH; Rodriguiz, RM; Wetsel, WC; Peters, KB; Spasojevic, I; Herndon, JE; Batinic-Haberle, I; Dewhirst, MW
MLA Citation
Weitzel, Douglas H., et al. “Radioprotection of the brain white matter by Mn(III) n-Butoxyethylpyridylporphyrin-based superoxide dismutase mimic MnTnBuOE-2-PyP5+..” Mol Cancer Ther, vol. 14, no. 1, Jan. 2015, pp. 70–79. Pubmed, doi:10.1158/1535-7163.MCT-14-0343.
PMID
25319393
Source
pubmed
Published In
Mol Cancer Ther
Volume
14
Issue
1
Publish Date
2015
Start Page
70
End Page
79
DOI
10.1158/1535-7163.MCT-14-0343

Prognostic significance of differential expression of angiogenic genes in women with high-grade serous ovarian carcinoma

© 2015 Elsevier Inc. All rights reserved.Objectives To identify angiogenic biomarkers associated with tumor angiogenesis and clinical outcome in high-grade serous ovarian cancer (HGSC). Methods 51 HGSC samples were analyzed using Affymetrix HG-U133A microarray. Microvessel density (MVD) counts were determined using CD31 and CD105. Associations between mRNA expression levels and overall survival were assessed using rank score statistic. Effect size was estimated as a hazard ratio (HR) under a proportional hazard model. The Storey q-value method was used to account for multiple testing within the false-discovery rate (FDR) framework. Publicly available databases including TCGA and GSE were used for external confirmation. Results Thirty-one angiogenic-related genes were significantly associated with survival (q 0.05). Of these 31 genes, 4 were also associated with outcome in the TCGA data: AKT1 (q = 0.02; TCGA p = 0.01, HR = 0.8), CD44 (q = 0.003; TCGA p = 0.05, HR = 0.9), EPHB2 (q = 0.01; TCGA p = 0.05, HR = 1.2), and ERBB2 (q = 0.02; TCGA p = 0.05, HR = 1.2). While 5 were associated with outcome in the GSE database: FLT1 (q = 0.03; GSE26712 p = 0.01, HR = 3.1); PF4 (q = 0.02; GSE26712 p = 0.01, HR = 3.0); NRP1 (q = 0.02; GSE26712 p 0.04, HR 1.4); COL4A3 (q = 0.04; GSE26712 p = 0.03, HR = 1.3); and ANGPTL3 (q = 0.02; GSE14764 p = 0.02, HR = 1.5). High AKT1 and CD44 were associated with longer survival. In contrast, high expression of EPHB2, ERBB2, FLT1; PF4, NRP1, COL4A3, and ANGPTL3 were associated with shorter survival. CD105-MVD and CD31-MVD were not significantly associated with angiogenic gene expression. Conclusions Thirty-one angiogenic-related genes were associated with survival in advanced HGSC and nine of these genes were confirmed in independent publicly available databases.

Authors
Siamakpour-Reihani, S; Owzar, K; Jiang, C; Turner, T; Deng, Y; Bean, SM; Horton, JK; Berchuck, A; Marks, JR; Dewhirst, MW; Secord, AA
MLA Citation
Siamakpour-Reihani, S., et al. “Prognostic significance of differential expression of angiogenic genes in women with high-grade serous ovarian carcinoma.” Gynecologic Oncology, vol. 139, no. 1, 2015, pp. 23–29. Scival, doi:10.1016/j.ygyno.2015.08.001.
Source
scival
Published In
Gynecologic Oncology
Volume
139
Issue
1
Publish Date
2015
Start Page
23
End Page
29
DOI
10.1016/j.ygyno.2015.08.001

Automated measurement of microcirculatory blood flow velocity in pulmonary metastases of rats.

Because the lung is a major target organ of metastatic disease, animal models to study the physiology of pulmonary metastases are of great importance. However, very few methods exist to date to investigate lung metastases in a dynamic fashion at the microcirculatory level, due to the difficulty to access the lung with a microscope. Here, an intravital microscopy method is presented to functionally image and quantify the microcirculation of superficial pulmonary metastases in rats, using a closed-chest pulmonary window and automated analysis of blood flow velocity and direction. The utility of this method is demonstrated to measure increases in blood flow velocity in response to pharmacological intervention, and to image the well-known tortuous vasculature of solid tumors. This is the first demonstration of intravital microscopy on pulmonary metastases in a closed-chest model. Because of its minimized invasiveness, as well as due to its relative ease and practicality, this technology has the potential to experience widespread use in laboratories that specialize on pulmonary tumor research.

Authors
Blueschke, G; Hanna, G; Fontanella, AN; Palmer, GM; Boico, A; Min, H; Dewhirst, MW; Irwin, DC; Zhao, Y; Schroeder, T
MLA Citation
Blueschke, Gert, et al. “Automated measurement of microcirculatory blood flow velocity in pulmonary metastases of rats..” J Vis Exp, no. 93, Nov. 2014. Pubmed, doi:10.3791/51630.
PMID
25490280
Source
pubmed
Published In
Journal of Visualized Experiments : Jove
Issue
93
Publish Date
2014
Start Page
e51630
DOI
10.3791/51630

The Role of Ascorbate in Therapeutic Actions of Cationic Mn Porphyrin-Based SOD Mimics

Authors
Tovmasyan, A; Roberts, ERH; Yuliana, Y; Haberle, S; Boss, M-K; Venkatraman, TN; Lascola, C; Dewhirst, MW; Lam, PYP; Benov, L; Leong, KW; Batinic-Haberle, I
MLA Citation
Tovmasyan, Artak, et al. “The Role of Ascorbate in Therapeutic Actions of Cationic Mn Porphyrin-Based SOD Mimics.” Free Radical Biology and Medicine, vol. 76, Elsevier BV, Nov. 2014, pp. S94–95. Crossref, doi:10.1016/j.freeradbiomed.2014.10.327.
Source
crossref
Published In
Free Radical Biology and Medicine
Volume
76
Publish Date
2014
Start Page
S94
End Page
S95
DOI
10.1016/j.freeradbiomed.2014.10.327

Changes in Gene Expression After Radiation in Human Breast Cancers: A Guide to Predicting and Modulating Radiation Response

Authors
Horton, JK; Dewhirst, MW; Siamakpour-Reihani, S; Zhou, Y; Geradts, J; Chi, J-TA; Chen, W
MLA Citation
Horton, Janet K., et al. “Changes in Gene Expression After Radiation in Human Breast Cancers: A Guide to Predicting and Modulating Radiation Response.” Journal of Womens Health, vol. 23, no. 10, MARY ANN LIEBERT, INC, Oct. 2014, pp. 861–861.
Source
wos
Published In
Journal of Women'S Health (2002)
Volume
23
Issue
10
Publish Date
2014
Start Page
861
End Page
861

Abstract 3774: Hyperthermia treatment overcomes temozolomide resistance in glioma cells by downregulatingMGMTexpression and increasing temozolomide uptake

Authors
Lee, C-T; Blackley, A; Landon, C; Spasojevic, I; Kirkpatrick, JP; Dewhirst, MW
MLA Citation
Lee, Chen-Ting, et al. “Abstract 3774: Hyperthermia treatment overcomes temozolomide resistance in glioma cells by downregulatingMGMTexpression and increasing temozolomide uptake.” Experimental and Molecular Therapeutics, American Association for Cancer Research, 2014. Crossref, doi:10.1158/1538-7445.am2014-3774.
Source
crossref
Published In
Experimental and Molecular Therapeutics
Publish Date
2014
DOI
10.1158/1538-7445.am2014-3774

The additive damage model: a mathematical model for cellular responses to drug combinations.

Mathematical models to describe dose-dependent cellular responses to drug combinations are an essential component of computational simulations for predicting therapeutic responses. Here, a new model, the additive damage model, is introduced and tested in cases where varying concentrations of two drugs are applied with a fixed exposure schedule. In the model, cell survival is determined by whether cellular damage, which depends on the concentrations of the drugs, exceeds a lethal threshold, which varies randomly in the cell population with a prescribed statistical distribution. Cellular damage is assumed to be additive, and is expressed as a sum of separate terms for each drug. Each term has a saturable dependence on drug concentration. The model has appropriate behavior over the entire range of drug concentrations, and is predictive, given single-agent dose-response data for each drug. The proposed model is compared with several other models, by testing their ability to fit 24 data sets for platinum-taxane combinations and 21 data sets for various other combinations. The Akaike Information Criterion is used to assess goodness of fit, taking into account the number of unknown parameters in each model. Overall, the additive damage model provides a better fit to the data sets than any previous model. The proposed model provides a basis for computational simulations of therapeutic responses. It predicts responses to drug combinations based on data for each drug acting as a single agent, and can be used as an improved null reference model for assessing synergy in the action of drug combinations.

Authors
Jones, LB; Secomb, TW; Dewhirst, MW; El-Kareh, AW
MLA Citation
Jones, Leslie Braziel, et al. “The additive damage model: a mathematical model for cellular responses to drug combinations..” J Theor Biol, vol. 357, Sept. 2014, pp. 10–20. Pubmed, doi:10.1016/j.jtbi.2014.04.032.
PMID
24799130
Source
pubmed
Published In
J Theor Biol
Volume
357
Publish Date
2014
Start Page
10
End Page
20
DOI
10.1016/j.jtbi.2014.04.032

Systemic anti-tumour effects of local thermally sensitive liposome therapy.

PURPOSE: There were two primary objectives of this study: (1) to determine whether treatment of a tumour site with systemically administered thermally sensitive liposomes and local hyperthermia (HT) for triggered release would have dual anti-tumour effect on the primary heated tumour as well as an unheated secondary tumour in a distant site, and (2) to determine the ability of non-invasive optical spectroscopy to predict treatment outcome. The optical end points studied included drug levels, metabolic markers flavin adenine dinucleotide (FAD), nicotinamide adenine dinucleotide phosphate (NAD(P)H), and physiological markers (total haemoglobin (Hb) and Hb oxygen saturation) before and after treatment. MATERIALS AND METHODS: Mice were inoculated with SKOV3 human ovarian carcinoma in both hind legs. One tumour was selected for local hyperthermia and subsequent systemic treatment. There were four treatment groups: control, DOXIL (non-thermally sensitive liposomes containing doxorubicin), and two different thermally sensitive liposome formulations containing doxorubicin. Optical spectroscopy was performed prior to therapy, immediately after treatment, and 6, 12, and 24 h post therapy. RESULTS: Tumour growth delay was seen with DOXIL and the thermally sensitive liposomes in the tumours that were heated, similar to previous studies. Tumour growth delay was also seen in the opposing tumour in the thermally sensitive liposome-treated groups. Optical spectroscopy demonstrated correlation between growth delay, doxorubicin (DOX) levels, and changes of NAD(P)H from baseline levels. Hb and Hb saturation were not correlated with growth delay. DISCUSSION: The study demonstrated that thermally sensitive liposomes affect the primary heated tumour as well as systemic efficacy. Non-invasive optical spectroscopy methods were shown to be useful in predicting efficacy at early time points post-treatment.

Authors
Viglianti, BL; Dewhirst, MW; Boruta, RJ; Park, J-Y; Landon, C; Fontanella, AN; Guo, J; Manzoor, A; Hofmann, CL; Palmer, GM
MLA Citation
Viglianti, Benjamin L., et al. “Systemic anti-tumour effects of local thermally sensitive liposome therapy..” Int J Hyperthermia, vol. 30, no. 6, Sept. 2014, pp. 385–92. Pubmed, doi:10.3109/02656736.2014.944587.
PMID
25164143
Source
pubmed
Published In
Int J Hyperthermia
Volume
30
Issue
6
Publish Date
2014
Start Page
385
End Page
392
DOI
10.3109/02656736.2014.944587

HIF-1α Regulates Radiation Resistance in Primary Sarcomas in a Tumor-Cell Autonomous Mechanism

Authors
Zhang, M; Qiu, Q; Min, H; Li, Z; Cardona, D; Ma, Y; Nichols, A; Han, T; Luo, L; Schroeder, T; Dewhirst, MW; Newgard, CB; Rathmell, JC; Kirsch, DG
MLA Citation
Zhang, M., et al. “HIF-1α Regulates Radiation Resistance in Primary Sarcomas in a Tumor-Cell Autonomous Mechanism.” International Journal of Radiation Oncology*Biology*Physics, vol. 90, no. 1, Elsevier BV, 2014, pp. S772–S772. Crossref, doi:10.1016/j.ijrobp.2014.05.2235.
Source
crossref
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
90
Issue
1
Publish Date
2014
Start Page
S772
End Page
S772
DOI
10.1016/j.ijrobp.2014.05.2235

Tuning optical properties of difluoroboron beta-diketonate biomaterials for oxygen sensing

Authors
Fraser, CL; DeRosa, C; Samonina-Kosicka, J; Morris, WA; Fan, Z; Demas, JN; Mathew, A; Palmer, GM; Dewhirst, MW; Hofmann, CL; Hendargo, H
MLA Citation
Fraser, Cassandra L., et al. “Tuning optical properties of difluoroboron beta-diketonate biomaterials for oxygen sensing.” Abstracts of Papers of the American Chemical Society, vol. 248, AMER CHEMICAL SOC, 2014.
Source
wos
Published In
Abstracts of Papers of the American Chemical Society
Volume
248
Publish Date
2014

Boron nanoparticles for oxygen sensing: Material design, optical properties, and bioimaging

Authors
Samonina-Kosicka, J; DeRosa, C; Hofmann, CL; Hendargo, H; Dewhirst, MW; Palmer, GM; Fraser, CL
MLA Citation
Samonina-Kosicka, Jelena, et al. “Boron nanoparticles for oxygen sensing: Material design, optical properties, and bioimaging.” Abstracts of Papers of the American Chemical Society, vol. 248, AMER CHEMICAL SOC, 2014.
Source
wos
Published In
Abstracts of Papers of the American Chemical Society
Volume
248
Publish Date
2014

Rationalization of thermal injury quantification methods: application to skin burns.

Classification of thermal injury is typically accomplished either through the use of an equivalent dosimetry method (equivalent minutes at 43 °C, CEM43 °C) or through a thermal-injury-damage metric (the Arrhenius method). For lower-temperature levels, the equivalent dosimetry approach is typically employed while higher-temperature applications are most often categorized by injury-damage calculations. The two methods derive from common thermodynamic/physical chemistry origins. To facilitate the development of the interrelationships between the two metrics, application is made to the case of skin burns. This thermal insult has been quantified by numerical simulation, and the extracted time-temperature results served for the evaluation of the respective characterizations. The simulations were performed for skin-surface exposure temperatures ranging from 60 to 90 °C, where each surface temperature was held constant for durations extending from 10 to 110 s. It was demonstrated that values of CEM43 at the basal layer of the skin were highly correlated with the depth of injury calculated from a thermal injury integral. Local values of CEM43 were connected to the local cell survival rate, and a correlating equation was developed relating CEM43 with the decrease in cell survival from 90% to 10%. Finally, it was shown that the cell survival/CEM43 relationship for the cases investigated here most closely aligns with isothermal exposure of tissue to temperatures of ~50 °C.

Authors
Viglianti, BL; Dewhirst, MW; Abraham, JP; Gorman, JM; Sparrow, EM
MLA Citation
Viglianti, Benjamin L., et al. “Rationalization of thermal injury quantification methods: application to skin burns..” Burns, vol. 40, no. 5, Aug. 2014, pp. 896–902. Pubmed, doi:10.1016/j.burns.2013.12.005.
PMID
24418648
Source
pubmed
Published In
Burns
Volume
40
Issue
5
Publish Date
2014
Start Page
896
End Page
902
DOI
10.1016/j.burns.2013.12.005

Verification of a novel method for tube voltage constancy measurement of orthovoltage x-ray irradiators.

PURPOSE: For orthovoltage x-ray irradiators, the tube voltage is one of the most fundamental system parameters as this directly relates to the dosimetry in radiation biology studies; however, to the best of our knowledge, there is no commercial portable quality assurance (QA) tool to directly test the constancy of the tube voltage greater than 160 kV. The purpose of this study is to establish the Beam Quality Index (BQI), a quantity strongly correlated to the tube voltage, as an alternative parameter for the verification of the tube voltage as part of the QA program of orthovoltage x-ray irradiators. METHODS: A multipurpose QA meter and its associated data acquisition software were used to customize the measurement parameters to measure the BQI and collect its time-plot. BQI measurements were performed at 320 kV with four filtration levels on three orthovoltage x-ray irradiators of the same model, one of which had been recently energy-calibrated at the factory. RESULTS: For each of the four filtration levels, the measured BQI values were in good agreement (<5%) between the three irradiators. BQI showed filtration-specificity, possibly due to the difference in beam quality. CONCLUSIONS: The BQI has been verified as a feasible alternative for monitoring the constancy of the tube voltage for orthovoltage irradiators. The time-plot of BQI offers information on the behavior of beam energy at different phases of the irradiation time line. In addition, this would provide power supply performance characteristics from initial ramp-up to plateau, and finally, the sharp drop-off at the end of the exposure.

Authors
Wang, C; Belley, MD; Chao, NJ; Dewhirst, MW; Yoshizumi, T
MLA Citation
Wang, Chu, et al. “Verification of a novel method for tube voltage constancy measurement of orthovoltage x-ray irradiators..” Med Phys, vol. 41, no. 8, Aug. 2014. Pubmed, doi:10.1118/1.4889778.
PMID
25086562
Source
pubmed
Published In
Med Phys
Volume
41
Issue
8
Publish Date
2014
Start Page
084101
DOI
10.1118/1.4889778

Two phase I dose-escalation/pharmacokinetics studies of low temperature liposomal doxorubicin (LTLD) and mild local hyperthermia in heavily pretreated patients with local regionally recurrent breast cancer.

PURPOSE: Unresectable chest wall recurrences of breast cancer (CWR) in heavily pretreated patients are especially difficult to treat. We hypothesised that thermally enhanced drug delivery using low temperature liposomal doxorubicin (LTLD), given with mild local hyperthermia (MLHT), will be safe and effective in this population. PATIENTS AND METHODS: This paper combines the results of two similarly designed phase I trials. Eligible CWR patients had progressed on the chest wall after prior hormone therapy, chemotherapy, and radiotherapy. Patients were to get six cycles of LTLD every 21-35 days, followed immediately by chest wall MLHT for 1 hour at 40-42 °C. In the first trial 18 subjects received LTLD at 20, 30, or 40 mg/m2; in the second trial, 11 subjects received LTLD at 40 or 50 mg/m2. RESULTS: The median age of all 29 patients enrolled was 57 years. Thirteen patients (45%) had distant metastases on enrolment. Patients had received a median dose of 256 mg/m2 of prior anthracyclines and a median dose of 61 Gy of prior radiation. The median number of study treatments that subjects completed was four. The maximum tolerated dose was 50 mg/m2, with seven subjects (24%) developing reversible grade 3-4 neutropenia and four (14%) reversible grade 3-4 leucopenia. The rate of overall local response was 48% (14/29, 95% CI: 30-66%), with. five patients (17%) achieving complete local responses and nine patients (31%) having partial local responses. CONCLUSION: LTLD at 50 mg/m2 and MLHT is safe. This combined therapy produces objective responses in heavily pretreated CWR patients. Future work should test thermally enhanced LTLD delivery in a less advanced patient population.

Authors
Zagar, TM; Vujaskovic, Z; Formenti, S; Rugo, H; Muggia, F; O'Connor, B; Myerson, R; Stauffer, P; Hsu, I-C; Diederich, C; Straube, W; Boss, M-K; Boico, A; Craciunescu, O; Maccarini, P; Needham, D; Borys, N; Blackwell, KL; Dewhirst, MW
MLA Citation
Zagar, Timothy M., et al. “Two phase I dose-escalation/pharmacokinetics studies of low temperature liposomal doxorubicin (LTLD) and mild local hyperthermia in heavily pretreated patients with local regionally recurrent breast cancer..” Int J Hyperthermia, vol. 30, no. 5, Aug. 2014, pp. 285–94. Pubmed, doi:10.3109/02656736.2014.936049.
PMID
25144817
Source
pubmed
Published In
Int J Hyperthermia
Volume
30
Issue
5
Publish Date
2014
Start Page
285
End Page
294
DOI
10.3109/02656736.2014.936049

Hyperspectral imaging of glucose uptake, mitochondrial membrane potential, and vascular oxygenation differentiates breast cancers with distinct metastatic potential in vivo

© OSA 2016. We performed in vivo hyperspectral imaging in a preclinical cancer model to capture key metabolic endpoints (glucose uptake, mitochondrial membrane potential, and vascular oxygenation) to successfully distinguish metastatic and non-metastatic tumors.

Authors
Martinez, AF; McCachren, SS; Lee, M; Murphy, HA; Rajaram, N; Dewhirst, MW; Ramanujam, N
MLA Citation
Martinez, A. F., et al. “Hyperspectral imaging of glucose uptake, mitochondrial membrane potential, and vascular oxygenation differentiates breast cancers with distinct metastatic potential in vivo.” Optics Infobase Conference Papers, 2014. Scopus, doi:10.1364/CANCER.2016.CTh4A.6.
Source
scopus
Published In
Optics Infobase Conference Papers
Publish Date
2014
DOI
10.1364/CANCER.2016.CTh4A.6

Imaging tumor hypoxia to advance radiation oncology.

SIGNIFICANCE: Most solid tumors contain regions of low oxygenation or hypoxia. Tumor hypoxia has been associated with a poor clinical outcome and plays a critical role in tumor radioresistance. RECENT ADVANCES: Two main types of hypoxia exist in the tumor microenvironment: chronic and cycling hypoxia. Chronic hypoxia results from the limited diffusion distance of oxygen, and cycling hypoxia primarily results from the variation in microvessel red blood cell flux and temporary disturbances in perfusion. Chronic hypoxia may cause either tumor progression or regressive effects depending on the tumor model. However, there is a general trend toward the development of a more aggressive phenotype after cycling hypoxia. With advanced hypoxia imaging techniques, spatiotemporal characteristics of tumor hypoxia and the changes to the tumor microenvironment can be analyzed. CRITICAL ISSUES: In this review, we focus on the biological and clinical consequences of chronic and cycling hypoxia on radiation treatment. We also discuss the advanced non-invasive imaging techniques that have been developed to detect and monitor tumor hypoxia in preclinical and clinical studies. FUTURE DIRECTIONS: A better understanding of the mechanisms of tumor hypoxia with non-invasive imaging will provide a basis for improved radiation therapeutic practices.

Authors
Lee, C-T; Boss, M-K; Dewhirst, MW
MLA Citation
Lee, Chen-Ting, et al. “Imaging tumor hypoxia to advance radiation oncology..” Antioxid Redox Signal, vol. 21, no. 2, July 2014, pp. 313–37. Pubmed, doi:10.1089/ars.2013.5759.
PMID
24329000
Source
pubmed
Published In
Antioxid Redox Signal
Volume
21
Issue
2
Publish Date
2014
Start Page
313
End Page
337
DOI
10.1089/ars.2013.5759

Making microvascular networks work: angiogenesis, remodeling and pruning

Authors
Pries, AR; Reglin, B; Dewhirst, MW; Secomb, TW
MLA Citation
Pries, Axel R., et al. “Making microvascular networks work: angiogenesis, remodeling and pruning.” Angiogenesis, vol. 17, no. 3, SPRINGER, July 2014, pp. 716–716.
Source
wos
Published In
Angiogenesis
Volume
17
Issue
3
Publish Date
2014
Start Page
716
End Page
716

Comparison of the Hypoxia PET Tracer (18)F-EF5 to Immunohistochemical Marker EF5 in 3 Different Human Tumor Xenograft Models.

UNLABELLED: The availability of (18)F-labeled and unlabeled 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide (EF5) allows for a comparative assessment of tumor hypoxia by PET and immunohistochemistry; however, the combined use of these 2 approaches has not been fully assessed in vivo. The aim of this study was to evaluate (18)F-EF5 tumor uptake versus EF5 binding and hypoxia as determined from immunohistochemistry at both macroscopic and microregional levels. METHODS: Three tumor models-PC3, HCT116, and H460-were evaluated. Tumor-bearing animals were coinjected with (18)F-EF5 and EF5 (30 mg/kg), and PET imaging was performed at 2.5 h after injection. After PET imaging and 2 min after Hoechst 33342 injection, the tumors were excised and evaluated for (18)F-EF5 distribution by autoradiography and EF5 binding by immunohistochemistry. Additionally, the effects of nonradioactive EF5 (30 mg/kg) on the hypoxia-imaging characteristics of (18)F-EF5 were evaluated by comparing the PET data for H460 tumors with those from animals injected with (18)F-EF5 alone. RESULTS: The uptake of (18)F-EF5 in hypoxic tumor regions and the spatial relationship between (18)F-EF5 uptake and EF5 binding varied among tumors. H460 tumors showed higher tumor-to-muscle contrast in PET imaging; however, the distribution and uptake of the tracer was less specific for hypoxia in H460 than in HCT116 and PC3 tumors. Correlation analyses revealed that the highest spatial correlation between (18)F-EF5 uptake and EF5 binding was in PC3 tumors (r = 0.73 ± 0.02) followed by HCT116 (r = 0.60 ± 0.06) and H460 (r = 0.53 ± 0.10). Uptake and binding of (18)F-EF5 and EF5 correlated negatively with Hoechst 33342 perfusion marker distribution in the 3 tumor models. Image contrast and heterogeneous uptake of (18)F-EF5 in H460 tumors was significantly higher when the radiotracer was used alone versus in combination with unlabeled EF5 (tumor-to-muscle ratio of 2.51 ± 0.33 vs. 1.71 ± 0.17, P < 0.001). CONCLUSION: The uptake and hypoxia selectivity of (18)F-EF5 varied among tumor models when animals also received nonradioactive EF5. Combined use of radioactive and nonradioactive EF5 for independent assessment of tumor hypoxia by PET and immunohistochemistry methods is promising; however, the EF5 drug concentrations that are required for immunohistochemistry assays may affect the uptake of (18)F-EF5 in hypoxic cells in certain tumor types as observed in H460 in this study.

Authors
Chitneni, SK; Bida, GT; Zalutsky, MR; Dewhirst, MW
MLA Citation
Chitneni, Satish K., et al. “Comparison of the Hypoxia PET Tracer (18)F-EF5 to Immunohistochemical Marker EF5 in 3 Different Human Tumor Xenograft Models..” J Nucl Med, vol. 55, no. 7, July 2014, pp. 1192–97. Pubmed, doi:10.2967/jnumed.114.137448.
PMID
24854792
Source
pubmed
Published In
Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
Volume
55
Issue
7
Publish Date
2014
Start Page
1192
End Page
1197
DOI
10.2967/jnumed.114.137448

Measuring tumor cycling hypoxia and angiogenesis using a side-firing fiber optic probe.

Hypoxia and angiogenesis can significantly influence the efficacy of cancer therapy and the behavior of surviving tumor cells. There is a growing demand for technologies to measure tumor hypoxia and angiogenesis temporally in vivo to enable advances in drug development and optimization. This paper reports the use of frequency-domain photon migration with a side-firing probe to quantify tumor oxygenation and hemoglobin concentrations in nude rats bearing human head/neck tumors administered with carbogen gas, cycling hypoxic gas or just room air. Significant increase (with carbogen gas breathing) or decrease (with hypoxic gas breathing) in tumor oxygenation was observed. The trend in tumor oxygenation during forced cycling hypoxia (CH) followed that of the blood oxygenation measured with a pulse oximeter. Natural CH was also observed in rats under room air. The studies demonstrated the potential of the technology for longitudinal monitoring of tumor CH during tumor growth or in response to therapy.

Authors
Yu, B; Shah, A; Wang, B; Rajaram, N; Wang, Q; Ramanujam, N; Palmer, GM; Dewhirst, MW
MLA Citation
Yu, Bing, et al. “Measuring tumor cycling hypoxia and angiogenesis using a side-firing fiber optic probe..” J Biophotonics, vol. 7, no. 7, July 2014, pp. 552–64. Pubmed, doi:10.1002/jbio.201200187.
PMID
23242854
Source
pubmed
Published In
J Biophotonics
Volume
7
Issue
7
Publish Date
2014
Start Page
552
End Page
564
DOI
10.1002/jbio.201200187

Linking the history of radiation biology to the hallmarks of cancer.

Hanahan and Weinberg recently updated their conceptual framework of the "Hallmarks of Cancer". The original article, published in 2000, is among the most highly cited reviews in the field of oncology. The goal of this review is to highlight important discoveries in radiation biology that pertain to the Hallmarks. We identified early studies that exemplified how ionizing radiation affects the hallmarks or how radiation was used experimentally to advance the understanding of key hallmarks. A literature search was performed to obtain relevant primary research, and topics were assigned to a particular hallmark to allow an organized, chronological account of the radiobiological advancements. The hallmarks are reviewed in an order that flows from cellular to microenvironmental effects.

Authors
Boss, M-K; Bristow, R; Dewhirst, MW
MLA Citation
Boss, Mary-Keara, et al. “Linking the history of radiation biology to the hallmarks of cancer..” Radiat Res, vol. 181, no. 6, June 2014, pp. 561–77. Pubmed, doi:10.1667/RR13675.1.
PMID
24811865
Source
pubmed
Published In
Radiat Res
Volume
181
Issue
6
Publish Date
2014
Start Page
561
End Page
577
DOI
10.1667/RR13675.1

Rational design of "heat seeking" drug loaded polypeptide nanoparticles that thermally target solid tumors.

This paper demonstrates the first example of targeting a solid tumor that is externally heated to 42 °C by "heat seeking" drug-loaded polypeptide nanoparticles. These nanoparticles consist of a thermally responsive elastin-like polypeptide (ELP) conjugated to multiple copies of a hydrophobic cancer drug. To rationally design drug-loaded nanoparticles that exhibit thermal responsiveness in the narrow temperature range between 37 and 42 °C, an analytical model was developed that relates ELP composition and chain length to the nanoparticle phase transition temperature. Suitable candidates were designed based on the predictions of the model and tested in vivo by intravital confocal fluorescence microscopy of solid tumors, which revealed that the nanoparticles aggregate in the vasculature of tumors heated to 42 °C and that the aggregation is reversible as the temperature reverts to 37 °C. Biodistribution studies showed that the most effective strategy to target the nanoparticles to tumors is to thermally cycle the tumors between 37 and 42 °C. These nanoparticles set the stage for the targeted delivery of a range of cancer chemotherapeutics by externally applied mild hyperthermia of solid tumors.

Authors
McDaniel, JR; MacEwan, SR; Li, X; Radford, DC; Landon, CD; Dewhirst, M; Chilkoti, A
MLA Citation
McDaniel, Jonathan R., et al. “Rational design of "heat seeking" drug loaded polypeptide nanoparticles that thermally target solid tumors..” Nano Lett, vol. 14, no. 5, May 2014, pp. 2890–95. Pubmed, doi:10.1021/nl5009376.
PMID
24738626
Source
pubmed
Published In
Nano Letters
Volume
14
Issue
5
Publish Date
2014
Start Page
2890
End Page
2895
DOI
10.1021/nl5009376

A pilot clinical trial of intravesical mitomycin-C and external deep pelvic hyperthermia for non-muscle-invasive bladder cancer.

PURPOSE: This paper aims to evaluate the safety and heating efficiency of external deep pelvic hyperthermia combined with intravesical mitomycin C (MMC) as a novel therapy for non-muscle-invasive bladder cancer (NMIBC). MATERIALS AND METHODS: We enrolled subjects with bacillus Calmette-Guérin (BCG) refractory NMIBC to an early phase clinical trial of external deep pelvic hyperthermia (using a BSD-2000 device) combined with MMC. Bladders were heated to 42 °C for 1 h during intravesical MMC treatment. Treatments were given weekly for 6 weeks, then monthly for 4 months. Heating parameters, treatment toxicity, and clinical outcomes were systematically measured. RESULTS: Fifteen patients were enrolled on the clinical trial. Median age was 66 years and 87% were male. Median European Organisation for Research and Treatment of Cancer (EORTC) recurrence and progression scores were 6 and 8, respectively. The full treatment course was attained in 73% of subjects. Effective bladder heating was possible in all but one patient who could not tolerate the supine position due to lung disease. Adverse events were all minor (grade 2 or less) and no systemic toxicity was observed. The most common adverse effects were Foley catheter pain (40%), abdominal discomfort (33%), chemical cystitis symptoms (27%), and abdominal skin swelling (27%). With a median follow-up of 3.18 years, 67% experienced another bladder cancer recurrence (none were muscle invasive) and 13% experienced an upper tract recurrence. CONCLUSIONS: External deep pelvic hyperthermia using the BSD-2000 device is a safe and reproducible method of heating the bladder in patients undergoing intravesical MMC. The efficacy of this treatment modality should be explored further in clinical trials.

Authors
Inman, BA; Stauffer, PR; Craciunescu, OA; Maccarini, PF; Dewhirst, MW; Vujaskovic, Z
MLA Citation
Inman, Brant A., et al. “A pilot clinical trial of intravesical mitomycin-C and external deep pelvic hyperthermia for non-muscle-invasive bladder cancer..” Int J Hyperthermia, vol. 30, no. 3, May 2014, pp. 171–75. Pubmed, doi:10.3109/02656736.2014.882021.
PMID
24490762
Source
pubmed
Published In
Int J Hyperthermia
Volume
30
Issue
3
Publish Date
2014
Start Page
171
End Page
175
DOI
10.3109/02656736.2014.882021

Thermal dosimetry characteristics of deep regional heating of non-muscle invasive bladder cancer.

PURPOSE: The aim of this paper is to report thermal dosimetry characteristics of external deep regional pelvic hyperthermia combined with intravesical mitomycin C (MMC) for treating bladder cancer following transurethral resection of bladder tumour, and to use thermal data to evaluate reliability of delivering the prescribed hyperthermia dose to bladder tissue. MATERIALS AND METHODS: A total of 14 patients were treated with MMC and deep regional hyperthermia (BSD-2000, Sigma Ellipse or Sigma 60). The hyperthermia objective was 42° ± 2 °C to bladder tissue for ≥40 min per treatment. Temperatures were monitored with thermistor probes and recorded values were used to calculate thermal dose and evaluate treatment. Anatomical characteristics were examined for possible correlations with heating. RESULTS: Combined with BSD-2000 standard treatment planning and patient feedback, real-time temperature monitoring allowed thermal steering of heat sufficient to attain the prescribed thermal dose to bladder tissue within patient tolerance in 91.6% of treatments. Mean treatment time for bladder tissue >40 °C was 61.9 ± 11.4 min and mean thermal dose was 21.3 ± 16.5 CEM43. Average thermal doses obtained in normal tissues were 1.6 ± 1.2 CEM43 for the rectum and 0.8 ± 1.3 CEM43 in superficial normal tissues. No significant correlation was seen between patient anatomical characteristics and thermal dose achieved in bladder tissue. CONCLUSIONS: This study demonstrates that a hyperthermia prescription of 42° ± 2 °C for 40-60 min can be delivered safely to bladder tissue with external radiofrequency phased array applicators for a typical range of patient sizes. Using the available thermometry and treatment planning, the BSD-2000 hyperthermia system was shown to be an effective method of focusing heat regionally around the bladder with good patient tolerance.

Authors
Juang, T; Stauffer, PR; Craciunescu, OA; Maccarini, PF; Yuan, Y; Das, SK; Dewhirst, MW; Inman, BA; Vujaskovic, Z
MLA Citation
Juang, Titania, et al. “Thermal dosimetry characteristics of deep regional heating of non-muscle invasive bladder cancer..” Int J Hyperthermia, vol. 30, no. 3, May 2014, pp. 176–83. Pubmed, doi:10.3109/02656736.2014.898338.
PMID
24669804
Source
pubmed
Published In
Int J Hyperthermia
Volume
30
Issue
3
Publish Date
2014
Start Page
176
End Page
183
DOI
10.3109/02656736.2014.898338

Hypoxia in melanoma: using optical spectroscopy and EF5 to assess tumor oxygenation before and during regional chemotherapy for melanoma.

BACKGROUND: There is increasing evidence that tumor hypoxia plays a significant role in the chemoresistance of melanoma, but to our knowledge, real-time tumor oxygenation during isolated limb infusion (ILI) has not been studied. We sought to demonstrate the feasibility of measuring real-time alterations in tissue oxygenation. METHODS: Consecutive patients with histologically confirmed in-transit melanoma were enrolled onto a prospective single-arm pilot study and administered the hypoxia marker drug EF5. All patients were treated with ILI. Optical spectroscopy readings were obtained at three locations: two discrete target lesions and one normal skin control. Measurements were taken at 11 predefined time points during ILI. RESULTS: A total of six patients were enrolled onto this pilot study. Intratumor and normal skin optical spectroscopy readings were found to have discrete inflection points throughout the duration of therapy, corresponding with established time points. Baseline hypoxia as measured by both optical spectroscopy and EF5 immunofluorescence was variable, but on the basis of optical spectra, tumors appeared to become more hypoxic compared to normal skin after tourniquet application. The optical hypoxia signature was variable between patients while hemoglobin absorption increased. CONCLUSIONS: To our knowledge, this is the first use of real-time optical spectroscopy to evaluate oxygenation and perfusion within melanoma lesions during regional chemotherapy. We report our development of this new noninvasive means of assessing tumor vascular function, which has the potential to be a powerful tool for noninvasive examination of the melanoma tumor microenvironment.

Authors
Speicher, PJ; Beasley, GM; Jiang, B; Lidsky, ME; Palmer, GM; Scarbrough, PM; Mosca, PJ; Dewhirst, MW; Tyler, DS
MLA Citation
Speicher, Paul J., et al. “Hypoxia in melanoma: using optical spectroscopy and EF5 to assess tumor oxygenation before and during regional chemotherapy for melanoma..” Ann Surg Oncol, vol. 21, no. 5, May 2014, pp. 1435–40. Pubmed, doi:10.1245/s10434-013-3222-0.
PMID
23982250
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
21
Issue
5
Publish Date
2014
Start Page
1435
End Page
1440
DOI
10.1245/s10434-013-3222-0

Therapeutic properties of aerobic training after a cancer diagnosis: more than a one-trick pony?

Authors
Jones, LW; Dewhirst, MW
MLA Citation
Jones, Lee W., and Mark W. Dewhirst. “Therapeutic properties of aerobic training after a cancer diagnosis: more than a one-trick pony?.” J Natl Cancer Inst, vol. 106, no. 4, Apr. 2014. Pubmed, doi:10.1093/jnci/dju042.
PMID
24627274
Source
pubmed
Published In
J Natl Cancer Inst
Volume
106
Issue
4
Publish Date
2014
Start Page
dju042
DOI
10.1093/jnci/dju042

Oxygen nanosensors based on dual emissive difluoroboron naphthyl alpha-diketonate polylactides for ratiometric tumor hypoxia imaging

Authors
DeRosa, CA; Samonina-Kosicka, J; Fan, Z; Hofmann, CL; Palmer, GM; Dewhirst, MW; Fraser, CL
MLA Citation
DeRosa, Christopher A., et al. “Oxygen nanosensors based on dual emissive difluoroboron naphthyl alpha-diketonate polylactides for ratiometric tumor hypoxia imaging.” Abstracts of Papers of the American Chemical Society, vol. 247, AMER CHEMICAL SOC, 2014.
Source
wos
Published In
Abstracts of Papers of the American Chemical Society
Volume
247
Publish Date
2014

Toward an organ based dose prescription method for the improved accuracy of murine dose in orthovoltage x-ray irradiators.

PURPOSE: Accurate dosimetry is essential when irradiating mice to ensure that functional and molecular endpoints are well understood for the radiation dose delivered. Conventional methods of prescribing dose in mice involve the use of a single dose rate measurement and assume a uniform average dose throughout all organs of the entire mouse. Here, the authors report the individual average organ dose values for the irradiation of a 12, 23, and 33 g mouse on a 320 kVp x-ray irradiator and calculate the resulting error from using conventional dose prescription methods. METHODS: Organ doses were simulated in the Geant4 application for tomographic emission toolkit using the MOBY mouse whole-body phantom. Dosimetry was performed for three beams utilizing filters A (1.65 mm Al), B (2.0 mm Al), and C (0.1 mm Cu + 2.5 mm Al), respectively. In addition, simulated x-ray spectra were validated with physical half-value layer measurements. RESULTS: Average doses in soft-tissue organs were found to vary by as much as 23%-32% depending on the filter. Compared to filters A and B, filter C provided the hardest beam and had the lowest variation in soft-tissue average organ doses across all mouse sizes, with a difference of 23% for the median mouse size of 23 g. CONCLUSIONS: This work suggests a new dose prescription method in small animal dosimetry: it presents a departure from the conventional approach of assigninga single dose value for irradiation of mice to a more comprehensive approach of characterizing individual organ doses to minimize the error and uncertainty. In human radiation therapy, clinical treatment planning establishes the target dose as well as the dose distribution, however, this has generally not been done in small animal research. These results suggest that organ dose errors will be minimized by calibrating the dose rates for all filters, and using different dose rates for different organs.

Authors
Belley, MD; Wang, C; Nguyen, G; Gunasingha, R; Chao, NJ; Chen, BJ; Dewhirst, MW; Yoshizumi, TT
MLA Citation
Belley, Matthew D., et al. “Toward an organ based dose prescription method for the improved accuracy of murine dose in orthovoltage x-ray irradiators..” Med Phys, vol. 41, no. 3, Mar. 2014. Pubmed, doi:10.1118/1.4864237.
PMID
24593746
Source
pubmed
Published In
Med Phys
Volume
41
Issue
3
Publish Date
2014
Start Page
034101
DOI
10.1118/1.4864237

Corrigendum

MLA Citation
Corrigendum.” Microcirculation, vol. 21, no. 2, Wiley, Feb. 2014, pp. 196–196. Crossref, doi:10.1111/micc.12118.
Source
crossref
Published In
Microcirculation (New York, N.Y. : 1994)
Volume
21
Issue
2
Publish Date
2014
Start Page
196
End Page
196
DOI
10.1111/micc.12118

Hypoxia in melanoma: Using optical spectroscopy and EF5 to assess tumor oxygenation before and during regional chemotherapy for melanoma

Background: There is increasing evidence that tumor hypoxia plays a significant role in the chemoresistance of melanoma, but to our knowledge, real-time tumor oxygenation during isolated limb infusion (ILI) has not been studied. We sought to demonstrate the feasibility of measuring real-time alterations in tissue oxygenation. Methods: Consecutive patients with histologically confirmed in-transit melanoma were enrolled onto a prospective single-arm pilot study and administered the hypoxia marker drug EF5. All patients were treated with ILI. Optical spectroscopy readings were obtained at three locations: two discrete target lesions and one normal skin control. Measurements were taken at 11 predefined time points during ILI. Results: A total of six patients were enrolled onto this pilot study. Intratumor and normal skin optical spectroscopy readings were found to have discrete inflection points throughout the duration of therapy, corresponding with established time points. Baseline hypoxia as measured by both optical spectroscopy and EF5 immunofluorescence was variable, but on the basis of optical spectra, tumors appeared to become more hypoxic compared to normal skin after tourniquet application. The optical hypoxia signature was variable between patients while hemoglobin absorption increased. Conclusions: To our knowledge, this is the first use of real-time optical spectroscopy to evaluate oxygenation and perfusion within melanoma lesions during regional chemotherapy. We report our development of this new noninvasive means of assessing tumor vascular function, which has the potential to be a powerful tool for noninvasive examination of the melanoma tumor microenvironment. © 2013 Society of Surgical Oncology.

Authors
Speicher, PJ; Beasley, GM; Jiang, B; Lidsky, ME; Palmer, GM; Scarbrough, PM; Mosca, PJ; Dewhirst, MW; Tyler, DS
MLA Citation
Speicher, P. J., et al. “Hypoxia in melanoma: Using optical spectroscopy and EF5 to assess tumor oxygenation before and during regional chemotherapy for melanoma.” Annals of Surgical Oncology, vol. 21, no. 5, Jan. 2014, pp. 1435–40. Scopus, doi:10.1245/s10434-013-3222-0.
Source
scopus
Published In
Annals of Surgical Oncology
Volume
21
Issue
5
Publish Date
2014
Start Page
1435
End Page
1440
DOI
10.1245/s10434-013-3222-0

Optical monitoring of glucose demand and vascular delivery in a preclinical murine model

Targeted therapies such as PI3K inhibition can affect tumor vasculature, and hence delivery of imaging agents like FDG, while independently modifying intrinsic glucose demand. Therefore, it is important to identify whether perceived changes in glucose uptake are caused by vascular or true metabolic changes. This study sought to develop an optical strategy for quantifying tissue glucose uptake free of cross-talk from tracer delivery effects. Glucose uptake kinetics were measured using a fluorescent D-glucose derivative 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-deoxy-Dglucose (2-NBDG), and 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-deoxy-L-glucose (2-NBDLG) was used as a control to report on non-specific uptake. Vascular oxygenation (SO2) was calculated from wavelength-dependent hemoglobin absorption. We have previously shown that the rate of 2-NBDG delivery in vivo profoundly affects perceived demand. In this study, we investigated the potential of the ratio of 2-NBDG uptake to the rate of delivery (2-NBDG60/R D) to report on 2-NBDG demand in vivo free from confounding delivery effects. In normal murine tissue, we show that 2-NBDG60/RD can distinguish specific uptake from non-specific cell membrane binding, whereas fluorescence intensity alone cannot. The ratio 2-NBDG 60/RD also correlates with blood glucose more strongly than 2-NBDG60 does in normal murine tissue. Additionally, 2-NBDG 60/RD can distinguish normal murine tissue from a murine metastatic tumor across a range of SO2 values. The results presented here indicate that the ratio of 2-NBDG uptake to the rate of 2-NBDG delivery (2- NBDG60/RD) is superior to 2-NBDG intensity alone for quantifying changes in glucose demand. © 2014 SPIE.

Authors
Frees, A; Rajaram, N; McCachren, S; Vaz, A; Dewhirst, M; Ramanujam, N
MLA Citation
Frees, A., et al. “Optical monitoring of glucose demand and vascular delivery in a preclinical murine model.” Progress in Biomedical Optics and Imaging  Proceedings of Spie, vol. 8947, 2014. Scopus, doi:10.1117/12.2040950.
Source
scopus
Published In
Progress in Biomedical Optics and Imaging Proceedings of Spie
Volume
8947
Publish Date
2014
DOI
10.1117/12.2040950

Rationalization of thermal injury quantification methods: Application to skin burns

Classification of thermal injury is typically accomplished either through the use of an equivalent dosimetry method (equivalent minutes at 43 °C, CEM43 °C) or through a thermal-injury-damage metric (the Arrhenius method). For lower-temperature levels, the equivalent dosimetry approach is typically employed while higher-temperature applications are most often categorized by injury-damage calculations. The two methods derive from common thermodynamic/physical chemistry origins. To facilitate the development of the interrelationships between the two metrics, application is made to the case of skin burns. This thermal insult has been quantified by numerical simulation, and the extracted time-temperature results served for the evaluation of the respective characterizations. The simulations were performed for skin-surface exposure temperatures ranging from 60 to 90 °C, where each surface temperature was held constant for durations extending from 10 to 110 s. It was demonstrated that values of CEM43 at the basal layer of the skin were highly correlated with the depth of injury calculated from a thermal injury integral. Local values of CEM43 were connected to the local cell survival rate, and a correlating equation was developed relating CEM43 with the decrease in cell survival from 90% to 10%. Finally, it was shown that the cell survival/CEM43 relationship for the cases investigated here most closely aligns with isothermal exposure of tissue to temperatures of ∼50 °C. © 2013 Elsevier Ltd and ISBI.

Authors
Viglianti, BL; Dewhirst, MW; Abraham, JP; Gorman, JM; Sparrow, EM
MLA Citation
Viglianti, B. L., et al. “Rationalization of thermal injury quantification methods: Application to skin burns.” Burns, vol. 40, no. 5, Jan. 2014, pp. 896–902. Scopus, doi:10.1016/j.burns.2013.12.005.
Source
scopus
Published In
Burns : Journal of the International Society for Burn Injuries
Volume
40
Issue
5
Publish Date
2014
Start Page
896
End Page
902
DOI
10.1016/j.burns.2013.12.005

Anti-hypotensive treatment and endothelin blockade synergistically antagonize exercise fatigue in rats under simulated high altitude.

Rapid ascent to high altitude causes illness and fatigue, and there is a demand for effective acute treatments to alleviate such effects. We hypothesized that increased oxygen delivery to the tissue using a combination of a hypertensive agent and an endothelin receptor A antagonist drugs would limit exercise-induced fatigue at simulated high altitude. Our data showed that the combination of 0.1 mg/kg ambrisentan with either 20 mg/kg ephedrine or 10 mg/kg methylphenidate significantly improved exercise duration in rats at simulated altitude of 4,267 m, whereas the individual compounds did not. In normoxic, anesthetized rats, ephedrine alone and in combination with ambrisentan increased heart rate, peripheral blood flow, carotid and pulmonary arterial pressures, breathing rate, and vastus lateralis muscle oxygenation, but under inspired hypoxia, only the combination treatment significantly enhanced muscle oxygenation. Our results suggest that sympathomimetic agents combined with endothelin-A receptor blockers offset altitude-induced fatigue in rats by synergistically increasing the delivery rate of oxygen to hypoxic muscle by concomitantly augmenting perfusion pressure and improving capillary conductance in the skeletal muscle. Our findings might therefore serve as a basis to develop an effective treatment to prevent high-altitude illness and fatigue in humans.

Authors
Radiloff, D; Zhao, Y; Boico, A; Blueschke, G; Palmer, G; Fontanella, A; Dewhirst, M; Piantadosi, CA; Noveck, R; Irwin, D; Hamilton, K; Klitzman, B; Schroeder, T
MLA Citation
Radiloff, Daniel, et al. “Anti-hypotensive treatment and endothelin blockade synergistically antagonize exercise fatigue in rats under simulated high altitude..” Plos One, vol. 9, no. 6, 2014. Pubmed, doi:10.1371/journal.pone.0099309.
Website
http://hdl.handle.net/10161/10340
PMID
24960187
Source
pubmed
Published In
Plos One
Volume
9
Issue
6
Publish Date
2014
Start Page
e99309
DOI
10.1371/journal.pone.0099309

Delivery-corrected imaging of fluorescently-labeled glucose reveals distinct metabolic phenotypes in murine breast cancer.

When monitoring response to cancer therapy, it is important to differentiate changes in glucose tracer uptake caused by altered delivery versus a true metabolic shift. Here, we propose an optical imaging method to quantify glucose uptake and correct for in vivo delivery effects. Glucose uptake was measured using a fluorescent D-glucose derivative 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-deoxy-D-glucose (2-NBDG) in mice implanted with dorsal skin flap window chambers. Additionally, vascular oxygenation (SO2) was calculated using only endogenous hemoglobin contrast. Results showed that the delivery factor proposed for correction, "RD", reported on red blood cell velocity and injected 2-NBDG dose. Delivery-corrected 2-NBDG uptake (2-NBDG60/RD) inversely correlated with blood glucose in normal tissue, indicating sensitivity to glucose demand. We further applied our method in metastatic 4T1 and nonmetastatic 4T07 murine mammary adenocarcinomas. The ratio 2-NBDG60/RD was increased in 4T1 tumors relative to 4T07 tumors yet average SO2 was comparable, suggesting a shift toward a "Warburgian" (aerobic glycolysis) metabolism in the metastatic 4T1 line. In heterogeneous regions of both 4T1 and 4T07, 2-NBDG60/RD increased slightly but significantly as vascular oxygenation decreased, indicative of the Pasteur effect in both tumors. These data demonstrate the utility of delivery-corrected 2-NBDG and vascular oxygenation imaging for differentiating metabolic phenotypes in vivo.

Authors
Frees, AE; Rajaram, N; McCachren, SS; Fontanella, AN; Dewhirst, MW; Ramanujam, N
MLA Citation
Frees, Amy E., et al. “Delivery-corrected imaging of fluorescently-labeled glucose reveals distinct metabolic phenotypes in murine breast cancer..” Plos One, vol. 9, no. 12, 2014. Pubmed, doi:10.1371/journal.pone.0115529.
PMID
25526261
Source
pubmed
Published In
Plos One
Volume
9
Issue
12
Publish Date
2014
Start Page
e115529
DOI
10.1371/journal.pone.0115529

Abstract P4-15-05: Novel targeted therapy for breast cancer chest wall recurrence: Low temperature liposomal doxorubicin and mild local hyperthermia

Authors
Rugo, HS; Zagar, TM; Formenti, SC; Vujaskovic, Z; Muggia, F; O'Connor, BM; Myerson, RJ; Hsu, IC-C; Borys, N; Blackwell, KL; Dewhirst, MW
MLA Citation
Rugo, H. S., et al. “Abstract P4-15-05: Novel targeted therapy for breast cancer chest wall recurrence: Low temperature liposomal doxorubicin and mild local hyperthermia.” Poster Session Abstracts, American Association for Cancer Research, Dec. 2013. Crossref, doi:10.1158/0008-5472.sabcs13-p4-15-05.
Source
crossref
Published In
Poster Session Abstracts
Publish Date
2013
DOI
10.1158/0008-5472.sabcs13-p4-15-05

Magnetic fluid hyperthermia for bladder cancer: a preclinical dosimetry study.

PURPOSE: This paper describes a preclinical investigation of the feasibility of thermotherapy treatment of bladder cancer with magnetic fluid hyperthermia (MFH), performed by analysing the thermal dosimetry of nanoparticle heating in a rat bladder model. MATERIALS AND METHODS: The bladders of 25 female rats were instilled with magnetite-based nanoparticles, and hyperthermia was induced using a novel small animal magnetic field applicator (Actium Biosystems, Boulder, CO). We aimed to increase the bladder lumen temperature to 42 °C in <10 min and maintain that temperature for 60 min. Temperatures were measured within the bladder lumen and throughout the rat with seven fibre-optic probes (OpSens Technologies, Quebec, Canada). An MRI analysis was used to confirm the effectiveness of the catheterisation method to deliver and maintain various nanoparticle volumes within the bladder. Thermal dosimetry measurements recorded the temperature rise of rat tissues for a variety of nanoparticle exposure conditions. RESULTS: Thermal dosimetry data demonstrated our ability to raise and control the temperature of rat bladder lumen ≥1 °C/min to a steady state of 42 °C with minimal heating of surrounding normal tissues. MRI scans confirmed the homogenous nanoparticle distribution throughout the bladder. CONCLUSION: These data demonstrate that our MFH system with magnetite-based nanoparticles provides well-localised heating of rat bladder lumen with effective control of temperature in the bladder and minimal heating of surrounding tissues.

Authors
Oliveira, TR; Stauffer, PR; Lee, C-T; Landon, CD; Etienne, W; Ashcraft, KA; McNerny, KL; Mashal, A; Nouls, J; Maccarini, PF; Beyer, WF; Inman, B; Dewhirst, MW
MLA Citation
Oliveira, Tiago R., et al. “Magnetic fluid hyperthermia for bladder cancer: a preclinical dosimetry study..” Int J Hyperthermia, vol. 29, no. 8, Dec. 2013, pp. 835–44. Pubmed, doi:10.3109/02656736.2013.834384.
PMID
24050253
Source
pubmed
Published In
Int J Hyperthermia
Volume
29
Issue
8
Publish Date
2013
Start Page
835
End Page
844
DOI
10.3109/02656736.2013.834384

Materials science and engineering of the low temperature sensitive liposome (LTSL): Composition-structure-property relationships that underlie its design and performance

Authors
Needham, D; Dewhirst, MW
MLA Citation
Needham, D., and M. W. Dewhirst. “Materials science and engineering of the low temperature sensitive liposome (LTSL): Composition-structure-property relationships that underlie its design and performance.” Rsc Smart Materials, vol. 1, no. 1, Nov. 2013, pp. 33–79.
Source
scopus
Published In
Rsc Smart Materials
Volume
1
Issue
1
Publish Date
2013
Start Page
33
End Page
79

Mechanistic Considerations of the Therapeutic Effects of Mn Porphyrins, Commonly Regarded as SOD Mimics, in Anticancer Therapy: Lessons from Brain and Lymphoma Studies

Authors
Batinic-Haberle, I; Tovmasyan, A; Weitner, T; Rajic, Z; Keir, ST; Huang, T-T; Leu, D; Weitzel, DH; Beausejour, CM; Miriyala, S; Roberts, ERH; Dewhirst, MW; Clair, DS; Leong, KW; Spasojevic, I; Piganelli, J; Tome, M
MLA Citation
Batinic-Haberle, Ines, et al. “Mechanistic Considerations of the Therapeutic Effects of Mn Porphyrins, Commonly Regarded as SOD Mimics, in Anticancer Therapy: Lessons from Brain and Lymphoma Studies.” Free Radical Biology and Medicine, vol. 65, Elsevier BV, Nov. 2013, pp. S120–21. Crossref, doi:10.1016/j.freeradbiomed.2013.10.691.
Source
crossref
Published In
Free Radical Biology and Medicine
Volume
65
Publish Date
2013
Start Page
S120
End Page
S121
DOI
10.1016/j.freeradbiomed.2013.10.691

Abstract B151: Monitoring tumor microenvironment (Hb saturation and oxygenation) in response to plasmonics-assisted photothermal cancer therapy.

Authors
Yuan, H; Hofmann, CL; Samonina-Kosicka, J; Hendargo, H; Hanna, G; Vo-Dinh, T; Fraser, CL; Dewhirst, MW; Palmer, GM
MLA Citation
Yuan, Hsiangkuo, et al. “Abstract B151: Monitoring tumor microenvironment (Hb saturation and oxygenation) in response to plasmonics-assisted photothermal cancer therapy..” Imaging, American Association for Cancer Research, Nov. 2013. Crossref, doi:10.1158/1535-7163.targ-13-b151.
Source
crossref
Published In
Imaging
Publish Date
2013
DOI
10.1158/1535-7163.targ-13-b151

Quantitative mapping of hemodynamics in the lung, brain, and dorsal window chamber-grown tumors using a novel, automated algorithm.

OBJECTIVE: Hemodynamic properties of vascular beds are of great interest in a variety of clinical and laboratory settings. However, there presently exists no automated, accurate, technically simple method for generating blood velocity maps of complex microvessel networks. METHODS: Here, we present a novel algorithm that addresses the problem of acquiring quantitative maps by applying pixel-by-pixel cross-correlation to video data. Temporal signals at every spatial coordinate are compared with signals at neighboring points, generating a series of correlation maps from which speed and direction are calculated. User-assisted definition of vessel geometries is not required, and sequential data are analyzed automatically, without user bias. RESULTS: Velocity measurements were validated against the dual-slit method and against in vitro capillary flow with known velocities. The algorithm was tested in three different biological models in order to demonstrate its versatility. CONCLUSIONS: The hemodynamic maps presented here demonstrate an accurate, quantitative method of analyzing dynamic vascular systems.

Authors
Fontanella, AN; Schroeder, T; Hochman, DW; Chen, RE; Hanna, G; Haglund, MM; Rajaram, N; Frees, AE; Secomb, TW; Palmer, GM; Dewhirst, MW
MLA Citation
Fontanella, Andrew N., et al. “Quantitative mapping of hemodynamics in the lung, brain, and dorsal window chamber-grown tumors using a novel, automated algorithm..” Microcirculation, vol. 20, no. 8, Nov. 2013, pp. 724–35. Pubmed, doi:10.1111/micc.12072.
PMID
23781901
Source
pubmed
Published In
Microcirculation
Volume
20
Issue
8
Publish Date
2013
Start Page
724
End Page
735
DOI
10.1111/micc.12072

PET with 62Cu-ATSM and 62Cu-PTSM is a useful imaging tool for hypoxia and perfusion in pulmonary lesions.

OBJECTIVE: Hypoxia is a characteristic of many tumors and portends a worse prognosis in lung, cervical, prostate, and rectal cancers. Unlike the others, lung cancers present a unique challenge in measuring hypoxia, with invasive biopsies and higher rates of complications. Noninvasive imaging studies detecting hypoxia using isotopes of copper-diacetyl-bis(N4-methylthiosemicarbazone) ((62)Cu-ATSM) have predicted prognosis and treatment outcomes in some small feasibility trials. These images, however, may not identify all areas of hypoxia. Hence, we hypothesize that the addition of another PET imaging agent, copper-pyruvaldehyde-bis(N4-methylthiosemicarbazone) ((62)Cu-PTSM), which can detect areas of perfusion, can augment the information obtained in (62)Cu-ATSM PET scans. SUBJECTS AND METHODS: To characterize tumors on the basis of both perfusion and hypoxia, 10 patients were studied using both (62)Cu-ATSM and (62)Cu-PTSM PET scans. In addition, proteomic arrays looking at specific proangiogenic, survival, and proinflammatory targets were assessed. RESULTS: Six of 10 patients had evaluable PET scans. Our initial experience of characterizing lung tumor hypoxia using (62)Cu-ATSM and (62)Cu-PTSM PET scans showed that visualization of areas with hypoxia normalized for perfusion is feasible. All studied tumors exhibited some hypoxia. Despite the small sample size, a positive relationship was noted between epidermal growth factor levels and (62)Cu-ATSM-detected hypoxia. CONCLUSION: This initial series of (62)Cu-ATSM and (62)Cu-PTSM PET scans shows that evaluating lung masses by visualizing hypoxia and perfusion is a feasible and novel technique to provide more information. Further investigation is warranted to assess the potential role of (62)Cu-ATSM and (62)Cu-PTSM PET techniques combined with proteomics as alternatives to invasive biopsy techniques in clinical care.

Authors
Zhang, T; Das, SK; Fels, DR; Hansen, KS; Wong, TZ; Dewhirst, MW; Vlahovic, G
MLA Citation
Zhang, Tian, et al. “PET with 62Cu-ATSM and 62Cu-PTSM is a useful imaging tool for hypoxia and perfusion in pulmonary lesions..” Ajr Am J Roentgenol, vol. 201, no. 5, Nov. 2013, pp. W698–706. Pubmed, doi:10.2214/AJR.12.9698.
PMID
24147499
Source
pubmed
Published In
Ajr. American Journal of Roentgenology
Volume
201
Issue
5
Publish Date
2013
Start Page
W698
End Page
W706
DOI
10.2214/AJR.12.9698

Tumor cells upregulate normoxic HIF-1α in response to doxorubicin.

Hypoxia-inducible factor 1 (HIF-1) is a master transcription factor that controls cellular homeostasis. Although its activation benefits normal tissue, HIF-1 activation in tumors is a major risk factor for angiogenesis, therapeutic resistance, and poor prognosis. HIF-1 activity is usually suppressed under normoxic conditions because of rapid oxygen-dependent degradation of HIF-1α. Here, we show that, under normoxic conditions, HIF-1α is upregulated in tumor cells in response to doxorubicin, a chemotherapeutic agent used to treat many cancers. In addition, doxorubicin enhanced VEGF secretion by normoxic tumor cells and stimulated tumor angiogenesis. Doxorubicin-induced accumulation of HIF-1α in normoxic cells was caused by increased expression and activation of STAT1, the activation of which stimulated expression of iNOS and its synthesis of nitric oxide (NO) in tumor cells. Mechanistic investigations established that blocking NO synthesis or STAT1 activation was sufficient to attenuate the HIF-1α accumulation induced by doxorubicin in normoxic cancer cells. To our knowledge, this is the first report that a chemotherapeutic drug can induce HIF-1α accumulation in normoxic cells, an efficacy-limiting activity. Our results argue that HIF-1α-targeting strategies may enhance doxorubicin efficacy. More generally, they suggest a broader perspective on the design of combination chemotherapy approaches with immediate clinical impact.

Authors
Cao, Y; Eble, JM; Moon, E; Yuan, H; Weitzel, DH; Landon, CD; Nien, CY-C; Hanna, G; Rich, JN; Provenzale, JM; Dewhirst, MW
MLA Citation
Cao, Yiting, et al. “Tumor cells upregulate normoxic HIF-1α in response to doxorubicin..” Cancer Res, vol. 73, no. 20, Oct. 2013, pp. 6230–42. Pubmed, doi:10.1158/0008-5472.CAN-12-1345.
PMID
23959856
Source
pubmed
Published In
Cancer Res
Volume
73
Issue
20
Publish Date
2013
Start Page
6230
End Page
6242
DOI
10.1158/0008-5472.CAN-12-1345

Temperature matters! And why it should matter to tumor immunologists.

A major goal of cancer immunology is to stimulate the generation of long-lasting, tumor antigen-specific immune responses that recognize and destroy tumor cells. This article discusses advances in thermal medicine with the potential to improve cancer immunotherapy. Accumulating evidence indicates that survival benefits are accorded to individuals who achieve an increase in body temperature (i.e. fever) following infection. Furthermore, accumulating evidence indicates that physiological responses to hyperthermia impact the tumor microenvironment through temperature-sensitive check-points that regulate tumor vascular perfusion, lymphocyte trafficking, inflammatory cytokine expression, tumor metabolism, and innate and adaptive immune function. Nevertheless, the influence of thermal stimuli on the immune system, particularly the antitum or immune response, remains incompletely understood. In fact, temperature is still rarely considered as a critical variable in experimental immunology. We suggest that more attention should be directed to the role of temperature in the regulation of the immune response and that thermal therapy should be tested in conjunction with immunotherapy as a multi-functional adjuvant that modulates the dynamics of the tumor microenvironment.

Authors
Repasky, EA; Evans, SS; Dewhirst, MW
MLA Citation
Repasky, Elizabeth A., et al. “Temperature matters! And why it should matter to tumor immunologists..” Cancer Immunol Res, vol. 1, no. 4, Oct. 2013, pp. 210–16. Pubmed, doi:10.1158/2326-6066.CIR-13-0118.
PMID
24490177
Source
pubmed
Published In
Cancer Immunol Res
Volume
1
Issue
4
Publish Date
2013
Start Page
210
End Page
216
DOI
10.1158/2326-6066.CIR-13-0118

Understanding the tumor microenvironment and radioresistance by combining functional imaging with global gene expression.

The objective of this review is to present an argument for performing joint analyses between functional imaging with global gene expression studies. The reason for making this link is that tumor microenvironmental influences on functional imaging can be uncovered. Such knowledge can lead to (1) more informed decisions regarding how to use functional imaging to guide therapy and (2) discovery of new therapeutic targets. As such, this approach could lead to identification of patients who need aggressive treatment tailored toward the phenotype of their tumor vs those who could be spared treatment that carries risk for more normal tissue complications. Only a handful of papers have been published on this topic thus far, but all show substantial promise.

Authors
Dewhirst, MW; Chi, J-T
MLA Citation
Dewhirst, Mark W., and Jen-Tsan Chi. “Understanding the tumor microenvironment and radioresistance by combining functional imaging with global gene expression..” Semin Radiat Oncol, vol. 23, no. 4, Oct. 2013, pp. 296–305. Pubmed, doi:10.1016/j.semradonc.2013.05.004.
PMID
24012344
Source
pubmed
Published In
Semin Radiat Oncol
Volume
23
Issue
4
Publish Date
2013
Start Page
296
End Page
305
DOI
10.1016/j.semradonc.2013.05.004

Introduction: tumor as an organ.

Authors
Dewhirst, MW
MLA Citation
Dewhirst, Mark W. “Introduction: tumor as an organ..” Semin Radiat Oncol, vol. 23, no. 4, Oct. 2013, pp. 235–36. Pubmed, doi:10.1016/j.semradonc.2013.05.005.
PMID
24012336
Source
pubmed
Published In
Semin Radiat Oncol
Volume
23
Issue
4
Publish Date
2013
Start Page
235
End Page
236
DOI
10.1016/j.semradonc.2013.05.005

Modulation of circulating angiogenic factors and tumor biology by aerobic training in breast cancer patients receiving neoadjuvant chemotherapy.

Aerobic exercise training (AET) is an effective adjunct therapy to attenuate the adverse side-effects of adjuvant chemotherapy in women with early breast cancer. Whether AET interacts with the antitumor efficacy of chemotherapy has received scant attention. We carried out a pilot study to explore the effects of AET in combination with neoadjuvant doxorubicin-cyclophosphamide (AC+AET), relative to AC alone, on: (i) host physiology [exercise capacity (VO2 peak), brachial artery flow-mediated dilation (BA-FMD)], (ii) host-related circulating factors [circulating endothelial progenitor cells (CEP) cytokines and angiogenic factors (CAF)], and (iii) tumor phenotype [tumor blood flow ((15)O-water PET), tissue markers (hypoxia and proliferation), and gene expression] in 20 women with operable breast cancer. AET consisted of three supervised cycle ergometry sessions/week at 60% to 100% of VO2 peak, 30 to 45 min/session, for 12 weeks. There was significant time × group interactions for VO2 peak and BA-FMD, favoring the AC+AET group (P < 0.001 and P = 0.07, respectively). These changes were accompanied by significant time × group interactions in CEPs and select CAFs [placenta growth factor, interleukin (IL)-1β, and IL-2], also favoring the AC+AET group (P < 0.05). (15)O-water positron emission tomography (PET) imaging revealed a 38% decrease in tumor blood flow in the AC+AET group. There were no differences in any tumor tissue markers (P > 0.05). Whole-genome microarray tumor analysis revealed significant differential modulation of 57 pathways (P < 0.01), including many that converge on NF-κB. Data from this exploratory study provide initial evidence that AET can modulate several host- and tumor-related pathways during standard chemotherapy. The biologic and clinical implications remain to be determined.

Authors
Jones, LW; Fels, DR; West, M; Allen, JD; Broadwater, G; Barry, WT; Wilke, LG; Masko, E; Douglas, PS; Dash, RC; Povsic, TJ; Peppercorn, J; Marcom, PK; Blackwell, KL; Kimmick, G; Turkington, TG; Dewhirst, MW
MLA Citation
Jones, Lee W., et al. “Modulation of circulating angiogenic factors and tumor biology by aerobic training in breast cancer patients receiving neoadjuvant chemotherapy..” Cancer Prev Res (Phila), vol. 6, no. 9, Sept. 2013, pp. 925–37. Pubmed, doi:10.1158/1940-6207.CAPR-12-0416.
PMID
23842792
Source
pubmed
Published In
Cancer Prev Res (Phila)
Volume
6
Issue
9
Publish Date
2013
Start Page
925
End Page
937
DOI
10.1158/1940-6207.CAPR-12-0416

A role for the copper transporter Ctr1 in the synergistic interaction between hyperthermia and cisplatin treatment.

PURPOSE: Hyperthermia enhances cytotoxic effects of chemotherapeutic agents such as cisplatin. However, the underlying molecular mechanisms remain unclear. We hypothesised that hyperthermia increases cisplatin accumulation and efficacy by modulating function of copper transport protein 1 (Ctr1), a major regulator of cellular cisplatin uptake. We examined the significance of Ctr1 in the synergistic interaction between hyperthermia and cisplatin. We assessed the importance of cisplatin- and hyperthermia-induced Ctr1 multimerisation in sensitising cells to cisplatin cytotoxicity. MATERIALS AND METHODS: Ctr1 protein levels and cisplatin sensitivities were assessed in bladder cancer cell lines with immunoblotting and clonogenic survival assays. Using Myc-tagged-Ctr1 HEK293 cells, we assessed the effect of hyperthermia on Ctr1 multimerisation with immunoblotting. The effect of hyperthermia on cisplatin sensitivity and accumulation was assessed in wild-type (WT) and Ctr1 knockout (Ctr1-/-) mouse embryonic fibroblasts (MEFs) with clonogenic assays and inductively coupled plasma-mass spectrometry (ICP-MS). RESULTS: Increased Ctr1 protein expression was observed for the most cisplatin-sensitive bladder cancer cell lines and MEFs. Heat-induced increase in Ctr1 multimerisation with cisplatin was observed in Myc-tagged Ctr1 cells. Hyperthermia enhanced cisplatin-mediated cytotoxicity in WT more than Ctr1-/- cells (dose modifying factors 1.75 versus 1.4, respectively). WT cells accumulated more platinum versus Ctr1-/- cells; this was further increased by hyperthermia in WT cells. CONCLUSIONS: Hyperthermia enhanced cisplatin uptake and cytotoxicity in WT cells. Heat increased Ctr1 activity by increasing multimerisation, enhancing drug cytotoxicity. Furthermore, Ctr1 protein profiles of bladder tumours, as well as other tumour types, may predict their response to cisplatin and overall efficacy of treatment.

Authors
Landon, CD; Benjamin, SE; Ashcraft, KA; Dewhirst, MW
MLA Citation
Landon, Chelsea D., et al. “A role for the copper transporter Ctr1 in the synergistic interaction between hyperthermia and cisplatin treatment..” Int J Hyperthermia, vol. 29, no. 6, Sept. 2013, pp. 528–38. Pubmed, doi:10.3109/02656736.2013.790563.
PMID
23879689
Source
pubmed
Published In
Int J Hyperthermia
Volume
29
Issue
6
Publish Date
2013
Start Page
528
End Page
538
DOI
10.3109/02656736.2013.790563

Actively targeting solid tumours with thermoresponsive drug delivery systems that respond to mild hyperthermia.

A diverse range of drug delivery vehicles have been developed to specifically target chemotherapeutics to solid tumours while avoiding systemic dose-limiting toxicity. Many of these active targeting strategies display limited efficacy because they rely on subtle differences in expression patterns between pathogenic tissue and healthy tissue. In contrast, drug delivery systems that exploit thermoresponsive behaviour allow a clinician to spatially and temporally control the accumulation and/or release of the toxic agents within tumour tissue by simply applying mild hyperthermia (defined as 39-43 °C) to the desired site. Although thermally sensitive materials comprise a significant portion of the literature on novel drug delivery systems, only a few systems have been methodically tuned to respond within this narrowly defined physiological temperature range in an in vivo environment. This review discusses the materials and strategies developed to control the primary tumour through the combined application of hyperthermia and chemotherapy.

Authors
McDaniel, JR; Dewhirst, MW; Chilkoti, A
MLA Citation
McDaniel, Jonathan R., et al. “Actively targeting solid tumours with thermoresponsive drug delivery systems that respond to mild hyperthermia..” Int J Hyperthermia, vol. 29, no. 6, Sept. 2013, pp. 501–10. Pubmed, doi:10.3109/02656736.2013.819999.
PMID
23924317
Source
pubmed
Published In
Int J Hyperthermia
Volume
29
Issue
6
Publish Date
2013
Start Page
501
End Page
510
DOI
10.3109/02656736.2013.819999

A method to convert MRI images of temperature change into images of absolute temperature in solid tumours.

PURPOSE: During hyperthermia (HT), the therapeutic response of tumours varies substantially within the target temperature range (39-43 °C). Current thermometry methods are either invasive or measure only temperature change, which limits the ability to study tissue responses to HT. This study combines manganese-containing low temperature sensitive liposomes (Mn-LTSL) with proton resonance frequency shift (PRFS) thermometry to measure absolute temperature in tumours with high spatial and temporal resolution using MRI. METHODS: Liposomes were loaded with 300 mM MnSO(4). The phase transition temperature (T(m)) of Mn-LTSL samples was measured by differential scanning calorimetry (DSC). The release of manganese from Mn-LTSL in saline was characterised with inductively coupled plasma atomic emission spectroscopy. A 2T GE small animal scanner was used to acquire dynamic T1-weighted images and temperature change images of Mn-LTSL in saline phantoms and fibrosarcoma-bearing Fisher-344 rats receiving hyperthermia after Mn-LTSL injection. RESULTS: The T(m) of Mn-LTSL in rat blood was 42.9 ± 0.2 °C (DSC). For Mn-LTSL samples (0.06 mM-0.5 mM Mn(2+) in saline) heated monotonically from 30 °C to 50 °C, a peak in the rate of MRI signal enhancement occurred at 43.1° ± 0.3 °C. The same peak in signal enhancement rate was observed during heating of fibrosarcoma tumours (N = 3) after injection of Mn-LTSL, and the peak was used to convert temperature change images into absolute temperature. Accuracies of calibrated temperature measurements were in the range 0.9-1.8 °C. CONCLUSION: The release of Mn(2+) from Mn-LTSL affects the rate of MR signal enhancement which enables conversion of MRI-based temperature change images to absolute temperature.

Authors
Davis, RM; Viglianti, BL; Yarmolenko, P; Park, J-Y; Stauffer, P; Needham, D; Dewhirst, MW
MLA Citation
Davis, Ryan M., et al. “A method to convert MRI images of temperature change into images of absolute temperature in solid tumours..” Int J Hyperthermia, vol. 29, no. 6, Sept. 2013, pp. 569–81. Pubmed, doi:10.3109/02656736.2013.790091.
PMID
23957326
Source
pubmed
Published In
Int J Hyperthermia
Volume
29
Issue
6
Publish Date
2013
Start Page
569
End Page
581
DOI
10.3109/02656736.2013.790091

CEM43°C thermal dose thresholds: a potential guide for magnetic resonance radiofrequency exposure levels?

OBJECTIVE: To define thresholds of safe local temperature increases for MR equipment that exposes patients to radiofrequency fields of high intensities for long duration. These MR systems induce heterogeneous energy absorption patterns inside the body and can create localised hotspots with a risk of overheating. METHODS: The MRI + EUREKA research consortium organised a "Thermal Workshop on RF Hotspots". The available literature on thresholds for thermal damage and the validity of the thermal dose (TD) model were discussed. RESULTS/CONCLUSIONS: The following global TD threshold guidelines for safe use of MR are proposed: 1. All persons: maximum local temperature of any tissue limited to 39 °C 2. Persons with compromised thermoregulation AND (a) Uncontrolled conditions: maximum local temperature limited to 39 °C (b) Controlled conditions: TD < 2 CEM43°C 3. Persons with uncompromised thermoregulation AND (a) Uncontrolled conditions: TD < 2 CEM43°C (b) Controlled conditions: TD < 9 CEM43°C The following definitions are applied: Controlled conditions A medical doctor or a dedicated trained person can respond instantly to heat-induced physiological stress Compromised thermoregulation All persons with impaired systemic or reduced local thermoregulation KEY POINTS: • Standard MRI can cause local heating by radiofrequency absorption. • Monitoring thermal dose (in units of CEM43°C) can control risk during MRI. • 9 CEM43°C seems an acceptable thermal dose threshold for most patients. • For skin, muscle, fat and bone,16 CEM43°C is likely acceptable.

Authors
van Rhoon, GC; Samaras, T; Yarmolenko, PS; Dewhirst, MW; Neufeld, E; Kuster, N
MLA Citation
van Rhoon, Gerard C., et al. “CEM43°C thermal dose thresholds: a potential guide for magnetic resonance radiofrequency exposure levels?.” Eur Radiol, vol. 23, no. 8, Aug. 2013, pp. 2215–27. Pubmed, doi:10.1007/s00330-013-2825-y.
PMID
23553588
Source
pubmed
Published In
Eur Radiol
Volume
23
Issue
8
Publish Date
2013
Start Page
2215
End Page
2227
DOI
10.1007/s00330-013-2825-y

18F-EF5 PET imaging as an early response biomarker for the hypoxia-activated prodrug SN30000 combined with radiation treatment in a non-small cell lung cancer xenograft model.

UNLABELLED: Hypoxia is a significant therapeutic problem for solid tumors because hypoxic cells are treatment-resistant and more aggressive. Hypoxia-activated prodrugs such as SN30000 use a mechanism of activation in hypoxic cells similar to that of 2-nitroimidazole hypoxia PET tracers. Therefore, we have evaluated the usefulness of 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-(18)F-pentafluoropropyl)-acetamide ((18)F-EF5) PET to monitor and predict tumor response to SN30000 plus radiation treatment (RT). METHODS: Human non-small cell lung cancer xenografts (H460) in athymic rats were imaged with (18)F-EF5 PET before and after treatment with SN30000 (90 mg/kg), with or without 15-Gy RT. The feasibility of imaging early changes in hypoxia in response to SN30000 was examined 24 h after treatment, followed by ex vivo γ-counting and immunohistochemical examination to study drug-induced apoptosis. Subsequently, the therapeutic effects of SN30000 with or without RT were evaluated in tumor growth delay studies and compared with early treatment-induced changes observed by (18)F-EF5 PET. Changes in tumor hemoglobin oxygen saturation as a function of time after treatment measured by optical spectroscopy were compared with PET data. RESULTS: The uptake of (18)F-EF5 was significantly lower in SN30000-treated tumors than in saline controls 24 h after treatment (mean standardized uptake value, 0.44 ± 0.08 vs. 0.56 ± 0.08 for control group; P < 0.05). Apoptosis was significantly higher in SN30000-treated tumors than in controls. Early treatment-induced changes in (18)F-EF5 uptake were indicative of tumor response in growth delay studies at the group level. SN30000 plus RT significantly decreased (18)F-EF5 uptake relative to baseline and resulted in complete tumor remission in 5 of 7 animals. SN30000 alone decreased (18)F-EF5 uptake, generally in tumors with high initial standardized uptake values, and showed a minor tumor growth delay effect. The changes induced by SN30000 with or without RT in (18)F-EF5 uptake correlated with baseline hypoxia levels. RT caused significant increases in tumor oxygen concentration and hemoglobin oxygen saturation. CONCLUSION: A hypoxia PET imaging agent can measure changes in tumor hypoxic fraction in response to SN30000. These results suggest the utility of (18)F-EF5 PET for monitoring early response to tumor treatment with SN30000 plus RT in the clinical development of this novel hypoxia-activated prodrug.

Authors
Chitneni, SK; Bida, GT; Yuan, H; Palmer, GM; Hay, MP; Melcher, T; Wilson, WR; Zalutsky, MR; Dewhirst, MW
MLA Citation
Chitneni, Satish K., et al. “18F-EF5 PET imaging as an early response biomarker for the hypoxia-activated prodrug SN30000 combined with radiation treatment in a non-small cell lung cancer xenograft model..” J Nucl Med, vol. 54, no. 8, Aug. 2013, pp. 1339–46. Pubmed, doi:10.2967/jnumed.112.116293.
PMID
23740105
Source
pubmed
Published In
Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
Volume
54
Issue
8
Publish Date
2013
Start Page
1339
End Page
1346
DOI
10.2967/jnumed.112.116293

Novel approaches to treatment of hepatocellular carcinoma and hepatic metastases using thermal ablation and thermosensitive liposomes.

Because of the limitations of surgical resection, thermal ablation is commonly used for the treatment of hepatocellular carcinoma and liver metastases. Current methods of ablation can result in marginal recurrences of larger lesions and in tumors located near large vessels. This review presents a novel approach for extending treatment out to the margins where temperatures do not provide complete treatment with ablation alone, by combining thermal ablation with drug-loaded thermosensitive liposomes. A history of the development of thermosensitive liposomes is presented. Clinical trials have shown that the combination of radiofrequency ablation and doxorubicin-loaded thermosensitive liposomes is a promising treatment.

Authors
Dewhirst, MW; Landon, CD; Hofmann, CL; Stauffer, PR
MLA Citation
Dewhirst, Mark W., et al. “Novel approaches to treatment of hepatocellular carcinoma and hepatic metastases using thermal ablation and thermosensitive liposomes..” Surg Oncol Clin N Am, vol. 22, no. 3, July 2013, pp. 545–61. Pubmed, doi:10.1016/j.soc.2013.02.009.
PMID
23622079
Source
pubmed
Published In
Surg Oncol Clin N Am
Volume
22
Issue
3
Publish Date
2013
Start Page
545
End Page
561
DOI
10.1016/j.soc.2013.02.009

WE-E-108-09: An Investigation of the Feasibility of Rodentmorphic 3D Dosimeters for Verification of Precision Micro-Irradiator Treatment.

PURPOSE: To evaluate the feasibility of novel rodentmorphic 3D dosimeters for comprehensive high-resolution verification of the treatment accuracy of a state-of-the-art micro-irradiator equipped with on-line cone-beam-CT guidance. METHODS: Anatomically accurate 3D dosimeter molds were created in a two step procedure. First, rodents were CT scanned and the structures of interest contoured (e.g. body and spine). These contours were then exported for input to a 3D printer, to generate positive dosimeter molds. The rat body dosimeter was made of regular water-equivalent PRESAGE, while the spine was made from high-Z PRESAGE with an effective atomic-number close to bone. Evaluation of the dosimeters involved (i) establishing the feasibility of manufacture and accurate positioning of heterogenous inserts, (ii) verification of accurate dose-readout by optical-CT, and (iii) verification of sufficient bony/soft-tissue contrast for representative CBCT IGRT positioning. Simulated rat prostate treatments were delivered with dose of 16Gy given by 4 2.5cm diameter circular fields. RESULTS: High resolution (0.5mm isotropic) 3D dosimetry data was acquired in rodentmorphic dosimeters both with and without the high-Z spinal insert. The spinal insert was visible under kV radiographs and CBCT, demonstrating the feasibility of IGRT positioning. Pronounced edge artifacts were observed near the flat undersurface of the rat, and near regions of sharp curvature. Further artifacts were observed in some regions near the spinal insert caused by bubbles trapped during manufacture. New manufacturing procedures utilizing the flexibility of 3D printing to precisely customize contours in non-critical regions have improved on both of these limitations. CONCLUSION: This work demonstrates promising feasibility for anatomically accurate 3D rodentmorphic dosimeters compatible with very high resolution 3D dosimetry. The ability to create such dosimeters is an important step forward in enabling accurate verification of complex micro-irradiator treatments in the pre-clinical setting. NIH Grant No. R01 CA 100835.

Authors
Bache, S; Juang, T; Adamovics, J; Benning, R; Koontz, B; Predmore, K; Dewhirst, M; Oldham, M
MLA Citation
Bache, S., et al. “WE-E-108-09: An Investigation of the Feasibility of Rodentmorphic 3D Dosimeters for Verification of Precision Micro-Irradiator Treatment..” Med Phys, vol. 40, no. 6Part29, June 2013. Pubmed, doi:10.1118/1.4815587.
PMID
28518639
Source
pubmed
Published In
Med Phys
Volume
40
Issue
6Part29
Publish Date
2013
Start Page
490
DOI
10.1118/1.4815587

MO-D-141-09: An Investigation of the Feasibility of Volumetric Imaging of Fluorescent Bio-Markers Using Optical-ECT.

PURPOSE: Toptical-ECT is a technique with potential for high resolution 3D imaging of the distribution of fluoresent biomarkers (including reporter proteins like GFP) in un-sectioned tissue samples. Accurate optical-ECT data is only feasible if the biomarkers survive an optical clearing procedure. This work presents investigates this question, and the feasibility of extracting volume metrics from optical-ECT data. METHODS: 4T1 tumors were grown in window chambers on nude mice, following an approved protocol. Tumor cells constitutively expressed RFP, and endogenously expressed GFP labeling HIF-1 transcription. Microvasculature was labeled by colloidal carbon. When the tumors were ∼5-7mm, they were imaged in-vivo (in the chamber) using conventional epi-fluorescent microspcopy. Tumors were then immediately removed, optically-cleared, and imaged ex-vivo by optical-CT/ECT. Comparison of the in-vivo and ex-vivo images enabled investigation of the stability of the biomarkers through optical clearing. Volume measurements of regions expressing different markers (GFP and RFP) were generated though automatic thresholding. RESULTS: Biomarker expressing regions (GFP and RFP) were generally consistent between comparable optical-ECT projections and in-vivo microscopy. In some tumors, GFP and RFP expression was observed to be partially obscured in in-vivo images, due to absorption in overlying tissue. In optical-ECT views, these regions became visible, due to optical clearing. In one tumor, 31% of the gross tumor was deemed viable, as determined from RFP expression. 13% of the tumor was hypoxic as inferred from HIF-1 expression. Almost all the GFP hypoxic volume was within the viable RFP tumor volume. CONCLUSION: Our preliminary data supports several key concepts: fluorescent biomarkers can survive the optical clearing process representative of in-vivo condition; the cleared tumor revealed new regions of signal that were partially obscured in in-vivo images; and 3D quantitative metrics can be determined from optical-CT/ECT that correspond to their 2D counterparts in standard microscopy (e.g. sub-volume of HIF-1 expression).

Authors
Oldham, M; Thomas, A; Dewhirst, M
MLA Citation
Oldham, M., et al. “MO-D-141-09: An Investigation of the Feasibility of Volumetric Imaging of Fluorescent Bio-Markers Using Optical-ECT..” Med Phys, vol. 40, no. 6Part24, June 2013. Pubmed, doi:10.1118/1.4815256.
PMID
28518425
Source
pubmed
Published In
Med Phys
Volume
40
Issue
6Part24
Publish Date
2013
Start Page
401
DOI
10.1118/1.4815256

Endothelial colony forming cells (ECFCs) as a model for studying effects of low-dose ionizing radiation: growth inhibition by a single dose.

Identification of measurable nontransient responses to low-dose radiation in human primary cell cultures remains a problem. To this end, circulating endothelial colony-forming (progenitor) cells (ECFCs) were examined as an experimental model. ECFCs were isolated from three cord blood donors. Cells were positive for endothelial cell markers and remained highly proliferative after long-term cryopreservation. A single dose of X-ray radiation (0.06-0.38 Gy) inhibited ECFC culture growth. This effect was evident at 48 hours and persisted up to 72 hr postirradiation. Such protracted cytostatic response of ECFCs to low-dose radiation suggests that ECFC primary cultures can be used to study low-dose radiation effects.

Authors
Kinev, AV; Levering, V; Young, K; Ali-Osman, F; Truskey, GA; Dewhirst, MW; Il'yasova, D
MLA Citation
Kinev, Alexander V., et al. “Endothelial colony forming cells (ECFCs) as a model for studying effects of low-dose ionizing radiation: growth inhibition by a single dose..” Cancer Invest, vol. 31, no. 5, June 2013, pp. 359–64. Pubmed, doi:10.3109/07357907.2013.789903.
PMID
23621632
Source
pubmed
Published In
Cancer Invest
Volume
31
Issue
5
Publish Date
2013
Start Page
359
End Page
364
DOI
10.3109/07357907.2013.789903

Monitoring of cycling hypoxia and angiogenesis in FaDu head and neck tumors using a side-firing sensor

Many studies have found that hypoxia, particularly cycling hypoxia (CH), can lead to enhanced tumor metastasis and resistance to radiation and chemotherapy. It was also reported that tumor total hemoglobin content (THb), which is directly related to tumor angiogenesis, can have significant impact on tumor's response to radiation and neoadjuvant chemotherapy. There is a growing demand for technologies to measure tumor hypoxia and angiogenesis temporally in vivo. In this paper, a side-firing fiber optic sensor based on a multi-wavelength frequency-domain near infrared spectroscopy (FD-NIRS) instrument was used to quantify tumor oxygenation and hemoglobin concentrations in nude rats bearing human FaDu head and neck (H & N) tumors during normoxia and forced hyperoxia and cyclic hypoxia. Significant increase (with carbogen gas inhalation) or decrease (with reduced O2 supply) in tumor oxygenation was observed. The studies demonstrated the feasibility of the technology for longitudinal monitoring of H and N tumor's response to therapy. © 2013 Copyright SPIE.

Authors
Yu, B; Shah, A; Wang, B; Rajaram, N; Wang, Q; Ramanujam, N; Palmer, GM; Dewhirst, MW
MLA Citation
Yu, B., et al. “Monitoring of cycling hypoxia and angiogenesis in FaDu head and neck tumors using a side-firing sensor.” Progress in Biomedical Optics and Imaging  Proceedings of Spie, vol. 8578, May 2013. Scopus, doi:10.1117/12.2002837.
Source
scopus
Published In
Progress in Biomedical Optics and Imaging Proceedings of Spie
Volume
8578
Publish Date
2013
DOI
10.1117/12.2002837

(62)cuatsm and (62)cuptsm PET is a useful imaging tool for hypoxia and perfusion in lung cancer.

Authors
Zhang, T; Das, SK; Crawford, J; Wong, T; Dewhirst, MW; Vlahovic, G
MLA Citation
Zhang, Tian, et al. “(62)cuatsm and (62)cuptsm PET is a useful imaging tool for hypoxia and perfusion in lung cancer..” Journal of Clinical Oncology, vol. 31, no. 15, AMER SOC CLINICAL ONCOLOGY, 2013.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Phase I clinical trial of external hyperthermia and intravesical mitomycin C to treat BCG-refractory bladder cancer.

Authors
Abern, M; Vujaskovic, Z; Dewhirst, MW; Lan, L; Craciunescu, OI; Stauffer, P; Inman, BA
MLA Citation
Abern, Michael, et al. “Phase I clinical trial of external hyperthermia and intravesical mitomycin C to treat BCG-refractory bladder cancer..” Journal of Clinical Oncology, vol. 31, no. 15, AMER SOC CLINICAL ONCOLOGY, 2013.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

A network of substrates of the E3 ubiquitin ligases MDM2 and HUWE1 control apoptosis independently of p53.

In the intrinsic pathway of apoptosis, cell-damaging signals promote the release of cytochrome c from mitochondria, triggering activation of the Apaf-1 and caspase-9 apoptosome. The ubiquitin E3 ligase MDM2 decreases the stability of the proapoptotic factor p53. We show that it also coordinated apoptotic events in a p53-independent manner by ubiquitylating the apoptosome activator CAS and the ubiquitin E3 ligase HUWE1. HUWE1 ubiquitylates the antiapoptotic factor Mcl-1, and we found that HUWE1 also ubiquitylated PP5 (protein phosphatase 5), which indirectly inhibited apoptosome activation. Breast cancers that are positive for the tyrosine receptor kinase HER2 (human epidermal growth factor receptor 2) tend to be highly aggressive. In HER2-positive breast cancer cells treated with the HER2 tyrosine kinase inhibitor lapatinib, MDM2 was degraded and HUWE1 was stabilized. In contrast, in breast cancer cells that acquired resistance to lapatinib, the abundance of MDM2 was not decreased and HUWE1 was degraded, which inhibited apoptosis, regardless of p53 status. MDM2 inhibition overcame lapatinib resistance in cells with either wild-type or mutant p53 and in xenograft models. These findings demonstrate broader, p53-independent roles for MDM2 and HUWE1 in apoptosis and specifically suggest the potential for therapy directed against MDM2 to overcome lapatinib resistance.

Authors
Kurokawa, M; Kim, J; Geradts, J; Matsuura, K; Liu, L; Ran, X; Xia, W; Ribar, TJ; Henao, R; Dewhirst, MW; Kim, W-J; Lucas, JE; Wang, S; Spector, NL; Kornbluth, S
MLA Citation
Kurokawa, Manabu, et al. “A network of substrates of the E3 ubiquitin ligases MDM2 and HUWE1 control apoptosis independently of p53..” Sci Signal, vol. 6, no. 274, May 2013. Pubmed, doi:10.1126/scisignal.2003741.
Website
http://hdl.handle.net/10161/8398
PMID
23652204
Source
pubmed
Published In
Sci Signal
Volume
6
Issue
274
Publish Date
2013
Start Page
ra32
DOI
10.1126/scisignal.2003741

Resveratrol worsens survival in SCID mice with prostate cancer xenografts in a cell-line specific manner, through paradoxical effects on oncogenic pathways.

BACKGROUND: Resveratrol increases lifespan and decreases the risk of many cancers. We hypothesized resveratrol will slow the growth of human prostate cancer xenografts. METHODS: SCID mice were fed Western diet (40% fat, 44% carbohydrate, 16% protein by kcal). One week later, human prostate cancer cells, either LAPC-4 (151 mice) or LNCaP (94 mice) were injected subcutaneously. Three weeks after injection, LAPC-4 mice were randomized to Western diet (control group), Western diet plus resveratrol 50 mg/kg/day, or Western diet plus resveratrol 100 mg/kg/day. The LNCaP mice were randomized to Western diet or Western diet plus resveratrol 50 mg/kg/day. Mice were sacrificed when tumors reached 1,000 mm(3). Survival differences among groups were assessed using Cox proportional hazards. Serum insulin and IGF axis were assessed using ELISAs. Gene expression was analyzed using Affymetrix gene arrays. RESULTS: Compared to control in the LAPC-4 study, resveratrol was associated with decreased survival (50 mg/kg/day--HR 1.53, P = 0.04; 100 mg/kg/day--HR 1.22, P = 0.32). In the LNCaP study, resveratrol did not change survival (HR 0.77, P = 0.22). In combined analysis of both resveratrol 50 mg/kg/day groups, IGF-1 was decreased (P = 0.05) and IGFBP-2 was increased (P = 0.01). Resveratrol induced different patterns of gene expression changes in each xenograft model, with upregulation of oncogenic pathways E2F3 and beta-catenin in LAPC-4 tumors. CONCLUSION: Resveratrol was associated with significantly worse survival with LAPC-4 tumors, but unchanged survival with LNCaP. Based on these preliminary data that resveratrol may be harmful, caution should be advised in using resveratrol for patients until further studies can be conducted.

Authors
Klink, JC; Tewari, AK; Masko, EM; Antonelli, J; Febbo, PG; Cohen, P; Dewhirst, MW; Pizzo, SV; Freedland, SJ
MLA Citation
Klink, Joseph C., et al. “Resveratrol worsens survival in SCID mice with prostate cancer xenografts in a cell-line specific manner, through paradoxical effects on oncogenic pathways..” Prostate, vol. 73, no. 7, May 2013, pp. 754–62. Pubmed, doi:10.1002/pros.22619.
PMID
23192356
Source
pubmed
Published In
Prostate
Volume
73
Issue
7
Publish Date
2013
Start Page
754
End Page
762
DOI
10.1002/pros.22619

The impact of temperature and urinary constituents on urine viscosity and its relevance to bladder hyperthermia treatment.

PURPOSE: The aim of this study was to determine the kinematic viscosity of human urine and factors associated with its variability. This value is necessary for accurate modelling of fluid mechanics and heat transfer during hyperthermia treatments of bladder cancer. MATERIALS AND METHODS: Urine samples from 64 patients undergoing routine clinical testing were subject to dipstick urinalysis and measurement of viscosity with a Cannon-Fenske viscometer. Viscosity measurements were taken at relevant temperatures for hyperthermia studies: 20 °C (room temperature), 37 °C (body temperature), and 42 °C (clinical hyperthermia temperature). Factors that might affect viscosity were assessed, including glucosuria, haematuria, urinary tract infection status, ketonuria and proteinuria status. The correlation of urine specific gravity and viscosity was measured with Spearman's rho. RESULTS: Urine kinematic viscosity at 20 °C was 1.0700 cSt (standard deviation (SD) = 0.1076), at 37 °C 0.8293 cSt (SD = 0.0851), and at 42 °C 0.6928 cSt (SD = 0.0247). Proteinuria appeared to increase urine viscosity, whereas age, gender, urinary tract infection, glucosuria, ketonuria, and haematuria did not affect it. Urine specific gravity was only modestly correlated with urine viscosity at 20 °C (rho = 0.259), 37 °C (rho = 0.266), and 42 °C (rho = 0.255). CONCLUSIONS: The kinematic viscosity of human urine is temperature dependent and higher than water. Urine specific gravity was not a good predictor of viscosity. Of factors that might affect urine viscosity, only proteinuria appeared to be clinically relevant. Estimates of urine viscosity provided in this manuscript may be useful for temperature modelling of bladder hyperthermia treatments with regard to correct prediction of the thermal conduction effects.

Authors
Inman, BA; Etienne, W; Rubin, R; Owusu, RA; Oliveira, TR; Rodriques, DB; Maccarini, PF; Stauffer, PR; Mashal, A; Dewhirst, MW
MLA Citation
Inman, Brant A., et al. “The impact of temperature and urinary constituents on urine viscosity and its relevance to bladder hyperthermia treatment..” Int J Hyperthermia, vol. 29, no. 3, May 2013, pp. 206–10. Pubmed, doi:10.3109/02656736.2013.775355.
PMID
23489163
Source
pubmed
Published In
Int J Hyperthermia
Volume
29
Issue
3
Publish Date
2013
Start Page
206
End Page
210
DOI
10.3109/02656736.2013.775355

Abstract 364: Exercise slows tumor progression and normalizes tumor vasculature in murine models of breast cancer.

Authors
Betof, AS; Jones, LW; Dewhirst, MW
MLA Citation
Betof, Allison S., et al. “Abstract 364: Exercise slows tumor progression and normalizes tumor vasculature in murine models of breast cancer..” Tumor Biology, American Association for Cancer Research, 2013. Crossref, doi:10.1158/1538-7445.am2013-364.
Source
crossref
Published In
Tumor Biology
Publish Date
2013
DOI
10.1158/1538-7445.am2013-364

The effect of carbohydrate restriction on prostate cancer tumor growth in a castrate mouse xenograft model.

BACKGROUND: No- and low-carbohydrate diets delay tumor growth compared to western diet (WD) in prostate cancer (PCa) xenograft studies. The effect of these diets in concert with androgen deprivation is unknown. METHODS: A total of 160 male SCID mice were injected with 1× 10(5) LAPC-4 human PCa cells. Of these, 150 mice were castrated and randomized to an ad libitum WD or fed via a paired-feeding protocol with a no-carbohydrate ketogenic diet (NCKD), 10% carbohydrate diet, or 20% carbohydrate diet. The remaining 10 mice were not castrated and were fed an ad libitum WD. The mice were sacrificed once volumes reached 1,000 mm3 and survival tested using the log-rank test. Serum from the median surviving 8 mice/group was assayed for insulin, IGF-1, and IGFBP-3. RESULTS: Body weights were roughly equal among groups. The 10 non-castrated mice experienced accelerated tumor growth. Among castrated mice, WD had the most rapid tumor growth; 20% carbohydrate diet the slowest (P = 0.046). Survival was not significantly different among the various carbohydrate restricted groups (P = 0.51). When pooled, there was a non-significant trend (P = 0.11) in improved survival among the carbohydrate restricted diets versus WD. No significant difference in serum insulin, IGF-1, and IGFBP-3 levels was noted among all groups at pre-randomization or at sacrifice. CONCLUSIONS: A 20% carbohydrate diet slowed tumor growth versus a WD. Though the benefit of carbohydrate restriction was somewhat less than in prior studies in non-castrate mice, these data still suggest diets achievable in humans may play a role in PCa management.

Authors
Caso, J; Masko, EM; Ii, JAT; Poulton, SH; Dewhirst, M; Pizzo, SV; Freedland, SJ
MLA Citation
Caso, Jorge, et al. “The effect of carbohydrate restriction on prostate cancer tumor growth in a castrate mouse xenograft model..” Prostate, vol. 73, no. 5, Apr. 2013, pp. 449–54. Pubmed, doi:10.1002/pros.22586.
PMID
23038057
Source
pubmed
Published In
Prostate
Volume
73
Issue
5
Publish Date
2013
Start Page
449
End Page
454
DOI
10.1002/pros.22586

Flaxseed-derived enterolactone is inversely associated with tumor cell proliferation in men with localized prostate cancer.

Enterolactone and enterodiol, mammalian lignans derived from dietary sources such as flaxseed, sesame seeds, kale, broccoli, and apricots, may impede tumor proliferation by inhibiting activation of nuclear factor kappa B (NFκB) and vascular endothelial growth factor (VEGF). We examined the associations between urinary enterolactone and enterodiol with prostatic tumor expression of NFκB, VEGF, and Ki67 among 147 patients with prostate cancer who participated in a presurgical trial of flaxseed supplementation (30 g/day) for ~30 days. Urinary enterolignans and tissue biomarkers were determined by high-performance liquid chromatography and immunohistochemistry, respectively. After supplementation, we observed significant correlations between intakes of plant lignan and urinary concentrations of total enterolignans (ρ=0.677, P<.0001), enterolactone (ρ=0.676, P<.0001), and enterodiol (ρ=0.628, P<.0001). Importantly, we observed that total urinary enterolignans and enterolactone were significantly and inversely correlated with Ki67 in the tumor tissue (ρ=-0.217, P=.011, and ρ=-0.230, P=.007, respectively), and a near-significant inverse association was observed for enterodiol (ρ=-0.159, P=.064). An inverse association was observed between enterolactone and VEGF (ρ=-0.143, P=.141), although this did not reach statistical significance. We did not observe an association between enterolignans and NFκB. In conclusion, flaxseed-derived enterolignans may hinder cancer cell proliferation via VEGF-associated pathways.

Authors
Azrad, M; Vollmer, RT; Madden, J; Dewhirst, M; Polascik, TJ; Snyder, DC; Ruffin, MT; Moul, JW; Brenner, DE; Demark-Wahnefried, W
MLA Citation
Azrad, Maria, et al. “Flaxseed-derived enterolactone is inversely associated with tumor cell proliferation in men with localized prostate cancer..” J Med Food, vol. 16, no. 4, Apr. 2013, pp. 357–60. Pubmed, doi:10.1089/jmf.2012.0159.
PMID
23566060
Source
pubmed
Published In
J Med Food
Volume
16
Issue
4
Publish Date
2013
Start Page
357
End Page
360
DOI
10.1089/jmf.2012.0159

Experimental radiotherapy Radiation induces aerobic glycolysis through reactive oxygen species

Background and purpose Although radiation induced reoxygenation has been thought to increase radiosensitivity, we have shown that its associated oxidative stress can have radioprotective effects, including stabilization of the transcription factor hypoxia inducible factor 1 (HIF-1). HIF-1 is known to regulate many of the glycolytic enzymes, thereby promoting aerobic glycolysis, which is known to promote treatment resistance. Thus, we hypothesized that reoxygenation after radiation would increase glycolysis. We previously showed that blockade of oxidative stress using a superoxide dismutase (SOD) mimic during reoxygenation can downregulate HIF-1 activity. Here we tested whether concurrent use of this drug with radiotherapy would reduce the switch to a glycolytic phenotype. Materials and methods 40 mice with skin fold window chambers implanted with 4T1 mammary carcinomas were randomized into (1) no treatment, (2) radiation alone, (3) SOD mimic alone, and (4) SOD mimic with concurrent radiation. All mice were imaged on the ninth day following tumor implantation (30 h following radiation treatment) following injection of a fluorescent glucose analog, 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2- deoxyglucose (2-NBDG). Hemoglobin saturation was measured by using hyperspectral imaging to quantify oxygenation state. Results Mice treated with radiation showed significantly higher 2-NBDG fluorescence compared to controls (p = 0.007). Hemoglobin saturation analysis demonstrated reoxygenation following radiation, coinciding with the observed increase in glycolysis. The concurrent use of the SOD mimic with radiation demonstrated a significant reduction in 2-NBDG fluorescence compared to effects seen after radiation alone, while having no effect on reoxygenation. Conclusions Radiation induces an increase in tumor glucose demand approximately 30 h following therapy during reoxygenation. The use of an SOD mimic can prevent the increase in aerobic glycolysis when used concurrently with radiation, without preventing reoxygenation. © 2013 Elsevier Ireland Ltd. All rights reserved.

Authors
Zhong, J; Rajaram, N; Brizel, DM; Frees, AE; Ramanujam, N; Batinic-Haberle, I; Dewhirst, MW
MLA Citation
Zhong, J., et al. “Experimental radiotherapy Radiation induces aerobic glycolysis through reactive oxygen species.” Radiotherapy and Oncology, vol. 106, no. 3, Mar. 2013, pp. 390–96. Scopus, doi:10.1016/j.radonc.2013.02.013.
Source
scopus
Published In
Radiotherapy and Oncology
Volume
106
Issue
3
Publish Date
2013
Start Page
390
End Page
396
DOI
10.1016/j.radonc.2013.02.013

Effects and potential mechanisms of exercise training on cancer progression: a translational perspective.

Over the past decade there has been increasing research and clinical interest in the role of exercise therapy/rehabilitation as an adjunct therapy to improve symptom control and management following a cancer diagnosis. More recently, the field of 'exercise - oncology' has broadened in scope to investigate whether the benefits extend beyond symptom control to modulate cancer-specific outcomes (i.e., cancer progression and metastasis). Here we review the extant epidemiological evidence examining the association between exercise behavior, functional capacity/exercise capacity, and cancer-specific recurrence and mortality as well as all-cause mortality individuals following a cancer diagnosis. We also evaluate evidence from clinical studies investigating the effects of structured exercise on blood-based biomarkers associated with cancer progression/metastasis as well findings from preclinical investigations examining the effects and molecular mechanisms of exercise in mouse models of cancer. Current gaps in knowledge are also discussed.

Authors
Betof, AS; Dewhirst, MW; Jones, LW
MLA Citation
Betof, Allison S., et al. “Effects and potential mechanisms of exercise training on cancer progression: a translational perspective..” Brain Behav Immun, vol. 30 Suppl, Mar. 2013, pp. S75–87. Pubmed, doi:10.1016/j.bbi.2012.05.001.
PMID
22610066
Source
pubmed
Published In
Brain Behav Immun
Volume
30 Suppl
Publish Date
2013
Start Page
S75
End Page
S87
DOI
10.1016/j.bbi.2012.05.001

Radiation induces aerobic glycolysis through reactive oxygen species.

BACKGROUND AND PURPOSE: Although radiation induced reoxygenation has been thought to increase radiosensitivity, we have shown that its associated oxidative stress can have radioprotective effects, including stabilization of the transcription factor hypoxia inducible factor 1 (HIF-1). HIF-1 is known to regulate many of the glycolytic enzymes, thereby promoting aerobic glycolysis, which is known to promote treatment resistance. Thus, we hypothesized that reoxygenation after radiation would increase glycolysis. We previously showed that blockade of oxidative stress using a superoxide dismutase (SOD) mimic during reoxygenation can downregulate HIF-1 activity. Here we tested whether concurrent use of this drug with radiotherapy would reduce the switch to a glycolytic phenotype. MATERIALS AND METHODS: 40 mice with skin fold window chambers implanted with 4T1 mammary carcinomas were randomized into (1) no treatment, (2) radiation alone, (3) SOD mimic alone, and (4) SOD mimic with concurrent radiation. All mice were imaged on the ninth day following tumor implantation (30 h following radiation treatment) following injection of a fluorescent glucose analog, 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2-deoxyglucose (2-NBDG). Hemoglobin saturation was measured by using hyperspectral imaging to quantify oxygenation state. RESULTS: Mice treated with radiation showed significantly higher 2-NBDG fluorescence compared to controls (p=0.007). Hemoglobin saturation analysis demonstrated reoxygenation following radiation, coinciding with the observed increase in glycolysis. The concurrent use of the SOD mimic with radiation demonstrated a significant reduction in 2-NBDG fluorescence compared to effects seen after radiation alone, while having no effect on reoxygenation. CONCLUSIONS: Radiation induces an increase in tumor glucose demand approximately 30 h following therapy during reoxygenation. The use of an SOD mimic can prevent the increase in aerobic glycolysis when used concurrently with radiation, without preventing reoxygenation.

Authors
Zhong, J; Rajaram, N; Brizel, DM; Frees, AE; Ramanujam, N; Batinic-Haberle, I; Dewhirst, MW
MLA Citation
Zhong, Jim, et al. “Radiation induces aerobic glycolysis through reactive oxygen species..” Radiother Oncol, vol. 106, no. 3, Mar. 2013, pp. 390–96. Pubmed, doi:10.1016/j.radonc.2013.02.013.
PMID
23541363
Source
pubmed
Published In
Radiother Oncol
Volume
106
Issue
3
Publish Date
2013
Start Page
390
End Page
396
DOI
10.1016/j.radonc.2013.02.013

Preclinical Dosimetry of Magnetic Fluid Hyperthermia for Bladder Cancer.

BACKGROUND: Despite positive efficacy, thermotherapy is not widely used in clinical oncology. Difficulties associated with field penetration and controlling power deposition patterns in heterogeneous tissue have limited its use for heating deep in the body. Heat generation using iron-oxide super-paramagnetic nanoparticles excited with magnetic fields has been demonstrated to overcome some of these limitations. The objective of this preclinical study is to investigate the feasibility of treating bladder cancer with magnetic fluid hyperthermia (MFH) by analyzing the thermal dosimetry of nanoparticle heating in a rat bladder model. METHODS: The bladders of 25 female rats were injected with 0.4 ml of Actium Biosystems magnetite-based nanoparticles (Actium Biosystems, Boulder CO) via catheters inserted in the urethra. To assess the distribution of nanoparticles in the rat after injection we used the 7 T small animal MRI system (Bruker ClinScan, Bruker BioSpin MRI GmbH, Ettlingen, Germany). Heat treatments were performed with a small animal magnetic field applicator (Actium Biosystems, Boulder CO) with a goal of raising bladder temperature to 42°C in <10min and maintaining for 60min. Temperatures were measured throughout the rat with seven fiberoptic temperature probes (OpSens Technologies, Quebec Canada) to characterize our ability to localize heat within the bladder target. RESULTS: The MRI study confirms the effectiveness of the catheterization procedure to homogenously distribute nanoparticles throughout the bladder. Thermal dosimetry data demonstrate our ability to controllably raise temperature of rat bladder ≥1°C/min to a steady-state of 42°C. CONCLUSION: Our data demonstrate that a MFH system provides well-localized heating of rat bladder with effective control of temperature in the bladder and minimal heating of surrounding tissues.

Authors
Oliveira, TR; Stauffer, PR; Lee, C-T; Landon, C; Etienne, W; Maccarini, PF; Inman, B; Dewhirst, MW
MLA Citation
Oliveira, Tiago R., et al. “Preclinical Dosimetry of Magnetic Fluid Hyperthermia for Bladder Cancer..” Proc Spie Int Soc Opt Eng, vol. 8584, 26 Feb. 2013. Pubmed, doi:10.1117/12.2005623.
PMID
23837123
Source
pubmed
Published In
Smart Structures and Materials 2005: Active Materials: Behavior and Mechanics
Volume
8584
Publish Date
2013
Start Page
1656985
DOI
10.1117/12.2005623

Automated measurement of blood flow velocity and direction and hemoglobin oxygen saturation in the rat lung using intravital microscopy.

Intravital microscopy of the pulmonary microcirculation in research animals is of great scientific interest for its utility in identifying regional changes in pulmonary microcirculatory blood flow. Although feasibility studies have been reported, the pulmonary window can be further refined into a practical tool for pharmaceutical research and drug development. We have established a method to visualize and quantify dynamic changes in three key features of lung function: microvascular red blood cell velocity, flow direction, and hemoglobin saturation. These physiological parameters were measured in an acute closed-chest pulmonary window, which allows real-time images to be captured by fluorescence and multispectral absorption microscopy; images were subsequently quantified using computerized analysis. We validated the model by quantifying changes in microcirculatory blood flow and hemoglobin saturation in two ways: 1) after changes in inspired oxygen content and 2) after pharmacological reduction of pulmonary blood flow via treatment with the β1 adrenergic receptor blocker metoprolol. This robust and relatively simple system facilitates pulmonary intravital microscopy in laboratory rats for pharmacological and physiological research.

Authors
Hanna, G; Fontanella, A; Palmer, G; Shan, S; Radiloff, DR; Zhao, Y; Irwin, D; Hamilton, K; Boico, A; Piantadosi, CA; Blueschke, G; Dewhirst, M; McMahon, T; Schroeder, T
MLA Citation
Hanna, Gabi, et al. “Automated measurement of blood flow velocity and direction and hemoglobin oxygen saturation in the rat lung using intravital microscopy..” Am J Physiol Lung Cell Mol Physiol, vol. 304, no. 2, Jan. 2013, pp. L86–91. Pubmed, doi:10.1152/ajplung.00178.2012.
PMID
23161885
Source
pubmed
Published In
Am J Physiol Lung Cell Mol Physiol
Volume
304
Issue
2
Publish Date
2013
Start Page
L86
End Page
L91
DOI
10.1152/ajplung.00178.2012

Sickle erythrocytes target cytotoxics to hypoxic tumor microvessels and potentiate a tumoricidal response.

Resistance of hypoxic solid tumor niches to chemotherapy and radiotherapy remains a major scientific challenge that calls for conceptually new approaches. Here we exploit a hitherto unrecognized ability of sickled erythrocytes (SSRBCs) but not normal RBCs (NLRBCs) to selectively target hypoxic tumor vascular microenviroment and induce diffuse vaso-occlusion. Within minutes after injection SSRBCs, but not NLRBCs, home and adhere to hypoxic 4T1 tumor vasculature with hemoglobin saturation levels at or below 10% that are distributed over 70% of the tumor space. The bound SSRBCs thereupon form microaggregates that obstruct/occlude up to 88% of tumor microvessels. Importantly, SSRBCs, but not normal RBCs, combined with exogenous prooxidant zinc protoporphyrin (ZnPP) induce a potent tumoricidal response via a mutual potentiating mechanism. In a clonogenic tumor cell survival assay, SSRBC surrogate hemin, along with H(2)O(2) and ZnPP demonstrate a similar mutual potentiation and tumoricidal effect. In contrast to existing treatments directed only to the hypoxic tumor cell, the present approach targets the hypoxic tumor vascular environment and induces injury to both tumor microvessels and tumor cells using intrinsic SSRBC-derived oxidants and locally generated ROS. Thus, the SSRBC appears to be a potent new tool for treatment of hypoxic solid tumors, which are notable for their resistance to existing cancer treatments.

Authors
Terman, DS; Viglianti, BL; Zennadi, R; Fels, D; Boruta, RJ; Yuan, H; Dreher, MR; Grant, G; Rabbani, ZN; Moon, E; Lan, L; Eble, J; Cao, Y; Sorg, B; Ashcraft, K; Palmer, G; Telen, MJ; Dewhirst, MW
MLA Citation
Terman, David S., et al. “Sickle erythrocytes target cytotoxics to hypoxic tumor microvessels and potentiate a tumoricidal response..” Plos One, vol. 8, no. 1, 2013. Pubmed, doi:10.1371/journal.pone.0052543.
Website
http://hdl.handle.net/10161/11164
PMID
23326340
Source
pubmed
Published In
Plos One
Volume
8
Issue
1
Publish Date
2013
Start Page
e52543
DOI
10.1371/journal.pone.0052543

Angiogenesis: an adaptive dynamic biological patterning problem.

Formation of functionally adequate vascular networks by angiogenesis presents a problem in biological patterning. Generated without predetermined spatial patterns, networks must develop hierarchical tree-like structures for efficient convective transport over large distances, combined with dense space-filling meshes for short diffusion distances to every point in the tissue. Moreover, networks must be capable of restructuring in response to changing functional demands without interruption of blood flow. Here, theoretical simulations based on experimental data are used to demonstrate that this patterning problem can be solved through over-abundant stochastic generation of vessels in response to a growth factor generated in hypoxic tissue regions, in parallel with refinement by structural adaptation and pruning. Essential biological mechanisms for generation of adequate and efficient vascular patterns are identified and impairments in vascular properties resulting from defects in these mechanisms are predicted. The results provide a framework for understanding vascular network formation in normal or pathological conditions and for predicting effects of therapies targeting angiogenesis.

Authors
Secomb, TW; Alberding, JP; Hsu, R; Dewhirst, MW; Pries, AR
MLA Citation
Secomb, Timothy W., et al. “Angiogenesis: an adaptive dynamic biological patterning problem..” Plos Comput Biol, vol. 9, no. 3, 2013. Pubmed, doi:10.1371/journal.pcbi.1002983.
PMID
23555218
Source
pubmed
Published In
Plos Computational Biology
Volume
9
Issue
3
Publish Date
2013
Start Page
e1002983
DOI
10.1371/journal.pcbi.1002983

The effect of carbohydrate restriction on prostate cancer tumor growth in a castrate mouse xenograft model

BACKGROUND No- and low-carbohydrate diets delay tumor growth compared to western diet (WD) in prostate cancer (PCa) xenograft studies. The effect of these diets in concert with androgen deprivation is unknown. METHODS A total of 160 male SCID mice were injected with 1× 105 LAPC-4 human PCa cells. Of these, 150 mice were castrated and randomized to an ad libitum WD or fed via a paired-feeding protocol with a no-carbohydrate ketogenic diet (NCKD), 10% carbohydrate diet, or 20% carbohydrate diet. The remaining 10 mice were not castrated and were fed an ad libitum WD. The mice were sacrificed once volumes reached 1,000 mm3 and survival tested using the log-rank test. Serum from the median surviving 8 mice/group was assayed for insulin, IGF-1, and IGFBP-3. RESULTS Body weights were roughly equal among groups. The 10 non-castrated mice experienced accelerated tumor growth. Among castrated mice, WD had the most rapid tumor growth; 20% carbohydrate diet the slowest (P = 0.046). Survival was not significantly different among the various carbohydrate restricted groups (P = 0.51). When pooled, there was a non-significant trend (P = 0.11) in improved survival among the carbohydrate restricted diets versus WD. No significant difference in serum insulin, IGF-1, and IGFBP-3 levels was noted among all groups at pre-randomization or at sacrifice. CONCLUSIONS A 20% carbohydrate diet slowed tumor growth versus a WD. Though the benefit of carbohydrate restriction was somewhat less than in prior studies in non-castrate mice, these data still suggest diets achievable in humans may play a role in PCa management. Copyright © 2012 Wiley Periodicals, Inc.

Authors
Caso, J; Masko, EM; Ii, JAT; Poulton, SH; Dewhirst, M; Pizzo, SV; Freedland, SJ
MLA Citation
Caso, J., et al. “The effect of carbohydrate restriction on prostate cancer tumor growth in a castrate mouse xenograft model.” Prostate, vol. 73, no. 5, 2013, pp. 449–54. Scival, doi:10.1002/pros.22586.
Source
scival
Published In
Prostate
Volume
73
Issue
5
Publish Date
2013
Start Page
449
End Page
454
DOI
10.1002/pros.22586

Effects and potential mechanisms of exercise training on cancer progression: A translational perspective

Over the past decade there has been increasing research and clinical interest in the role of exercise therapy/rehabilitation as an adjunct therapy to improve symptom control and management following a cancer diagnosis. More recently, the field of 'exercise - oncology' has broadened in scope to investigate whether the benefits extend beyond symptom control to modulate cancer-specific outcomes (i.e., cancer progression and metastasis). Here we review the extant epidemiological evidence examining the association between exercise behavior, functional capacity/exercise capacity, and cancer-specific recurrence and mortality as well as all-cause mortality individuals following a cancer diagnosis. We also evaluate evidence from clinical studies investigating the effects of structured exercise on blood-based biomarkers associated with cancer progression/metastasis as well findings from preclinical investigations examining the effects and molecular mechanisms of exercise in mouse models of cancer. Current gaps in knowledge are also discussed. © 2012 Elsevier Inc.

Authors
Betof, AS; Dewhirst, MW; Jones, LW
MLA Citation
Betof, A. S., et al. “Effects and potential mechanisms of exercise training on cancer progression: A translational perspective.” Brain, Behavior, and Immunity, vol. 30, no. SUPPL., 2013, pp. S75–87. Scival, doi:10.1016/j.bbi.2012.05.001.
Source
scival
Published In
Brain, Behavior, and Immunity
Volume
30
Issue
SUPPL.
Publish Date
2013
Start Page
S75
End Page
S87
DOI
10.1016/j.bbi.2012.05.001

Resveratrol worsens survival in SCID mice with prostate cancer xenografts in a cell-line specific manner, through paradoxical effects on oncogenic pathways

BACKGROUND Resveratrol increases lifespan and decreases the risk of many cancers. We hypothesized resveratrol will slow the growth of human prostate cancer xenografts. METHODS SCID mice were fed Western diet (40% fat, 44% carbohydrate, 16% protein by kcal). One week later, human prostate cancer cells, either LAPC-4 (151 mice) or LNCaP (94 mice) were injected subcutaneously. Three weeks after injection, LAPC-4 mice were randomized to Western diet (control group), Western diet plus resveratrol 50 mg/kg/day, or Western diet plus resveratrol 100 mg/kg/day. The LNCaP mice were randomized to Western diet or Western diet plus resveratrol 50 mg/kg/day. Mice were sacrificed when tumors reached 1,000 mm3. Survival differences among groups were assessed using Cox proportional hazards. Serum insulin and IGF axis were assessed using ELISAs. Gene expression was analyzed using Affymetrix gene arrays. RESULTS Compared to control in the LAPC-4 study, resveratrol was associated with decreased survival (50 mg/kg/day - HR 1.53, P = 0.04; 100 mg/kg/day - HR 1.22, P = 0.32). In the LNCaP study, resveratrol did not change survival (HR 0.77, P = 0.22). In combined analysis of both resveratrol 50 mg/kg/day groups, IGF-1 was decreased (P = 0.05) and IGFBP-2 was increased (P = 0.01). Resveratrol induced different patterns of gene expression changes in each xenograft model, with upregulation of oncogenic pathways E2F3 and beta-catenin in LAPC-4 tumors. CONCLUSION Resveratrol was associated with significantly worse survival with LAPC-4 tumors, but unchanged survival with LNCaP. Based on these preliminary data that resveratrol may be harmful, caution should be advised in using resveratrol for patients until further studies can be conducted. Prostate 73: 754-762, 2013. © 2012 Wiley Periodicals, Inc. Copyright © 2012 Wiley Periodicals, Inc.

Authors
Klink, JC; Tewari, AK; Masko, EM; Antonelli, J; Febbo, PG; Cohen, P; Dewhirst, MW; Pizzo, SV; Freedland, SJ
MLA Citation
Klink, J. C., et al. “Resveratrol worsens survival in SCID mice with prostate cancer xenografts in a cell-line specific manner, through paradoxical effects on oncogenic pathways.” Prostate, vol. 73, no. 7, 2013, pp. 754–62. Scival, doi:10.1002/pros.22619.
Source
scival
Published In
Prostate
Volume
73
Issue
7
Publish Date
2013
Start Page
754
End Page
762
DOI
10.1002/pros.22619

Novel Approaches to Treatment of Hepatocellular Carcinoma and Hepatic Metastases Using Thermal Ablation and Thermosensitive Liposomes

Because of the limitations of surgical resection, thermal ablation is commonly used for the treatment of hepatocellular carcinoma and liver metastases. Current methods of ablation can result in marginal recurrences of larger lesions and in tumors located near large vessels. This review presents a novel approach for extending treatment out to the margins where temperatures do not provide complete treatment with ablation alone, by combining thermal ablation with drug-loaded thermosensitive liposomes. A history of the development of thermosensitive liposomes is presented. Clinical trials have shown that the combination of radiofrequency ablation and doxorubicin-loaded thermosensitive liposomes is a promising treatment. © 2013 Elsevier Inc.

Authors
Dewhirst, MW; Landon, CD; Hofmann, CL; Stauffer, PR
MLA Citation
Dewhirst, M. W., et al. “Novel Approaches to Treatment of Hepatocellular Carcinoma and Hepatic Metastases Using Thermal Ablation and Thermosensitive Liposomes.” Surgical Oncology Clinics of North America, vol. 22, no. 3, 2013, pp. 545–61. Scival, doi:10.1016/j.soc.2013.02.009.
Source
scival
Published In
Surgical Oncology Clinics of North America
Volume
22
Issue
3
Publish Date
2013
Start Page
545
End Page
561
DOI
10.1016/j.soc.2013.02.009

CEM43°C thermal dose thresholds: A potential guide for magnetic resonance radiofrequency exposure levels?

Objective: To define thresholds of safe local temperature increases for MR equipment that exposes patients to radiofrequency fields of high intensities for long duration. These MR systems induce heterogeneous energy absorption patterns inside the body and can create localised hotspots with a risk of overheating. Methods: The MRI + EUREKA research consortium organised a "Thermal Workshop on RF Hotspots". The available literature on thresholds for thermal damage and the validity of the thermal dose (TD) model were discussed. Results/Conclusions: The following global TD threshold guidelines for safe use of MR are proposed: 1. All persons: maximum local temperature of any tissue limited to 39°C 2. Persons with compromised thermoregulation AND (a) Uncontrolled conditions: maximum local temperature limited to 39 °C (b) Controlled conditions: TD < 2 CEM43 °C 3. Persons with uncompromised thermoregulation AND (a) Uncontrolled conditions: TD < 2 CEM43° C (b) Controlled conditions: TD < 9 CEM43 °C The following definitions are applied: Controlled conditions A medical doctor or a dedicated trained person can respond instantly to heat-induced physiological stress Compromised thermoregulation All persons with impaired systemic or reduced local thermoregulation Key Points: • Standard MRI can cause local heating by radiofrequency absorption. • Monitoring thermal dose (in units of CEM43° C) can control risk during MRI. • 9 CEM43° C seems an acceptable thermal dose threshold for most patients. • For skin, muscle, fat and bone,16 CEM43° C is likely acceptable. © 2013 European Society of Radiology.

Authors
Rhoon, GCV; Samaras, T; Yarmolenko, PS; Dewhirst, MW; Neufeld, E; Kuster, N
MLA Citation
Rhoon, G. C. V., et al. “CEM43°C thermal dose thresholds: A potential guide for magnetic resonance radiofrequency exposure levels?.” European Radiology, vol. 23, no. 8, 2013, pp. 2215–27. Scival, doi:10.1007/s00330-013-2825-y.
Source
scival
Published In
European Radiology
Volume
23
Issue
8
Publish Date
2013
Start Page
2215
End Page
2227
DOI
10.1007/s00330-013-2825-y

Catabolism of exogenous lactate reveals it as a legitimate metabolic substrate in breast cancer.

Lactate accumulation in tumors has been associated with metastases and poor overall survival in cancer patients. Lactate promotes angiogenesis and metastasis, providing rationale for understanding how it is processed by cells. The concentration of lactate in tumors is a balance between the amount produced, amount carried away by vasculature and if/how it is catabolized by aerobic tumor or stromal cells. We examined lactate metabolism in human normal and breast tumor cell lines and rat breast cancer: 1. at relevant concentrations, 2. under aerobic vs. hypoxic conditions, 3. under conditions of normo vs. hypoglucosis. We also compared the avidity of tumors for lactate vs. glucose and identified key lactate catabolites to reveal how breast cancer cells process it. Lactate was non-toxic at clinically relevant concentrations. It was taken up and catabolized to alanine and glutamate by all cell lines. Kinetic uptake rates of lactate in vivo surpassed that of glucose in R3230Ac mammary carcinomas. The uptake appeared specific to aerobic tumor regions, consistent with the proposed "metabolic symbiont" model; here lactate produced by hypoxic cells is used by aerobic cells. We investigated whether treatment with alpha-cyano-4-hydroxycinnamate (CHC), a MCT1 inhibitor, would kill cells in the presence of high lactate. Both 0.1 mM and 5 mM CHC prevented lactate uptake in R3230Ac cells at lactate concentrations at ≤ 20 mM but not at 40 mM. 0.1 mM CHC was well-tolerated by R3230Ac and MCF7 cells, but 5 mM CHC killed both cell lines ± lactate, indicating off-target effects. This study showed that breast cancer cells tolerate and use lactate at clinically relevant concentrations in vitro (± glucose) and in vivo. We provided additional support for the metabolic symbiont model and discovered that breast cells prevailingly take up and catabolize lactate, providing rationale for future studies on manipulation of lactate catabolism pathways for therapy.

Authors
Kennedy, KM; Scarbrough, PM; Ribeiro, A; Richardson, R; Yuan, H; Sonveaux, P; Landon, CD; Chi, J-T; Pizzo, S; Schroeder, T; Dewhirst, MW
MLA Citation
Kennedy, Kelly M., et al. “Catabolism of exogenous lactate reveals it as a legitimate metabolic substrate in breast cancer..” Plos One, vol. 8, no. 9, 2013. Pubmed, doi:10.1371/journal.pone.0075154.
PMID
24069390
Source
pubmed
Published In
Plos One
Volume
8
Issue
9
Publish Date
2013
Start Page
e75154
DOI
10.1371/journal.pone.0075154

Delivery rate affects uptake of a fluorescent glucose analog in murine metastatic breast cancer.

We demonstrate an optical strategy using intravital microscopy of dorsal skin flap window chamber models to image glucose uptake and vascular oxygenation in vivo. Glucose uptake was imaged using a fluorescent glucose analog, 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2-deoxyglucose (2-NBDG). SO2 was imaged using the differential absorption properties of oxygenated [HbO2] and deoxygenated hemoglobin [dHb]. This study was carried out on two sibling murine mammary adenocarcinoma lines, 4T1 and 4T07. 2-NBDG uptake in the 4T1 tumors was lowest when rates of delivery and clearance were lowest, indicating perfusion-limited uptake in poorly oxygenated tumor regions. For increasing rates of delivery that were still lower than the glucose consumption rate (as measured in vitro), both 2-NBDG uptake and the clearance rate from the tumor increased. When the rate of delivery of 2-NBDG exceeded the glucose consumption rate, 2-NBDG uptake decreased with any further increase in rate of delivery, but the clearance rate continued to increase. This inflection point was not observed in the 4T07 tumors due to an absence of low delivery rates close to the glucose consumption rate. In the 4T07 tumors, 2-NBDG uptake increased with increasing rates of delivery at low rates of clearance. Our results demonstrate that 2-NBDG uptake in tumors is influenced by the rates of delivery and clearance of the tracer. The rates of delivery and clearance are, in turn, dependent on vascular oxygenation of the tumors. Knowledge of the kinetics of tracer uptake as well as vascular oxygenation is essential to make an informed assessment of glucose demand of a tumor.

Authors
Rajaram, N; Frees, AE; Fontanella, AN; Zhong, J; Hansen, K; Dewhirst, MW; Ramanujam, N
MLA Citation
Rajaram, Narasimhan, et al. “Delivery rate affects uptake of a fluorescent glucose analog in murine metastatic breast cancer..” Plos One, vol. 8, no. 10, 2013. Pubmed, doi:10.1371/journal.pone.0076524.
PMID
24204635
Source
pubmed
Published In
Plos One
Volume
8
Issue
10
Publish Date
2013
Start Page
e76524
DOI
10.1371/journal.pone.0076524

A multi-institution experience comparing the clinical and physiologic differences between upper extremity and lower extremity melphalan-based isolated limb infusion.

BACKGROUND: Although studies of melphalan-based isolated limb infusion (ILI) combine data from upper extremity (UE) treatments with those from lower extremity (LE) treatments, differences between the 2 may be clinically important. METHODS: Candidates for UE ILI (n = 51) and LE ILI (n = 192) were identified from prospective databases at 2 institutions. The Response Evaluation Criteria in Solid Tumors and Wieberdink toxicity scale were used as appropriate. RESULTS: The following patients had indications for UE ILI: melanoma, 36 of 47 patients (77%); sarcoma, 5 of 47 patients (11%); Merkel cell sarcoma, 3 of 47 patients (6%), and squamous cell carcinoma, 3 of 47 patients (6%). The patients who underwent UE ILI, as expected, had lower limb volumes (mean, 2.5 L vs 8.6 L; P < .001) and lower mean melphalan doses (20.7 mg vs 49.5 mg; P < .001). On perfusate blood gas analysis, the mean base excess at 30 minutes (-13.9 vs -9.1; P < .001) and the mean pH at 30 minutes (7.06 vs 7.15; P < .001) were lower for UE procedures than for LE procedures, although the mean ischemic time was longer in LE procedures (67.2 minutes) than in UE procedures (61.6 minutes; P = .03). The rate of regional toxicity grade ≥3 for UE ILI was 7% compared with 24% (P = .005) for LE ILI. There was no difference in the complete response rate for melanoma UE procedures (28%; 95% confidence interval, 16%-44%) compared with LE ILI procedures (32%; 95% confidence interval, 25%-39%). CONCLUSIONS: ILI for UE disease was associated with similar complete response rates but lower toxicity than ILI for LE disease and with different physiologic sequelae despite comparable methods. The UE appears relatively resistant to toxic effects of melphalan-based ILI as currently performed, which suggests a potential for further optimization of drug dosing for UE ILI.

Authors
Beasley, GM; Sharma, K; Wong, J; Miller, M; Turley, RS; Lidsky, M; Masoud, M; Dewhirst, MW; Mosca, PJ; Zager, JS; Tyler, DS
MLA Citation
Beasley, Georgia M., et al. “A multi-institution experience comparing the clinical and physiologic differences between upper extremity and lower extremity melphalan-based isolated limb infusion..” Cancer, vol. 118, no. 24, Dec. 2012, pp. 6136–43. Pubmed, doi:10.1002/cncr.27676.
PMID
22674423
Source
pubmed
Published In
Cancer
Volume
118
Issue
24
Publish Date
2012
Start Page
6136
End Page
6143
DOI
10.1002/cncr.27676

Overcoming limitations in nanoparticle drug delivery: triggered, intravascular release to improve drug penetration into tumors.

Traditionally, the goal of nanoparticle-based chemotherapy has been to decrease normal tissue toxicity by improving drug specificity to tumors. The enhanced permeability and retention effect can permit passive accumulation into tumor interstitium. However, suboptimal delivery is achieved with most nanoparticles because of heterogeneities of vascular permeability, which limits nanoparticle penetration. Furthermore, slow drug release limits bioavailability. We developed a fast drug-releasing liposome triggered by local heat that has already shown substantial antitumor efficacy and is in human trials. Here, we show that thermally sensitive liposomes (Dox-TSL) release doxorubicin inside the tumor vasculature. Real-time confocal imaging of doxorubicin delivery to murine tumors in window chambers and histologic analysis of flank tumors illustrates that intravascular drug release increases free drug in the interstitial space. This increases both the time that tumor cells are exposed to maximum drug levels and the drug penetration distance, compared with free drug or traditional pegylated liposomes. These improvements in drug bioavailability establish a new paradigm in drug delivery: rapidly triggered drug release in the tumor bloodstream.

Authors
Manzoor, AA; Lindner, LH; Landon, CD; Park, J-Y; Simnick, AJ; Dreher, MR; Das, S; Hanna, G; Park, W; Chilkoti, A; Koning, GA; ten Hagen, TLM; Needham, D; Dewhirst, MW
MLA Citation
Manzoor, Ashley A., et al. “Overcoming limitations in nanoparticle drug delivery: triggered, intravascular release to improve drug penetration into tumors..” Cancer Res, vol. 72, no. 21, Nov. 2012, pp. 5566–75. Pubmed, doi:10.1158/0008-5472.CAN-12-1683.
PMID
22952218
Source
pubmed
Published In
Cancer Res
Volume
72
Issue
21
Publish Date
2012
Start Page
5566
End Page
5575
DOI
10.1158/0008-5472.CAN-12-1683

Gene Expression Response to Ionizing Radiation in Luminal and Basal Breast Cancer Cell Lines

Authors
Horton, JK; Fels, DR; Kung, H; Ashcraft, K; Dewhirst, MW; Chi, JA
MLA Citation
Horton, J. K., et al. “Gene Expression Response to Ionizing Radiation in Luminal and Basal Breast Cancer Cell Lines.” International Journal of Radiation Oncology*Biology*Physics, vol. 84, no. 3, Elsevier BV, 2012, pp. S710–S710. Crossref, doi:10.1016/j.ijrobp.2012.07.1900.
Source
crossref
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
84
Issue
3
Publish Date
2012
Start Page
S710
End Page
S710
DOI
10.1016/j.ijrobp.2012.07.1900

Heat induces gene amplification in cancer cells.

BACKGROUND: Hyperthermia plays an important role in cancer therapy. However, as with radiation, it can cause DNA damage and therefore genetic instability. We studied whether hyperthermia can induce gene amplification in cancer cells and explored potential underlying molecular mechanisms. MATERIALS AND METHODS: (1) Hyperthermia: HCT116 colon cancer cells received water-submerged heating treatment at 42 or 44°C for 30 min; (2) gene amplification assay using N-(phosphoacetyl)-L-aspartate (PALA) selection of cabamyl-P-synthetase, aspartate transcarbarmylase, dihydro-orotase (cad) gene amplified cells; (3) southern blotting for confirmation of increased cad gene copies in PALA-resistant cells; (4) γH2AX immunostaining to detect γH2AX foci as an indication for DNA double strand breaks. RESULTS: (1) Heat exposure at 42 or 44°C for 30 min induces gene amplification. The frequency of cad gene amplification increased by 2.8 and 6.5 folds respectively; (2) heat exposure at both 42 and 44°C for 30 min induces DNA double strand breaks in HCT116 cells as shown by γH2AX immunostaining. CONCLUSION: This study shows that heat exposure can induce gene amplification in cancer cells, likely through the generation of DNA double strand breaks, which are believed to be required for the initiation of gene amplification. This process may be promoted by heat when cellular proteins that are responsible for checkpoints, DNA replication, DNA repair and telomere functions are denatured. To our knowledge, this is the first study to provide direct evidence of hyperthermia induced gene amplification.

Authors
Yan, B; Ouyang, R; Huang, C; Liu, F; Neill, D; Li, C; Dewhirst, M
MLA Citation
Yan, Bin, et al. “Heat induces gene amplification in cancer cells..” Biochem Biophys Res Commun, vol. 427, no. 3, Oct. 2012, pp. 473–77. Pubmed, doi:10.1016/j.bbrc.2012.09.011.
PMID
22975353
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
427
Issue
3
Publish Date
2012
Start Page
473
End Page
477
DOI
10.1016/j.bbrc.2012.09.011

Differential Activation of Cell Death Pathways After Ionizing Radiation in Luminal and Basal Breast Cancer Cell Lines

Authors
Horton, JK; Fels, DR; Kung, H-N; Zhou, Y; Ashcraft, K; Dewhirst, MW; Chi, J-TA
MLA Citation
Horton, Janet K., et al. “Differential Activation of Cell Death Pathways After Ionizing Radiation in Luminal and Basal Breast Cancer Cell Lines.” Journal of Womens Health, vol. 21, no. 10, MARY ANN LIEBERT INC, Oct. 2012, pp. 992–992.
Source
wos
Published In
Journal of Women'S Health (2002)
Volume
21
Issue
10
Publish Date
2012
Start Page
992
End Page
992

Carbohydrate restriction and lactate transporter inhibition in a mouse xenograft model of human prostate cancer.

UNLABELLED: What's known on the subject? and What does the study add? It is known that both lactate inhibition and carbohydrate restriction inhibit tumour growth. What is unknown is whether the two work synergistically together. This study adds that though the combination of lactate inhibition and carbohydrate restriction did not synergistically slow tumour growth in our model, we confirmed that carbohydrate restriction started after tumour inoculation slowed tumour growth. Moreover, lactate inhibition resulted in changes in the tumour microenvironment that may have implications for future metabolic targeting of prostate cancer growth. OBJECTIVE: To determine if a no-carbohydrate ketogenic diet (NCKD) and lactate transporter inhibition can exert a synergistic effect on delaying prostate tumour growth in a xenograft mouse model of human prostate cancer. MATERIALS AND METHODS: 120 nude athymic male mice (aged 6-8 weeks) were injected s.c. in the flank with 1.0 × 10(5) LAPC-4 prostate cancer cells. • Mice were randomized to one of four treatment groups: Western diet (WD, 35% fat, 16% protein, 49% carbohydrate) and vehicle (Veh) treatment; WD and mono-carboxylate transporter-1 (MCT1) inhibition via α-cyano-4-hydroxycinnamate (CHC) delivered through a mini osmotic pump; NCKD (84% fat, 16% protein, 0% carbohydrate) plus Veh; or NCKD and MCT1 inhibition. • Mice were fed and weighed three times per week and feed was adjusted to maintain similar body weights. • Tumour size was measured twice weekly and the combined effect of treatment was tested via Kruskal-Wallis analysis of all four groups. Independent effects of treatment (NCKD vs WD and CHC vs Veh) on tumour volume were tested using linear regression analysis. • All mice were killed on Day 53 (conclusion of pump ejection), and serum and tumour sections were analysed for various markers. Again, combined and independent effects of treatment were tested using Kruskal-Wallis and linear regression analysis, respectively. RESULTS: There were no significant differences in tumour volumes among the four groups (P= 0.09). • When testing the independent effects of treatment, NCKD was significantly associated with lower tumour volumes at the end of the experiment (P= 0.026), while CHC administration was not (P= 0.981). However, CHC was associated with increased necrotic fraction (P < 0.001). CONCLUSIONS: Differences in tumour volumes were observed only in comparisons between mice fed a NCKD and mice fed a WD. • MCT1 inhibition did not have a significant effect on tumour volume, although it was associated with increased necrotic fraction.

Authors
Kim, HS; Masko, EM; Poulton, SL; Kennedy, KM; Pizzo, SV; Dewhirst, MW; Freedland, SJ
MLA Citation
Kim, Howard S., et al. “Carbohydrate restriction and lactate transporter inhibition in a mouse xenograft model of human prostate cancer..” Bju Int, vol. 110, no. 7, Oct. 2012, pp. 1062–69. Pubmed, doi:10.1111/j.1464-410X.2012.10971.x.
PMID
22394625
Source
pubmed
Published In
Bju Int
Volume
110
Issue
7
Publish Date
2012
Start Page
1062
End Page
1069
DOI
10.1111/j.1464-410X.2012.10971.x

A simplified synthesis of the hypoxia imaging agent 2-(2-Nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-[(18)F]pentafluoropropyl)-acetamide ([18F]EF5).

INTRODUCTION: [(18)F]EF5 is a validated marker for PET imaging of tumor hypoxia. It is prepared by reacting a trifluoroallyl precursor with carrier-added [(18)F]F(2) gas in trifluoroacetic acid (TFA) solvent. We report here an improved radiosynthesis and purification of [(18)F]EF5 by utilizing an electroformed nickel (Ni) target for [(18)F]F(2) production, and Oasis® HLB cartridges for on-line solid phase extraction of [(18)F]EF5 prior to HPLC purification. METHODS: [(18)F]F(2) was produced by deuteron bombardment of neon plus F(2) in an Ni target, and bubbled through the radiolabelling precursor solution. Purification was achieved by extracting the contents of the crude reaction mixture onto Oasis HLB cartridges, and subsequently eluted onto a semi-preparative HPLC column for further separation. Purified [(18)F]EF5 was evaluated in small animal PET studies using HCT116 tumor xenografts in nude mice. RESULTS: The electroformed Ni target enabled recovery of >75% of the radioactivity from the cyclotron target, resulting in 16.2 ± 2.2 GBq (438 ± 58 mCi) of [(18)F]F(2) available for the synthesis. Use of Oasis cartridges yielded a less complex mixture for purification. On average, 1140 ± 200 MBq (30.8 ± 5.4 mCi) of [(18)F]EF5 were collected at EOS. Small animal PET imaging studies showed specific retention of [(18)F]EF5 in tumors, with tumor-to-muscle ratios of 2.7 ± 0.3 at about 160 min after injection. CONCLUSION: A simple procedure has been developed for the routine synthesis of [(18)F]EF5 in amounts and purity required for clinical studies. This new method avoids the need for TFA evaporation and also enables facile automation of the synthesis using commercially available radiosynthesis modules.

Authors
Chitneni, SK; Bida, GT; Dewhirst, MW; Zalutsky, MR
MLA Citation
Chitneni, Satish K., et al. “A simplified synthesis of the hypoxia imaging agent 2-(2-Nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-[(18)F]pentafluoropropyl)-acetamide ([18F]EF5)..” Nucl Med Biol, vol. 39, no. 7, Oct. 2012, pp. 1012–18. Pubmed, doi:10.1016/j.nucmedbio.2012.05.006.
PMID
22727821
Source
pubmed
Published In
Nucl Med Biol
Volume
39
Issue
7
Publish Date
2012
Start Page
1012
End Page
1018
DOI
10.1016/j.nucmedbio.2012.05.006

Exercise modulation of the host-tumor interaction in an orthotopic model of murine prostate cancer.

The purpose of this study is to investigate the effects of exercise on cancer progression, metastasis, and underlying mechanisms in an orthotopic model of murine prostate cancer. C57BL/6 male mice (6-8 wk of age) were orthotopically injected with transgenic adenocarcinoma of mouse prostate C-1 cells (5 × 10(5)) and randomly assigned to exercise (n = 28) or a non-intervention control (n = 31) groups. The exercise group was given voluntary access to a wheel 24 h/day for the duration of the study. Four mice per group were serially killed on days 14, 31, and 36; the remaining 38 mice (exercise, n = 18; control, n = 20) were killed on day 53. Before death, MRI was performed to assess tumor blood perfusion. Primary tumor growth rate was comparable between groups, but expression of prometastatic genes was significantly modulated in exercising animals with a shift toward reduced metastasis. Exercise was associated with increased activity of protein kinases within the MEK/MAPK and PI3K/mTOR signaling cascades with subsequent increased intratumoral protein levels of HIF-1α and VEGF. This was associated with improved tumor vascularization. Multiplex ELISAs revealed distinct reductions in plasma concentrations of several angiogenic cytokines in the exercise group, which was associated with increased expression of angiogenic and metabolic genes in the skeletal muscle. Exercise-induced stabilization of HIF-1α and subsequent upregulation of VEGF was associated with "productive" tumor vascularization with a shift toward suppressed metastasis in an orthotopic model of prostate cancer.

Authors
Jones, LW; Antonelli, J; Masko, EM; Broadwater, G; Lascola, CD; Fels, D; Dewhirst, MW; Dyck, JRB; Nagendran, J; Flores, CT; Betof, AS; Nelson, ER; Pollak, M; Dash, RC; Young, ME; Freedland, SJ
MLA Citation
Jones, Lee W., et al. “Exercise modulation of the host-tumor interaction in an orthotopic model of murine prostate cancer..” J Appl Physiol (1985), vol. 113, no. 2, July 2012, pp. 263–72. Pubmed, doi:10.1152/japplphysiol.01575.2011.
PMID
22604887
Source
pubmed
Published In
J Appl Physiol (1985)
Volume
113
Issue
2
Publish Date
2012
Start Page
263
End Page
272
DOI
10.1152/japplphysiol.01575.2011

Bevacizumab-induced alterations in vascular permeability and drug delivery: a novel approach to augment regional chemotherapy for in-transit melanoma.

PURPOSE: To investigate whether the systemically administered anti-VEGF monoclonal antibody bevacizumab could improve regional chemotherapy treatment of advanced extremity melanoma by enhancing delivery and tumor uptake of regionally infused melphalan (LPAM). EXPERIMENTAL DESIGN: After treatment with systemic bevacizumab or saline, changes in vascular permeability were determined by spectrophotometric analysis of tumors infused with Evan's blue dye. Changes in vascular structure and tumor hemoglobin-oxygen saturation HbO(2) were determined by intravital microscopy and diffuse reflectance spectroscopy, respectively. Rats bearing the low-VEGF secreting DM738 and the high-VEGF secreting DM443 melanoma xenografts underwent isolated limb infusion (ILI) with melphalan (LPAM) or saline via the femoral vessels. The effect of bevacizumab on terminal drug delivery was determined by immunohistochemical analysis of LPAM-DNA adducts in tumor tissues. RESULTS: Single-dose bevacizumab given three days before ILI with LPAM significantly decreased vascular permeability (50.3% in DM443, P < 0.01 and 35% in DM738, P < 0.01) and interstitial fluid pressure (57% in DM443, P < 0.01 and 50% in DM738, P = 0.01). HbO(2) decreased from baseline in mice following treatment with bevacizumab. Systemic bevacizumab significantly enhanced tumor response to ILI with LPAM in two melanoma xenografts, DM443 and DM738, increasing quadrupling time 37% and 113%, respectively (P = 0.03). Immunohistochemical analyses of tumor specimens showed that pretreatment with systemic bevacizumab markedly increased LPAM-DNA adduct formation. CONCLUSIONS: Systemic treatment with bevacizumab before regional chemotherapy increases delivery of LPAM to tumor cells and represents a novel way to augment response to regional therapy for advanced extremity melanoma.

Authors
Turley, RS; Fontanella, AN; Padussis, JC; Toshimitsu, H; Tokuhisa, Y; Cho, EH; Hanna, G; Beasley, GM; Augustine, CK; Dewhirst, MW; Tyler, DS
MLA Citation
Turley, Ryan S., et al. “Bevacizumab-induced alterations in vascular permeability and drug delivery: a novel approach to augment regional chemotherapy for in-transit melanoma..” Clin Cancer Res, vol. 18, no. 12, June 2012, pp. 3328–39. Pubmed, doi:10.1158/1078-0432.CCR-11-3000.
PMID
22496203
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
18
Issue
12
Publish Date
2012
Start Page
3328
End Page
3339
DOI
10.1158/1078-0432.CCR-11-3000

SU-E-I-07: Proposal for a Novel Algorithm of Effective Dose Evaluation for Medical Radiation Exposure.

PURPOSE: The validity of effective dose (ED) in medical applications, which mostly involving partial-organ irradiation, has long been argued. We now propose a new algorithm of effective dose evaluation for medical radiation exposure. The new algorithm will include new Relative Volume Factors, or RVFs, to account for the relative irradiated volume of the partially-irradiated organs, such as skin and bone marrow. METHODS: To validate the proposed algorithm, three ED evaluation methods were applied to five neuro-imaging protocols of a C-arm cone-beam CT: 1) MOSFET-anthropomorphic- phantom measurement for organ doses, ED evaluated with the original ICRP algorithm; 2) using the same MOSFET-measured organ doses, ED evaluated with the new algorithm; and 3) Monte Carlo (PCXMC, developed by STUK) dose estimation as gold standard. RESULTS: For all five imaging protocols, the ED evaluations by the new algorithm agreed very well with the Monte Carlo simulation results (within 10% difference), whereas the original ICRP algorithm overestimated EDs by approximately a factor of 2. CONCLUSIONS: The proposed algorithm provides a more accurate estimation of ED in medical exposures than the original ICRP algorithm. It potentially establishes the ED as a more reasonable index for cross-protocol dose comparison.

Authors
Wang, C; Dewhirst, M; Jiang, X; Qian, Z; Boon, S; Yoshizumi, T
MLA Citation
Wang, C., et al. “SU-E-I-07: Proposal for a Novel Algorithm of Effective Dose Evaluation for Medical Radiation Exposure..” Med Phys, vol. 39, no. 6Part4, June 2012. Pubmed, doi:10.1118/1.4734721.
PMID
28519482
Source
pubmed
Published In
Med Phys
Volume
39
Issue
6Part4
Publish Date
2012
Start Page
3626
DOI
10.1118/1.4734721

Cellular responses to lactate in breast cancer

Authors
Kennedy, KM; Dewhirst, MW
MLA Citation
Kennedy, Kelly Marie, and Mark W. Dewhirst. “Cellular responses to lactate in breast cancer.” Journal of Clinical Oncology, vol. 30, no. 15, AMER SOC CLINICAL ONCOLOGY, 2012.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

Doxorubicin-conjugated chimeric polypeptide nanoparticles that respond to mild hyperthermia.

This paper reports the design, physicochemical characterization and in vitro cytotoxicity of a thermally responsive chimeric polypeptide (CP), derived from an elastin-like polypeptide (ELP). The CP self-assembles into ~40 nm diameter nanoparticles upon conjugation of multiple copies of doxorubicin (Dox), and displays a nanoparticle-to-aggregate phase transition between 39 and 42 °C in media, a temperature range suitable for mild hyperthermia of solid tumors. The CP-Dox nanoparticle is stable upon dilution to low micromolar concentrations, and is cytotoxic at both 37 and 42 °C. A thermally responsive nanoparticle formulation of Dox may prove to be broadly useful in hyperthermia targeted chemotherapy of a variety of solid tumors.

Authors
McDaniel, JR; Macewan, SR; Dewhirst, M; Chilkoti, A
MLA Citation
McDaniel, Jonathan R., et al. “Doxorubicin-conjugated chimeric polypeptide nanoparticles that respond to mild hyperthermia..” J Control Release, vol. 159, no. 3, May 2012, pp. 362–67. Pubmed, doi:10.1016/j.jconrel.2012.02.030.
PMID
22421424
Source
pubmed
Published In
J Control Release
Volume
159
Issue
3
Publish Date
2012
Start Page
362
End Page
367
DOI
10.1016/j.jconrel.2012.02.030

Abstract 3220: The effects of cholesterol treatment drugs alone and in combination on prostate tumor xenograft growth

Authors
Masko, EM; Solomon, KR; Valilis, NA; Gaines, AR; Muehlbauer, MJ; Newgard, CB; Dewhirst, MW; Pizzo, SV; Freedland, SJ
MLA Citation
Masko, Elizabeth M., et al. “Abstract 3220: The effects of cholesterol treatment drugs alone and in combination on prostate tumor xenograft growth.” Molecular and Cellular Biology, American Association for Cancer Research, Apr. 2012. Crossref, doi:10.1158/1538-7445.am2012-3220.
Source
crossref
Published In
Molecular and Cellular Biology
Publish Date
2012
DOI
10.1158/1538-7445.am2012-3220

A heterogeneous human tissue mimicking phantom for RF heating and MRI thermal monitoring verification.

This paper describes a heterogeneous phantom that mimics a human thigh with a deep-seated tumor, for the purpose of studying the performance of radiofrequency (RF) heating equipment and non-invasive temperature monitoring with magnetic resonance imaging (MRI). The heterogeneous cylindrical phantom was constructed with an outer fat layer surrounding an inner core of phantom material mimicking muscle, tumor and marrow-filled bone. The component materials were formulated to have dielectric and thermal properties similar to human tissues. The dielectric properties of the tissue mimicking phantom materials were measured with a microwave vector network analyzer and impedance probe over the frequency range of 80-500 MHz and at temperatures of 24, 37 and 45 °C. The specific heat values of the component materials were measured using a differential scanning calorimeter over the temperature range of 15-55 °C. The thermal conductivity value was obtained from fitting the curves obtained from one-dimensional heat transfer measurement. The phantom was used to verify the operation of a cylindrical four-antenna annular phased array extremity applicator (140 MHz) by examining the proton resonance frequency shift (PRFS) thermal imaging patterns for various magnitude/phase settings (including settings to focus heating in tumors). For muscle and tumor materials, MRI was also used to measure T1/T2* values (1.5 T) and to obtain the slope of the PRFS phase change versus temperature change curve. The dielectric and thermal properties of the phantom materials were in close agreement to well-accepted published results for human tissues. The phantom was able to successfully demonstrate satisfactory operation of the tested heating equipment. The MRI-measured thermal distributions matched the expected patterns for various magnitude/phase settings of the applicator, allowing the phantom to be used as a quality assurance tool. Importantly, the material formulations for the various tissue types may be used to construct customized phantoms that are tailored for different anatomical sites.

Authors
Yuan, Y; Wyatt, C; Maccarini, P; Stauffer, P; Craciunescu, O; Macfall, J; Dewhirst, M; Das, SK
MLA Citation
Yuan, Yu, et al. “A heterogeneous human tissue mimicking phantom for RF heating and MRI thermal monitoring verification..” Phys Med Biol, vol. 57, no. 7, Apr. 2012, pp. 2021–37. Pubmed, doi:10.1088/0031-9155/57/7/2021.
PMID
22430012
Source
pubmed
Published In
Phys Med Biol
Volume
57
Issue
7
Publish Date
2012
Start Page
2021
End Page
2037
DOI
10.1088/0031-9155/57/7/2021

Theoretical simulation of angiogenesis and structural adaptation in microvascular networks

Authors
Secomb, TW; Alberding, JP; Dewhirst, MW; Pries, AR
MLA Citation
Secomb, Timothy W., et al. “Theoretical simulation of angiogenesis and structural adaptation in microvascular networks.” Faseb Journal, vol. 26, FEDERATION AMER SOC EXP BIOL, 2012.
Source
wos
Published In
Faseb Journal
Volume
26
Publish Date
2012

Introduction to the special issue on molecular imaging in radiation biology.

Molecular imaging is an evolving science that is concerned with the development of novel imaging probes and biomarkers that can be used to non-invasively image molecular and cellular processes. This special issue approaches molecular imaging in the context of radiation research, focusing on biomarkers and imaging methods that provide measurable signals that can assist in the quantification of radiation-induced effects of living systems at the physical, chemical and biological levels. The potential to image molecular changes in response to a radiation insult opens new and exciting opportunities for a more profound understanding of radiation biology, with the possibility of translation of these techniques to radiotherapy practice. This special issue brings together 14 reviews dedicated to the use of molecular imaging in the field of radiation research. The initial three reviews are introductory overviews of the key molecular imaging modalities: magnetic resonance, nuclear and optical. This is followed by 11 reviews each focusing on a specialist area within the field of radiation research. These include: hypoxia and perfusion, tissue metabolism, normal tissue injury, cell death and viability, receptor targeting and nanotechnology, reporter genes, reactive oxygen species (ROS), and biological dosimetry. Over the preceding decade, molecular imaging brought significant new advances to our understanding of every area of radiation biology. This special issue shows us these advances and points to the vibrant future of our field armed with these new capabilities.

Authors
Humm, JL; Dewhirst, MW; Bhujwalla, ZM
MLA Citation
Humm, John L., et al. “Introduction to the special issue on molecular imaging in radiation biology..” Radiat Res, vol. 177, no. 4, Apr. 2012, pp. 329–30.
PMID
22332930
Source
pubmed
Published In
Radiat Res
Volume
177
Issue
4
Publish Date
2012
Start Page
329
End Page
330

Application of optical imaging and spectroscopy to radiation biology.

Optical imaging and spectroscopy is a diverse field that has been of critical importance in a wide range of areas in radiation research. It is capable of spanning a wide range of spatial and temporal scales, and has the sensitivity and specificity needed for molecular and functional imaging. This review will describe the basic principles of optical imaging and spectroscopy, highlighting a few relevant applications to radiation research.

Authors
Palmer, GM; Vishwanath, K; Dewhirst, MW
MLA Citation
Palmer, Gregory M., et al. “Application of optical imaging and spectroscopy to radiation biology..” Radiat Res, vol. 177, no. 4, Apr. 2012, pp. 365–75.
PMID
22360397
Source
pubmed
Published In
Radiat Res
Volume
177
Issue
4
Publish Date
2012
Start Page
365
End Page
375

225 THE EFFECTS OF CHOLESTEROL TREATMENT DRUGS ALONE AND IN COMBINATION ON PROSTATE TUMOR XENOGRAFT GROWTH

Authors
Masko, EM; Solomon, KR; Valilis, NA; Gaines, AR; Muehlbauer, MJ; Newgard, CB; Dewhirst, MW; Pizzo, SV; Freedland, SJ
MLA Citation
Masko, Elizabeth M., et al. “225 THE EFFECTS OF CHOLESTEROL TREATMENT DRUGS ALONE AND IN COMBINATION ON PROSTATE TUMOR XENOGRAFT GROWTH.” Journal of Urology, vol. 187, no. 4S, Ovid Technologies (Wolters Kluwer Health), 2012. Crossref, doi:10.1016/j.juro.2012.02.279.
Source
crossref
Published In
The Journal of Urology
Volume
187
Issue
4S
Publish Date
2012
DOI
10.1016/j.juro.2012.02.279

A novel angiopoietin-derived peptide displays anti-angiogenic activity and inhibits tumour-induced and retinal neovascularization.

BACKGROUND AND PURPOSE: Pathological angiogenesis is associated with various human diseases, such as cancer, autoimmune diseases and retinopathy. The angiopoietin (Ang)-Tie2 system plays critical roles in several steps of angiogenic remodelling. Here, we have investigated the anti-angiogenic effect of a novel angiopoietin-derived peptide. EXPERIMENTAL APPROACH: Using computational methods, we identified peptides from helical segments within angiopoietins, which were predicted to inhibit their activity. These peptides were tested using biochemical methods and models of angiogenesis. The peptide with best efficacy, A11, was selected for further characterization as an anti-angiogenic compound. KEY RESULTS: The potent anti-angiogenic activity of A11 was demonstrated in a multicellular assay of angiogenesis and in the chorioallantoic membrane model. A11 bound to angiopoietins and reduced the binding of Ang-2 to Tie2. A11 was also significantly reduced vascular density in a model of tumour-induced angiogenesis. Its ability to inhibit Ang-2 but not Ang-1-induced endothelial cell migration, and to down-regulate Tie2 levels in tumour microvessels, suggests that A11 targets the Ang-Tie2 pathway. In a rat model of oxygen-induced retinopathy, A11 strongly inhibited retinal angiogenesis. Moreover, combination of A11 with an anti-VEGF antibody showed a trend for further inhibition of angiogenesis, suggesting an additive effect. CONCLUSIONS AND IMPLICATIONS: Our results indicate that A11 is a potent anti-angiogenic compound, through modulation of the Ang-Tie2 system, underlining its potential as a therapeutic agent for the treatment of ocular and tumour neovascularization, as well as other pathological conditions that are dependent on angiogenesis.

Authors
Palmer, GM; Tiran, Z; Zhou, Z; Capozzi, ME; Park, W; Coletta, C; Pyriochou, A; Kliger, Y; Levy, O; Borukhov, I; Dewhirst, MW; Rotman, G; Penn, JS; Papapetropoulos, A
MLA Citation
Palmer, G. M., et al. “A novel angiopoietin-derived peptide displays anti-angiogenic activity and inhibits tumour-induced and retinal neovascularization..” Br J Pharmacol, vol. 165, no. 6, Mar. 2012, pp. 1891–903. Pubmed, doi:10.1111/j.1476-5381.2011.01677.x.
PMID
21943108
Source
pubmed
Published In
British Journal of Pharmacology
Volume
165
Issue
6
Publish Date
2012
Start Page
1891
End Page
1903
DOI
10.1111/j.1476-5381.2011.01677.x

Utility of treatment planning for thermochemotherapy treatment of nonmuscle invasive bladder carcinoma.

PURPOSE: A recently completed Phase I clinical trial combined concurrent Mitomycin-C chemotherapy with deep regional heating using BSD-2000 Sigma-Ellipse applicator (BSD Corporation, Salt Lake City, UT, U.S.A.) for the treatment of nonmuscle invasive bladder cancer. This work presents a new treatment planning approach, and demonstrates potential impact of this approach on improvement of treatment quality. METHODS: This study retrospectively analyzes a subset of five patients on the trial. For each treatment, expert operators selected "clinical-optimal" settings based on simple model calculation on the BSD-2000 control console. Computed tomography (CT) scans acquired prior to treatment were segmented to create finite element patient models for retrospective simulations with Sigma-HyperPlan (Dr. Sennewald Medizintechnik GmbH, Munchen, Germany). Since Sigma-HyperPlan does not account for the convective nature of heat transfer within a fluid filled bladder, an effective thermal conductivity for bladder was introduced. This effective thermal conductivity value was determined by comparing simulation results with clinical measurements of bladder and rectum temperatures. Regions of predicted high temperature in normal tissues were compared with patient complaints during treatment. Treatment results using "computed-optimal" settings from the planning system were compared with clinical results using clinical-optimal settings to evaluate potential of treatment improvement by reducing hot spot volume. RESULTS: For all five patients, retrospective treatment planning indicated improved matches between simulated and measured bladder temperatures with increasing effective thermal conductivity. The differences were mostly within 1.3 °C when using an effective thermal conductivity value above 10 W/K/m. Changes in effective bladder thermal conductivity affected surrounding normal tissues within a distance of ∼1.5 cm from the bladder wall. Rectal temperature differences between simulation and measurement were large due to sensitivity to the sampling locations in rectum. The predicted bladder T90 correlated well with single-point bladder temperature measurement. Hot spot locations predicted by the simulation agreed qualitatively with patient complaints during treatment. Furthermore, comparison between the temperature distributions with clinical and computed-optimal settings demonstrated that the computed-optimal settings resulted in substantially reduced hot spot volumes. CONCLUSIONS: Determination of an effective thermal conductivity value for fluid filled bladder was essential for matching simulation and treatment temperatures. Prospectively planning patients using the effective thermal conductivity determined in this work can potentially improve treatment efficacy (compared to manual operator adjustments) by potentially lower discomfort from reduced hot spots in normal tissue.

Authors
Yuan, Y; Cheng, K-S; Craciunescu, OI; Stauffer, PR; Maccarini, PF; Arunachalam, K; Vujaskovic, Z; Dewhirst, MW; Das, SK
MLA Citation
Yuan, Yu, et al. “Utility of treatment planning for thermochemotherapy treatment of nonmuscle invasive bladder carcinoma..” Med Phys, vol. 39, no. 3, Mar. 2012, pp. 1170–81. Pubmed, doi:10.1118/1.3679839.
PMID
22380348
Source
pubmed
Published In
Medical Physics
Volume
39
Issue
3
Publish Date
2012
Start Page
1170
End Page
1181
DOI
10.1118/1.3679839

Carbonic anhydrase IX is a predictive marker of doxorubicin resistance in early-stage breast cancer independent of HER2 and TOP2A amplification.

BACKGROUND: In early-stage breast cancer, adjuvant chemotherapy is associated with significant systemic toxicity with only a modest survival benefit. Therefore, there is considerable interest in identifying predictive markers of response to therapy. Doxorubicin, one of the most common drugs used to treat breast cancer, is an anthracycline chemotherapeutic agent, a class of drugs known to be affected by hypoxia. Accordingly, we examined whether expression of the endogenous hypoxia marker carbonic anhydrase IX (CA IX) is predictive of outcome in early-stage breast cancer patients treated with doxorubicin. METHODS: We obtained 209 early-stage pre-treatment surgically-resected breast tumours from patients, who received doxorubicin in their chemotherapeutic regimen and had >10 years of follow-up. Immunohistochemistry was used to detect CA IX, and we used fluorescence in situ hybridisation to detect both human epidermal growth factor receptor (HER2) and DNA topoisomerase II-alpha (TOP2A) gene amplification. RESULTS: Carbonic anhydrase IX intensity was significantly correlated with progression-free survival (PFS) and overall survival (OS) in patients receiving 300 mg m(-2) of doxorubicin (HR=1.82 and 3.77; P=0.0014 and 0.010, respectively). There was a significant, inverse correlation between CA IX score and oestrogen receptor expression, but no significant correlations were seen with either HER2 or TOP2A ratio. CONCLUSION: We demonstrate that CA IX expression is correlated with worse PFS and OS for breast cancer patients treated with doxorubicin, independent of HER2 or TOP2A gene amplification. This study provides evidence that using CA IX to detect hypoxia in surgically-resected breast tumours may be of clinical use in choosing an appropriate chemotherapy regimen.

Authors
Betof, AS; Rabbani, ZN; Hardee, ME; Kim, SJ; Broadwater, G; Bentley, RC; Snyder, SA; Vujaskovic, Z; Oosterwijk, E; Harris, LN; Horton, JK; Dewhirst, MW; Blackwell, KL
MLA Citation
Betof, A. S., et al. “Carbonic anhydrase IX is a predictive marker of doxorubicin resistance in early-stage breast cancer independent of HER2 and TOP2A amplification..” Br J Cancer, vol. 106, no. 5, Feb. 2012, pp. 916–22. Pubmed, doi:10.1038/bjc.2012.32.
PMID
22333602
Source
pubmed
Published In
Br J Cancer
Volume
106
Issue
5
Publish Date
2012
Start Page
916
End Page
922
DOI
10.1038/bjc.2012.32

ErbB1/2 tyrosine kinase inhibitor mediates oxidative stress-induced apoptosis in inflammatory breast cancer cells.

Overexpression of epidermal growth factor receptors (ErbB) is frequently seen in inflammatory breast cancer (IBC). Treatment with ErbB1/2-targeting agents (lapatinib) mediates tumor apoptosis by downregulating ErbB1/2 phosphorylation and downstream survival signaling. In this study, using carboxy-H(2)DCFDA, DHE, and MitoSOX Red to examine changes in hydrogen peroxide radicals, cytoplasmic and mitochondrial superoxide, respectively, we observed that GW583340 (a lapatinib-analog) increases reactive oxygen species (ROS) in two models of IBC (SUM149, SUM190) that are sensitive to ErbB1/2 blockade. This significant increase in ROS levels was similar to those generated by classical oxidative agents H(2)O(2) and paraquat. In contrast, minimal to basal levels of ROS were measured in a clonal population of GW583340-resistant IBC cells (rSUM149 and rSUM190). The GW583340-resistant IBC cells displayed increased SOD1, SOD2, and glutathione expression, which correlated with decreased sensitivity to the apoptotic-inducing effects of GW583340, H(2)O(2), and paraquat. The ROS increase and cell death in the GW583340-sensitive cells was reversed by simultaneous treatment with a superoxide dismutase (SOD) mimic. Additionally, overcoming the high levels of antioxidants using redox modulators induced apoptosis in the GW583340-resistant cells. Taken together, these data demonstrate a novel mechanism of lapatinib-analog-induced apoptosis and indicate that resistant cells have increased antioxidant potential, which can be overcome by treatment with SOD modulators.

Authors
Aird, KM; Allensworth, JL; Batinic-Haberle, I; Lyerly, HK; Dewhirst, MW; Devi, GR
MLA Citation
Aird, Katherine M., et al. “ErbB1/2 tyrosine kinase inhibitor mediates oxidative stress-induced apoptosis in inflammatory breast cancer cells..” Breast Cancer Res Treat, vol. 132, no. 1, Feb. 2012, pp. 109–19. Pubmed, doi:10.1007/s10549-011-1568-1.
PMID
21559822
Source
pubmed
Published In
Breast Cancer Res Treat
Volume
132
Issue
1
Publish Date
2012
Start Page
109
End Page
119
DOI
10.1007/s10549-011-1568-1

β-arrestin1 mediates metastatic growth of breast cancer cells by facilitating HIF-1-dependent VEGF expression.

β-Arrestins 1 and 2 are multifunctional adaptor proteins originally discovered for their role in desensitizing seven-transmembrane receptor signaling via the heterotrimeric guanine nucleotide-binding proteins. Recently identified roles of β-arrestins include regulation of cancer cell chemotaxis and proliferation. Herein, we report that β-arrestin1 expression regulates breast tumor colonization in nude mice and cancer cell viability during hypoxia. β-Arrestin1 robustly interacts with nuclear hypoxia-induced factor-1α (HIF-1α) that is stabilized during hypoxia and potentiates HIF-1-dependent transcription of the angiogenic factor vascular endothelial growth factor-A (VEGF-A). Increased expression of β-arrestin1 in human breast cancer (infiltrating ductal carcinoma or IDC and metastatic IDC) correlates with increased levels of VEGF-A. While the anti-angiogenic drug thalidomide inhibits HIF-1-dependent VEGF transcription in breast carcinoma cells, it does not prevent HIF-1α stabilization, but leads to aberrant localization of HIF-1α to the perinuclear compartments and surprisingly stimulates nuclear export of β-arrestin1. Additionally, imatinib mesylate that inhibits release of VEGF induces nuclear export of β-arrestin1-HIF-1α complexes. Our findings suggest that β-arrestin1 regulates nuclear signaling during hypoxia to promote survival of breast cancer cells via VEGF signaling and that drugs that induce its translocation from the nucleus to the cytoplasm could be useful in anti-angiogenic and breast cancer therapies.

Authors
Shenoy, SK; Han, S; Zhao, YL; Hara, MR; Oliver, T; Cao, Y; Dewhirst, MW
MLA Citation
Shenoy, S. K., et al. “β-arrestin1 mediates metastatic growth of breast cancer cells by facilitating HIF-1-dependent VEGF expression..” Oncogene, vol. 31, no. 3, Jan. 2012, pp. 282–92. Pubmed, doi:10.1038/onc.2011.238.
PMID
21685944
Source
pubmed
Published In
Oncogene
Volume
31
Issue
3
Publish Date
2012
Start Page
282
End Page
292
DOI
10.1038/onc.2011.238

Upregulation of VEGF-A and CD24 gene expression by the tGLI1 transcription factor contributes to the aggressive behavior of breast cancer cells.

The Hedgehog signaling pathway is one of the most dysregulated pathways in human cancers. The glioma-associated oncogene homolog 1 (GLI1) transcription factor is the terminal effector of the Hedgehog pathway, frequently activated in human breast cancer and an emerging target of breast cancer therapy. While somatic mutations in the human GLI1 gene have never been reported in any cell or tumor type, we recently uncovered the existence of a novel alternatively spliced, truncated GLI1 (tGLI1) that has an in-frame deletion of 41 codons spanning the entire exon 3 and part of exon 4 of the GLI1 gene. Using glioblastoma models, we showed that tGLI1 has gained the ability to promote glioblastoma migration and invasion via its gain-of-function transcriptional activity. However, the pathological impact of tGLI1 on breast cancer remains undefined. Here, we report that tGLI1 is frequently expressed in human breast cancer cell lines and primary specimens we have examined to date, but is undetectable in normal breast tissues. We found for the first time that tGLI1, but not GLI1, binds to and enhances the human vascular endothelial growth factor-A (VEGF-A) gene promoter, leading to its upregulation. Consequently, tGLI1-expressing MDA-MB-231 breast cancer cells secret higher levels of VEGF-A and contain a higher propensity, than the isogenic cells with control vector and GLI1, to stimulate in vitro angiogenesis of human vascular endothelial cells. We further showed that tGLI1 has gained the ability to enhance the motility and invasiveness of breast cancer cells in a proliferation-independent manner and that this functional gain is associated with increased expression of migration/invasion-associated genes, CD24, MMP-2 and MMP-9. tGLI1 has also acquired the property to facilitate anchorage-independent growth of breast cancer cells. Collectively, our results define tGLI1 as a gain-of-function GLI1 transcription factor and a novel mediator of the behavior of clinically more aggressive breast cancer.

Authors
Cao, X; Geradts, J; Dewhirst, MW; Lo, H-W
MLA Citation
Cao, X., et al. “Upregulation of VEGF-A and CD24 gene expression by the tGLI1 transcription factor contributes to the aggressive behavior of breast cancer cells..” Oncogene, vol. 31, no. 1, Jan. 2012, pp. 104–15. Pubmed, doi:10.1038/onc.2011.219.
PMID
21666711
Source
pubmed
Published In
Oncogene
Volume
31
Issue
1
Publish Date
2012
Start Page
104
End Page
115
DOI
10.1038/onc.2011.219

Erratum: Design of Mn porphyrins for treating oxidative stress injuries and their redox-based regulation of cellular transcriptional activities (Amino Acids DOI: 10.1007/s00726-010-0603-6)

Authors
Batinic-Haberle, I; Spasojevic, I; Tse, HM; Tovmasyan, A; Rajic, Z; Clair, DKS; Vujaskovic, Z; Dewhirst, MW; Piganelli, JD
MLA Citation
Batinic-Haberle, I., et al. “Erratum: Design of Mn porphyrins for treating oxidative stress injuries and their redox-based regulation of cellular transcriptional activities (Amino Acids DOI: 10.1007/s00726-010-0603-6).” Amino Acids, vol. 42, no. 1, Jan. 2012, pp. 115–16. Scopus, doi:10.1007/s00726-010-0821-y.
Source
scopus
Published In
Amino Acids
Volume
42
Issue
1
Publish Date
2012
Start Page
115
End Page
116
DOI
10.1007/s00726-010-0821-y

Design of Mn porphyrins for treating oxidative stress injuries and their redox-based regulation of cellular transcriptional activities.

The most efficacious Mn(III) porphyrinic (MnPs) scavengers of reactive species have positive charges close to the Mn site, whereby they afford thermodynamic and electrostatic facilitation for the reaction with negatively charged species such as O (2) (•-) and ONOO(-). Those are Mn(III) meso tetrakis(N-alkylpyridinium-2-yl)porphyrins, more specifically MnTE-2-PyP(5+) (AEOL10113) and MnTnHex-2-PyP(5+) (where alkyls are ethyl and n-hexyl, respectively), and their imidazolium analog, MnTDE-2-ImP(5+) (AEOL10150, Mn(III) meso tetrakis(N,N'-diethylimidazolium-2-yl) porphyrin). The efficacy of MnPs in vivo is determined not only by the compound antioxidant potency, but also by its bioavailability. The former is greatly affected by the lipophilicity, size, structure, and overall shape of the compound. These porphyrins have the ability to both eliminate reactive oxygen species and impact the progression of oxidative stress-dependent signaling events. This will effectively lead to the regulation of redox-dependent transcription factors and the suppression of secondary inflammatory- and oxidative stress-mediated immune responses. We have reported on the inhibition of major transcription factors HIF-1α, AP-1, SP-1, and NF-κB by Mn porphyrins. While the prevailing mechanistic view of the suppression of transcription factors activation is via antioxidative action (presumably in cytosol), the pro-oxidative action of MnPs in suppressing NF-κB activation in nucleus has been substantiated. The magnitude of the effect is dependent upon the electrostatic (porphyrin charges) and thermodynamic factors (porphyrin redox ability). The pro-oxidative action of MnPs has been suggested to contribute at least in part to the in vitro anticancer action of MnTE-2-PyP(5+) in the presence of ascorbate, and in vivo when combined with chemotherapy of lymphoma. Given the remarkable therapeutic potential of metalloporphyrins, future studies are warranted to further our understanding of in vivo action/s of Mn porphyrins, particularly with respect to their subcellular distribution.

Authors
Batinic-Haberle, I; Spasojevic, I; Tse, HM; Tovmasyan, A; Rajic, Z; St Clair, DK; Vujaskovic, Z; Dewhirst, MW; Piganelli, JD
MLA Citation
Batinic-Haberle, Ines, et al. “Design of Mn porphyrins for treating oxidative stress injuries and their redox-based regulation of cellular transcriptional activities..” Amino Acids, vol. 42, no. 1, Jan. 2012, pp. 95–113. Pubmed, doi:10.1007/s00726-010-0603-6.
PMID
20473774
Source
pubmed
Published In
Amino Acids
Volume
42
Issue
1
Publish Date
2012
Start Page
95
End Page
113
DOI
10.1007/s00726-010-0603-6

Structural adaptation of normal and tumour vascular networks.

Vascular networks are dynamic structures, adapting to changing conditions by structural remodelling of vessel diameters and by growth of new vessels and regression of existing vessels. The vast number of blood vessels in the circulatory system, more than 10⁹, implies that vessels' arrangement and structure are not under individual genetic control but emerge as a result of generic responses of each segment to the various stimuli that it experiences. To obtain insight into the types of response that are needed, a network-oriented approach has been used, in which theoretical models are used to simulate structural adaptation in vascular networks, and the results are compared with experimental observations. With regard to the structural control of vessel diameters, this approach shows that responses to both haemodynamic and metabolic stimuli are needed for the formation of functionally adequate and efficient network structures. Furthermore, information transfer in both upstream and downstream directions is essential for balancing flows between long and short flow pathways. Otherwise, functional shunting occurs, that is, short pathways become enlarged and flow bypasses longer pathways. Information transfer in the upstream direction is achieved by conducted responses communicated along vessel walls. Simulations of structural adaptation in tumour microvascular networks indicate that impaired vascular communication, resulting in functional shunting, may be an important factor causing the dysfunctional microcirculation and local hypoxia typically observed in tumours. Anti-angiogenic treatment of tumours may restore vascular communication and thereby improve or normalize flow distribution in tumour vasculature.

Authors
Secomb, TW; Dewhirst, MW; Pries, AR
MLA Citation
Secomb, Timothy W., et al. “Structural adaptation of normal and tumour vascular networks..” Basic Clin Pharmacol Toxicol, vol. 110, no. 1, Jan. 2012, pp. 63–69. Pubmed, doi:10.1111/j.1742-7843.2011.00815.x.
PMID
21995550
Source
pubmed
Published In
Basic Clin Pharmacol Toxicol
Volume
110
Issue
1
Publish Date
2012
Start Page
63
End Page
69
DOI
10.1111/j.1742-7843.2011.00815.x

Thermal dose fractionation affects tumour physiological response.

PURPOSE: It is unknown whether a thermal dose should be administered using a few large fractions with higher temperatures or a larger number of fractions with lower temperatures. To evaluate this we assessed the effect of administering the same total thermal dose, approximately 30 CEM43T(90), in one versus three to four fractions per week, over 5 weeks. MATERIALS AND METHODS: Canine sarcomas were randomised to receive one of the hyperthermia fractionation schemes along with fractionated radiotherapy. Tumour response was based on changes in tumour volume, oxygenation, water diffusion quantified using MRI, and a panel of histological and immunohistochemical end points. RESULTS: There was a greater reduction in tumour volume and water diffusion at the end of therapy in tumours receiving one hyperthermia fraction per week. There was a weak but significant association between improved tumour oxygenation 24 h after the first hyperthermia treatment and extent of volume reduction at the end of therapy. Finally, the direction of change of HIF-1α and CA-IX immunoreactivity after the first hyperthermia fraction was similar and there was an inverse relationship between temperature and the direction of change of CA-IX. There were no significant changes in interstitial fluid pressure, VEGF, vWF, apoptosis or necrosis as a function of treatment group or temperature. CONCLUSIONS: We did not identify an advantage to a three to four per week hyperthermia prescription, and response data pointed to a one per week prescription being superior.

Authors
Thrall, DE; Maccarini, P; Stauffer, P; Macfall, J; Hauck, M; Snyder, S; Case, B; Linder, K; Lan, L; McCall, L; Dewhirst, MW
MLA Citation
Thrall, Donald E., et al. “Thermal dose fractionation affects tumour physiological response..” Int J Hyperthermia, vol. 28, no. 5, 2012, pp. 431–40. Pubmed, doi:10.3109/02656736.2012.689087.
PMID
22804741
Source
pubmed
Published In
Int J Hyperthermia
Volume
28
Issue
5
Publish Date
2012
Start Page
431
End Page
440
DOI
10.3109/02656736.2012.689087

Miniature microwave applicator for murine bladder hyperthermia studies.

PURPOSE: Novel combinations of heat with chemotherapeutic agents are often studied in murine tumour models. Currently, no device exists to selectively heat small tumours at depth in mice. In this project we modelled, built and tested a miniature microwave heat applicator, the physical dimensions of which can be scaled to adjust the volume and depth of heating to focus on the tumour volume. Of particular interest is a device that can selectively heat murine bladder. MATERIALS AND METHODS: Using Avizo(®) segmentation software, we created a numerical mouse model based on micro-MRI scan data. The model was imported into HFSS™ (Ansys) simulation software and parametric studies were performed to optimise the dimensions of a water-loaded circular waveguide for selective power deposition inside a 0.15 mL bladder. A working prototype was constructed operating at 2.45 GHz. Heating performance was characterised by mapping fibre-optic temperature sensors along catheters inserted at depths of 0-1 mm (subcutaneous), 2-3 mm (vaginal), and 4-5 mm (rectal) below the abdominal wall, with the mid depth catheter adjacent to the bladder. Core temperature was monitored orally. RESULTS: Thermal measurements confirm the simulations which demonstrate that this applicator can provide local heating at depth in small animals. Measured temperatures in murine pelvis show well-localised bladder heating to 42-43°C while maintaining normothermic skin and core temperatures. CONCLUSIONS: Simulation techniques facilitate the design optimisation of microwave antennas for use in pre-clinical applications such as localised tumour heating in small animals. Laboratory measurements demonstrate the effectiveness of a new miniature water-coupled microwave applicator for localised heating of murine bladder.

Authors
Salahi, S; Maccarini, PF; Rodrigues, DB; Etienne, W; Landon, CD; Inman, BA; Dewhirst, MW; Stauffer, PR
MLA Citation
Salahi, Sara, et al. “Miniature microwave applicator for murine bladder hyperthermia studies..” Int J Hyperthermia, vol. 28, no. 5, 2012, pp. 456–65. Pubmed, doi:10.3109/02656736.2012.677931.
PMID
22690856
Source
pubmed
Published In
Int J Hyperthermia
Volume
28
Issue
5
Publish Date
2012
Start Page
456
End Page
465
DOI
10.3109/02656736.2012.677931

Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis.

Switching to a glycolytic metabolism is a rapid adaptation of tumor cells to hypoxia. Although this metabolic conversion may primarily represent a rescue pathway to meet the bioenergetic and biosynthetic demands of proliferating tumor cells, it also creates a gradient of lactate that mirrors the gradient of oxygen in tumors. More than a metabolic waste, the lactate anion is known to participate to cancer aggressiveness, in part through activation of the hypoxia-inducible factor-1 (HIF-1) pathway in tumor cells. Whether lactate may also directly favor HIF-1 activation in endothelial cells (ECs) thereby offering a new druggable option to block angiogenesis is however an unanswered question. In this study, we therefore focused on the role in ECs of monocarboxylate transporter 1 (MCT1) that we previously identified to be the main facilitator of lactate uptake in cancer cells. We found that blockade of lactate influx into ECs led to inhibition of HIF-1-dependent angiogenesis. Our demonstration is based on the unprecedented characterization of lactate-induced HIF-1 activation in normoxic ECs and the consecutive increase in vascular endothelial growth factor receptor 2 (VEGFR2) and basic fibroblast growth factor (bFGF) expression. Furthermore, using a variety of functional assays including endothelial cell migration and tubulogenesis together with in vivo imaging of tumor angiogenesis through intravital microscopy and immunohistochemistry, we documented that MCT1 blockers could act as bona fide HIF-1 inhibitors leading to anti-angiogenic effects. Together with the previous demonstration of MCT1 being a key regulator of lactate exchange between tumor cells, the current study identifies MCT1 inhibition as a therapeutic modality combining antimetabolic and anti-angiogenic activities.

Authors
Sonveaux, P; Copetti, T; De Saedeleer, CJ; Végran, F; Verrax, J; Kennedy, KM; Moon, EJ; Dhup, S; Danhier, P; Frérart, F; Gallez, B; Ribeiro, A; Michiels, C; Dewhirst, MW; Feron, O
MLA Citation
Sonveaux, Pierre, et al. “Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis..” Plos One, vol. 7, no. 3, 2012. Pubmed, doi:10.1371/journal.pone.0033418.
PMID
22428047
Source
pubmed
Published In
Plos One
Volume
7
Issue
3
Publish Date
2012
Start Page
e33418
DOI
10.1371/journal.pone.0033418

High-resolution in vivo imaging of fluorescent proteins using window chamber models.

Fluorescent proteins enable in vivo characterization of a wide and growing array of morphological and functional biomarkers. To fully capitalize on the spatial and temporal information afforded by these reporter proteins, a method for imaging these proteins at high resolution longitudinally is required. This chapter describes the use of window chamber models as a means of imaging fluorescent proteins and other optical parameters. Such models essentially involve surgically implanting a window through which tumor or normal tissue can be imaged using existing microscopy techniques. This enables acquisition of high-quality images down to the cellular or subcellular scale, exploiting the diverse array of optical contrast mechanisms, while also maintaining the native microenvironment of the tissue of interest. This makes these techniques applicable to a wide array of problems in the biomedical sciences.

Authors
Palmer, GM; Fontanella, AN; Shan, S; Dewhirst, MW
MLA Citation
Palmer, Gregory M., et al. “High-resolution in vivo imaging of fluorescent proteins using window chamber models..” Methods Mol Biol, vol. 872, 2012, pp. 31–50. Pubmed, doi:10.1007/978-1-61779-797-2_3.
PMID
22700402
Source
pubmed
Published In
Methods Mol Biol
Volume
872
Publish Date
2012
Start Page
31
End Page
50
DOI
10.1007/978-1-61779-797-2_3

Carbohydrate restriction and lactate transporter inhibition in a mouse xenograft model of human prostate cancer

What's known on the subject? and What does the study add? It is known that both lactate inhibition and carbohydrate restriction inhibit tumour growth. What is unknown is whether the two work synergistically together. This study adds that though the combination of lactate inhibition and carbohydrate restriction did not synergistically slow tumour growth in our model, we confirmed that carbohydrate restriction started after tumour inoculation slowed tumour growth. Moreover, lactate inhibition resulted in changes in the tumour microenvironment that may have implications for future metabolic targeting of prostate cancer growth. OBJECTIVE To determine if a no-carbohydrate ketogenic diet (NCKD) and lactate transporter inhibition can exert a synergistic effect on delaying prostate tumour growth in a xenograft mouse model of human prostate cancer. MATERIALS AND METHODS 120 nude athymic male mice (aged 6-8 weeks) were injected s.c. in the flank with 1.0 × 105 LAPC-4 prostate cancer cells. Mice were randomized to one of four treatment groups: Western diet (WD, 35% fat, 16% protein, 49% carbohydrate) and vehicle (Veh) treatment; WD and mono-carboxylate transporter-1 (MCT1) inhibition via α-cyano-4- hydroxycinnamate (CHC) delivered through a mini osmotic pump; NCKD (84% fat, 16% protein, 0% carbohydrate) plus Veh; or NCKD and MCT1 inhibition. Mice were fed and weighed three times per week and feed was adjusted to maintain similar body weights. Tumour size was measured twice weekly and the combined effect of treatment was tested via Kruskal-Wallis analysis of all four groups. Independent effects of treatment (NCKD vs WD and CHC vs Veh) on tumour volume were tested using linear regression analysis. All mice were killed on Day 53 (conclusion of pump ejection), and serum and tumour sections were analysed for various markers. Again, combined and independent effects of treatment were tested using Kruskal-Wallis and linear regression analysis, respectively. RESULTS There were no significant differences in tumour volumes among the four groups (P= 0.09). When testing the independent effects of treatment, NCKD was significantly associated with lower tumour volumes at the end of the experiment (P= 0.026), while CHC administration was not (P= 0.981). However, CHC was associated with increased necrotic fraction (P < 0.001). CONCLUSIONS Differences in tumour volumes were observed only in comparisons between mice fed a NCKD and mice fed a WD. MCT1 inhibition did not have a significant effect on tumour volume, although it was associated with increased necrotic fraction. © 2012 BJU International.

Authors
Kim, HS; Masko, EM; Poulton, SL; Kennedy, KM; Pizzo, SV; Dewhirst, MW; Freedland, SJ
MLA Citation
Kim, H. S., et al. “Carbohydrate restriction and lactate transporter inhibition in a mouse xenograft model of human prostate cancer.” Bju International, vol. 110, no. 7, 2012, pp. 1062–69. Scival, doi:10.1111/j.1464-410X.2012.10971.x.
Source
scival
Published In
Bju International
Volume
110
Issue
7
Publish Date
2012
Start Page
1062
End Page
1069
DOI
10.1111/j.1464-410X.2012.10971.x

Cytotoxic effects of Mn(III) N-alkylpyridylporphyrins in the presence of cellular reductant, ascorbate.

Due to the ability to easily accept and donate electrons Mn(III)N-alkylpyridylporphyrins (MnPs) can dismute O(2)(·-), reduce peroxynitrite, but also generate reactive species and behave as pro-oxidants if conditions favour such action. Herein two ortho isomers, MnTE-2-PyP(5+), MnTnHex-2-PyP(5+), and a meta isomer MnTnHex-3-PyP(5+), which differ greatly with regard to their metal-centered reduction potential, E(1/2) (Mn(III)P/Mn(II)P) and lipophilicity, were explored. Employing Mn(III)P/Mn(II)P redox system for coupling with ascorbate, these MnPs catalyze ascorbate oxidation and thus peroxide production. Consequently, cancer oxidative burden may be enhanced, which in turn would suppress its growth. Cytotoxic effects on Caco-2, Hela, 4T1, HCT116 and SUM149 were studied. When combined with ascorbate, MnPs killed cancer cells via peroxide produced outside of the cell. MnTE-2-PyP(5+) was the most efficacious catalyst for peroxide production, while MnTnHex-3-PyP(5+) is most prone to oxidative degradation with H(2) , and thus the least efficacious. A 4T1 breast cancer mouse study of limited scope and success was conducted. The tumour oxidative stress was enhanced and its microvessel density reduced when mice were treated either with ascorbate or MnP/ascorbate; the trend towards tumour growth suppression was detected.

Authors
Ye, X; Fels, D; Tovmasyan, A; Aird, KM; Dedeugd, C; Allensworth, JL; Kos, I; Park, W; Spasojevic, I; Devi, GR; Dewhirst, MW; Leong, KW; Batinic-Haberle, I
MLA Citation
Ye, Xiaodong, et al. “Cytotoxic effects of Mn(III) N-alkylpyridylporphyrins in the presence of cellular reductant, ascorbate..” Free Radic Res, vol. 45, no. 11–12, Nov. 2011, pp. 1289–306. Pubmed, doi:10.3109/10715762.2011.616199.
PMID
21859376
Source
pubmed
Published In
Free Radic Res
Volume
45
Issue
11-12
Publish Date
2011
Start Page
1289
End Page
1306
DOI
10.3109/10715762.2011.616199

In vivo tumor targeting by a NGR-decorated micelle of a recombinant diblock copolypeptide.

Antivascular targeting is a promising strategy for tumor therapy. This strategy has the potential to overcome many of the transport barriers associated with targeting tumor cells in solid tumors, because the tumor vasculature is directly accessible to targeting vehicles in systemic circulation. We report a novel nanoscale delivery system consisting of multivalent polymer micelles to target receptors that are preferentially upregulated in the tumor vasculature and perivascular cells, specifically CD13. To this end we utilized amphiphilic block copolymers, composed of a genetically engineered elastin-like polypeptide (ELP) that self-assemble into monodisperse spherical micelles. These polymer micelles were functionalized by incorporating the NGR tripeptide ligand, which targets the CD13 receptor, on their corona. We examined the self-assembly and in vivo tumor targeting by these NGR-functionalized nanoparticles and show that multivalent presentation of NGR by micelle self-assembly selectively targets the tumor vasculature by targeting CD13. Furthermore, we show greater vascular retention and extravascular accumulation of nanoparticles in tumor tissue compared to normal tissue, although the enhancement is modest. These results suggest that enhanced delivery to solid tumors can be achieved by targeting upregulated receptors in the tumor vasculature with multivalent ligand-presenting nanoparticles, but additional work is required to optimize such systems for multivalent targeting.

Authors
Simnick, AJ; Amiram, M; Liu, W; Hanna, G; Dewhirst, MW; Kontos, CD; Chilkoti, A
MLA Citation
Simnick, Andrew J., et al. “In vivo tumor targeting by a NGR-decorated micelle of a recombinant diblock copolypeptide..” J Control Release, vol. 155, no. 2, Oct. 2011, pp. 144–51. Pubmed, doi:10.1016/j.jconrel.2011.06.044.
PMID
21763734
Source
pubmed
Published In
J Control Release
Volume
155
Issue
2
Publish Date
2011
Start Page
144
End Page
151
DOI
10.1016/j.jconrel.2011.06.044

Hyperthermia

Authors
Dewhirst, M; Das, S; Stauffer, P; Craciunescu, O; Vujaskovic, Z; Thrall, D
MLA Citation
Dewhirst, M., et al. “Hyperthermia.” Clinical Radiation Oncology: Third Edition, 2011, pp. 385–403. Scopus, doi:10.1016/B978-1-4377-1637-5.00021-3.
Source
scopus
Publish Date
2011
Start Page
385
End Page
403
DOI
10.1016/B978-1-4377-1637-5.00021-3

Gene Expression Response of Luminal and Basal Breast Cancer Cell Lines to Ionizing Radiation

Authors
Horton, JK; Fels, DR; Kung, H-N; Dewhirst, MW; Chi, J-TA
MLA Citation
Horton, Janet K., et al. “Gene Expression Response of Luminal and Basal Breast Cancer Cell Lines to Ionizing Radiation.” Journal of Womens Health, vol. 20, no. 10, MARY ANN LIEBERT INC, Oct. 2011, pp. 1404–05.
Source
wos
Published In
Journal of Women'S Health (2002)
Volume
20
Issue
10
Publish Date
2011
Start Page
1404
End Page
1405

Effect of low-fat diets on plasma levels of NF-κB-regulated inflammatory cytokines and angiogenic factors in men with prostate cancer.

Diet, nutritional status, and certain dietary supplements are postulated to influence the development and progression of prostate cancer. Angiogenesis and inflammation are central to tumor growth and progression, but the effect of diet on these processes remains uncertain. We explored changes in 50 plasma cytokines and angiogenic factors (CAF) in 145 men with prostate cancer enrolled in a preoperative, randomized controlled phase II trial with four arms: control (usual diet), low-fat (LF) diet, flaxseed-supplemented (FS) diet, and FS+LS diet. The mean duration of dietary intervention was 30 to 31 days. Among the individual arms, the largest number of significant changes (baseline vs. preoperative follow-up) was observed in the LF arm, with 19 CAFs decreasing and one increasing (P < 0.05). Compared with the control arm, 6 CAFs-including proangiogenic factors (stromal-cell derived-1α) and myeloid factors (granulocyte-colony-stimulating factor, macrophage colony-stimulating factor)-all decreased in the LF arm compared with controls; three and four CAFs changed in the FS and FS+LF arms, respectively. Weight loss occurred in the LF arms and significantly correlated with VEGF decreases (P < 0.001). The CAFs that changed in the LF arm are all known to be regulated by NF-κB, and a pathway analysis identified NF-κB as the most likely regulatory network associated with these changes in the LF arm but not in the FS-containing arms. These results suggest that a LF diet without flaxseed may reduce levels of specific inflammatory CAFs and suggests that the NF-κB pathway may be a mediator of these changes.

Authors
Heymach, JV; Shackleford, TJ; Tran, HT; Yoo, S-Y; Do, K-A; Wergin, M; Saintigny, P; Vollmer, RT; Polascik, TJ; Snyder, DC; Ruffin, MT; Yan, S; Dewhirst, M; Kunnumakkara, AB; Aggarwal, BB; Demark-Wahnefried, W
MLA Citation
Heymach, John V., et al. “Effect of low-fat diets on plasma levels of NF-κB-regulated inflammatory cytokines and angiogenic factors in men with prostate cancer..” Cancer Prev Res (Phila), vol. 4, no. 10, Oct. 2011, pp. 1590–98. Pubmed, doi:10.1158/1940-6207.CAPR-10-0136.
PMID
21764858
Source
pubmed
Published In
Cancer Prev Res (Phila)
Volume
4
Issue
10
Publish Date
2011
Start Page
1590
End Page
1598
DOI
10.1158/1940-6207.CAPR-10-0136

IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells.

Immune cells are key regulators of neoplastic progression, which is often mediated through their release of cytokines. Inflammatory cytokines such as IL-6 exert tumor-promoting activities by driving growth and survival of neoplastic cells. However, whether these cytokines also have a role in recruiting mediators of adaptive anticancer immunity has not been investigated. Here, we report that homeostatic trafficking of tumor-reactive CD8+ T cells across microvascular checkpoints is limited in tumors despite the presence of inflammatory cytokines. Intravital imaging in tumor-bearing mice revealed that systemic thermal therapy (core temperature elevated to 39.5°C ± 0.5°C for 6 hours) activated an IL-6 trans-signaling program in the tumor blood vessels that modified the vasculature such that it could support enhanced trafficking of CD8+ effector/memory T cells (Tems) into tumors. A concomitant decrease in tumor infiltration by Tregs during systemic thermal therapy resulted in substantial enhancement of Tem/Treg ratios. Mechanistically, IL-6 produced by nonhematopoietic stromal cells acted cooperatively with soluble IL-6 receptor-α and thermally induced gp130 to promote E/P-selectin- and ICAM-1-dependent extravasation of cytotoxic T cells in tumors. Parallel increases in vascular adhesion were induced by IL-6/soluble IL-6 receptor-α fusion protein in mouse tumors and patient tumor explants. Finally, a causal link was established between IL-6-dependent licensing of tumor vessels for Tem trafficking and apoptosis of tumor targets. These findings suggest that the unique IL-6-rich tumor microenvironment can be exploited to create a therapeutic window to boost T cell-mediated antitumor immunity and immunotherapy.

Authors
Fisher, DT; Chen, Q; Skitzki, JJ; Muhitch, JB; Zhou, L; Appenheimer, MM; Vardam, TD; Weis, EL; Passanese, J; Wang, W-C; Gollnick, SO; Dewhirst, MW; Rose-John, S; Repasky, EA; Baumann, H; Evans, SS
MLA Citation
Fisher, Daniel T., et al. “IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells..” J Clin Invest, vol. 121, no. 10, Oct. 2011, pp. 3846–59. Pubmed, doi:10.1172/JCI44952.
PMID
21926464
Source
pubmed
Published In
J Clin Invest
Volume
121
Issue
10
Publish Date
2011
Start Page
3846
End Page
3859
DOI
10.1172/JCI44952

42 and 44°C Hyperthermia Induces Gene Amplification in Colorectal Cancer HCT116 Cells

Authors
Yan, B; Neill, DM; Liu, T; Dewhirst, MW
MLA Citation
Yan, B., et al. “42 and 44°C Hyperthermia Induces Gene Amplification in Colorectal Cancer HCT116 Cells.” International Journal of Radiation Oncology*Biology*Physics, vol. 81, no. 2, Elsevier BV, Oct. 2011, pp. S701–S701. Crossref, doi:10.1016/j.ijrobp.2011.06.1340.
Source
crossref
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
81
Issue
2
Publish Date
2011
Start Page
S701
End Page
S701
DOI
10.1016/j.ijrobp.2011.06.1340

Diverse functions of cationic Mn(III) N-substituted pyridylporphyrins, recognized as SOD mimics.

Oxidative stress, a redox imbalance between the endogenous reactive species and antioxidant systems, is common to numerous pathological conditions such as cancer, central nervous system injuries, radiation injury, diabetes etc. Therefore, compounds able to reduce oxidative stress have been actively sought for over 3 decades. Superoxide is the major species involved in oxidative stress either in its own right or through its progeny, such as ONOO⁻, H₂O₂, •OH, CO₃•⁻, and •NO₂. Hence, the very first compounds developed in the late 1970-ies were the superoxide dismutase (SOD) mimics. Thus far the most potent mimics have been the cationic meso Mn(III) N-substituted pyridylporphyrins and N,N'-disubstituted imidazolylporphyrins (MnPs), some of them with k(cat)(O₂·⁻) similar to the k(cat) of SOD enzymes. Most frequently studied are ortho isomers MnTE-2-PyP⁵⁺, MnTnHex-2-PyP⁵⁺, and MnTDE-2-ImP⁵⁺. The ability to disproportionate O₂·⁻ parallels their ability to remove the other major oxidizing species, peroxynitrite, ONOO⁻. The same structural feature that gives rise to the high k(cat)(O₂·⁻) and k(red)(ONOO⁻), allows MnPs to strongly impact the activation of the redox-sensitive transcription factors, HIF-1α, NF-κB, AP-1, and SP-1, and therefore modify the excessive inflammatory and immune responses. Coupling with cellular reductants and other redox-active endogenous proteins seems to be involved in the actions of Mn porphyrins. While hydrophilic analogues, such as MnTE-2-PyP⁵⁺ and MnTDE-2-ImP⁵⁺ are potent in numerous animal models of diseases, the lipophilic analogues, such as MnTnHex-2-PyP⁵⁺, were developed to cross blood brain barrier and target central nervous system and critical cellular compartments, mitochondria. The modification of its structure, aimed to preserve the SOD-like potency and lipophilicity, and diminish the toxicity, has presently been pursued. The pulmonary radioprotection by MnTnHex-2-PyP⁵⁺ was the first efficacy study performed successfully with non-human primates. The Phase I toxicity clinical trials were done on amyotrophic lateral sclerosis patients with N,N'-diethylimidazolium analogue, MnTDE-2-ImP⁵⁺ (AEOL10150). Its aggressive development as a wide spectrum radioprotector by Aeolus Pharmaceuticals has been supported by USA Federal government. The latest generation of compounds, bearing oxygens in pyridyl substituents is presently under aggressive development for cancer and CNS injuries at Duke University and is supported by Duke Translational Research Institute, The Wallace H. Coulter Translational Partners Grant Program, Preston Robert Tisch Brain Tumor Center at Duke, and National Institute of Allergy and Infectious Diseases. Metal center of cationic MnPs easily accepts and donates electrons as exemplified in the catalysis of O₂·⁻ dismutation. Thus such compounds may be equally good anti- and pro-oxidants; in either case the beneficial therapeutic effects may be observed. Moreover, while the in vivo effects may appear antioxidative, the mechanism of action of MnPs that produced such effects may be pro-oxidative; the most obvious example being the inhibition of NF-κB. The experimental data therefore teach us that we need to distinguish between the mechanism/s of action/s of MnPs and the effects we observe. A number of factors impact the type of action of MnPs leading to favorable therapeutic effects: levels of reactive species and oxygen, levels of endogenous antioxidants (enzymes and low-molecular compounds), levels of MnPs, their site of accumulation, and the mutual encounters of all of those species. The complexity of in vivo redox systems and the complex redox chemistry of MnPs challenge and motivate us to further our understanding of the physiology of the normal and diseased cell with ultimate goal to successfully treat human diseases.

Authors
Batinic-Haberle, I; Rajic, Z; Tovmasyan, A; Reboucas, JS; Ye, X; Leong, KW; Dewhirst, MW; Vujaskovic, Z; Benov, L; Spasojevic, I
MLA Citation
Batinic-Haberle, Ines, et al. “Diverse functions of cationic Mn(III) N-substituted pyridylporphyrins, recognized as SOD mimics..” Free Radic Biol Med, vol. 51, no. 5, Sept. 2011, pp. 1035–53. Pubmed, doi:10.1016/j.freeradbiomed.2011.04.046.
PMID
21616142
Source
pubmed
Published In
Free Radic Biol Med
Volume
51
Issue
5
Publish Date
2011
Start Page
1035
End Page
1053
DOI
10.1016/j.freeradbiomed.2011.04.046

Luminescent boron b-diketonate biomaterials: Synthesis, properties and applications

Authors
Fraser, CL; Zhang, G; Nguyen, ND; Xu, S; Zestos, AG; Palmer, GM; Dewhirst, MW; Hochman, D; Haglund, MM; Neal, RA; Murray, RA; Botchwey, EA; Peirce-Cottler, SM; Seaman, SA; Brayman, KL; Lin, KYK
MLA Citation
Fraser, Cassandra L., et al. “Luminescent boron b-diketonate biomaterials: Synthesis, properties and applications.” Abstracts of Papers of the American Chemical Society, vol. 242, AMER CHEMICAL SOC, 2011.
Source
wos
Published In
Abstracts of Papers of the American Chemical Society
Volume
242
Publish Date
2011

In vivo optical molecular imaging and analysis in mice using dorsal window chamber models applied to hypoxia, vasculature and fluorescent reporters.

Optical techniques for functional imaging in mice have a number of key advantages over other common imaging modalities such as magnetic resonance imaging, positron emission tomography or computed tomography, including high resolution, low cost and an extensive library of available contrast agents and reporter genes. A major challenge to such work is the limited penetration depth imposed by tissue turbidity. We describe a window chamber technique by which these limitations can be avoided. This facilitates the study of a wide range of processes, with potential endpoints including longitudinal gene expression, vascular remodeling and angiogenesis, and tumor growth and invasion. We further describe several quantitative imaging and analysis techniques for characterizing in vivo fluorescence properties and functional endpoints, including vascular morphology and oxygenation. The procedure takes ∼2 h to complete, plus up to several weeks for tumor growth and treatment procedures.

Authors
Palmer, GM; Fontanella, AN; Shan, S; Hanna, G; Zhang, G; Fraser, CL; Dewhirst, MW
MLA Citation
Palmer, Gregory M., et al. “In vivo optical molecular imaging and analysis in mice using dorsal window chamber models applied to hypoxia, vasculature and fluorescent reporters..” Nat Protoc, vol. 6, no. 9, Aug. 2011, pp. 1355–66. Pubmed, doi:10.1038/nprot.2011.349.
PMID
21886101
Source
pubmed
Published In
Nat Protoc
Volume
6
Issue
9
Publish Date
2011
Start Page
1355
End Page
1366
DOI
10.1038/nprot.2011.349

Analysis of tumor environmental response and oncogenic pathway activation identifies distinct basal and luminal features in HER2-related breast tumor subtypes.

INTRODUCTION: Breast cancer heterogeneity occurs as a consequence of the dysregulation of numerous oncogenic pathways as well as many non-genetic factors, including tumor microenvironmental stresses such as hypoxia, lactic acidosis, and glucose deprivation. Although the importance of these non-genetic factors is well recognized, it is not clear how to integrate these factors within the genetic framework of cancer as the next logical step in understanding tumor heterogeneity. METHODS: We report here the development of a series of gene expression signatures to measure the influences of microenvironmental stresses. The pathway activities of hypoxia, lactic acidosis, acidosis and glucose deprivation were investigated in a collection of 1,143 breast tumors, which have been separated into 17 breast tumor subgroups defined by their distinct patterns of oncogenic pathways. A validation dataset comprised of 547 breast tumors was also used to confirm the major findings, and representative breast cancer cell lines were utilized to validate in silico results and mechanistic studies. RESULTS: Through the integrative pathway analysis of microenvironmental stresses and oncogenic events in breast tumors, we identified many known and novel correlations between these two sources of tumor heterogeneity. Focusing on differences between two human epidermal growth factor receptor 2 (HER2)-related subgroups, previously identified based on patterns of oncogenic pathway activity, we determined that these subgroups differ with regards to tumor microenvironmental signatures, including hypoxia. We further demonstrate that each of these subgroups have features consistent with basal and luminal breast tumors including patterns of oncogenic signaling pathways, expression of subtype specific genes, and cellular mechanisms that regulate the hypoxia response. Importantly, we also demonstrate that the correlated pattern of hypoxia-related gene expression and basal-associated gene expression are consistent across HER2-related tumors whether we analyze the tumors as a function of our pathway-based classification scheme, using the intrinsic gene list (ERBB2+), or based on HER2 IHC status. Our results demonstrate a cell lineage-specific phenomenon in which basal-like tumors, HER2-related tumors with high hypoxia, as well as normal basal epithelial cells express increased mRNA levels of HIF-1α compared to luminal types and silencing of HIF-1α results in decreased expression of hypoxia-induced genes. CONCLUSIONS: This study demonstrates differences in microenvironmental conditions in HER2-related subgroups defined by distinct oncogenic pathway activities, and provides a mechanistic explanation for differences in the observed hypoxia response between these subgroups. Collectively, these data demonstrate the potential of a pathway-based classification strategy as a framework to integrate genetic and non-genetic factors to investigate the basis of tumor heterogeneity.

Authors
Gatza, ML; Kung, H-N; Blackwell, KL; Dewhirst, MW; Marks, JR; Chi, J-T
MLA Citation
Gatza, Michael L., et al. “Analysis of tumor environmental response and oncogenic pathway activation identifies distinct basal and luminal features in HER2-related breast tumor subtypes..” Breast Cancer Res, vol. 13, no. 3, June 2011. Pubmed, doi:10.1186/bcr2899.
PMID
21672245
Source
pubmed
Published In
Breast Cancer Res
Volume
13
Issue
3
Publish Date
2011
Start Page
R62
DOI
10.1186/bcr2899

62CUATSM AND 62CUPTSM PET IS A USEFUL IMAGING TOOL FOR HYPOXIA AND PERFUSION IN LUNG CANCER

Authors
Zhang, T; Fels, DR; Hansen, KS; Das, SK; Wong, TZ; Dewhirst, MW; Vlahovic, G
MLA Citation
Zhang, Tian, et al. “62CUATSM AND 62CUPTSM PET IS A USEFUL IMAGING TOOL FOR HYPOXIA AND PERFUSION IN LUNG CANCER.” Journal of Thoracic Oncology, vol. 6, no. 6, LIPPINCOTT WILLIAMS & WILKINS, June 2011, pp. S919–20.
Source
wos
Published In
Journal of Thoracic Oncology
Volume
6
Issue
6
Publish Date
2011
Start Page
S919
End Page
S920

Abstract 5306:18F-EF5 microPET imaging of treatment response from a novel, hypoxia-selective cytotoxin SN30000 in a human lung cancer xenograft model

Authors
Chitneni, SK; Bida, GT; Hay, MP; Zalutsky, MR; Melcher, T; Wilson, WR; Dewhirst, MW
MLA Citation
Chitneni, Satish K., et al. “Abstract 5306:18F-EF5 microPET imaging of treatment response from a novel, hypoxia-selective cytotoxin SN30000 in a human lung cancer xenograft model.” Tumor Biology, American Association for Cancer Research, Apr. 2011. Crossref, doi:10.1158/1538-7445.am2011-5306.
Source
crossref
Published In
Tumor Biology
Publish Date
2011
DOI
10.1158/1538-7445.am2011-5306

Comparison of genomics and functional imaging from canine sarcomas treated with thermoradiotherapy predicts therapeutic response and identifies combination therapeutics.

PURPOSE: While hyperthermia is an effective adjuvant treatment to radiotherapy, we do not completely understand the nature of the response heterogeneity. EXPERIMENTAL DESIGN: We performed gene expression analysis of 22 spontaneous canine sarcomas before and after the first hyperthermia treatment administered as an adjuvant to radiotherapy. In parallel, diffusion-weighted MRI (DWI) was done prior to the treatment course and at the end of therapy. RESULTS: From the integrative analysis of gene expression and DWI, we identified significant correlation between tumor responses with genes involved in VEGF signaling, telomerase, DNA repair, and inflammation. The treatment-induced changes in gene expression identified 2 distinct tumor subtypes with significant differences in their gene expression and treatment response, as defined by changes in DWI. The 2 tumor subtypes could also be readily identified by pretreatment gene expression. The tumor subtypes, with stronger expression response and DWI increase, had higher levels of HSP70, POT1, and centrosomal proteins, and lower levels of CD31, vWF, and transferrin. Such differential gene expression between the 2 subtypes was used to interrogate connectivity map and identify linkages to an HSP90 inhibitor, geldanamycin. We further validated the ability of geldanamycin to enhance cell killing of human tumor cells with hyperthermia and radiotherapy in clonogenic assays. CONCLUSIONS: To our knowledge, this is one of the first successful attempts to link changes in gene expression and functional imaging to understand the response heterogeneity and identify compounds enhancing thermoradiotherapy. This study also demonstrates the value of canine tumors to provide information generalizable to human tumors.

Authors
Chi, J-T; Thrall, DE; Jiang, C; Snyder, S; Fels, D; Landon, C; McCall, L; Lan, L; Hauck, M; MacFall, JR; Viglianti, BL; Dewhirst, MW
MLA Citation
Chi, Jen-Tsan, et al. “Comparison of genomics and functional imaging from canine sarcomas treated with thermoradiotherapy predicts therapeutic response and identifies combination therapeutics..” Clin Cancer Res, vol. 17, no. 8, Apr. 2011, pp. 2549–60. Pubmed, doi:10.1158/1078-0432.CCR-10-2583.
PMID
21292819
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
17
Issue
8
Publish Date
2011
Start Page
2549
End Page
2560
DOI
10.1158/1078-0432.CCR-10-2583

Cellular redox modulator, ortho Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP(5+) in the treatment of brain tumors.

Despite intensive efforts to improve multimodal treatment of brain tumor, survival remains limited. Current therapy consists of a combination of surgery, irradiation and chemotherapy with predisposition to long-term complications. Identifying novel targeted therapies is therefore at the forefront of brain tumor research. This study explores the utility of a manganese porphyrin in a brain tumor model. The compound used is ortho isomer, mangnese(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP(5+). It is a powerful SOD mimic and peroxynitrite scavenger and a potent modulator of redox-based cellular transcriptional activity, able to suppress excessive immune and inflammatory responses and in turn proliferative pathways. It is further one of the most lipophilic compound among cationic Mn(III) N-alkylpyridylporphyrins, and thus accumulates predominantly in mitochondria relative to cytosol. In mitochondria, MnTnHex-2-PyP(5+) mimics our key antioxidant system, mitochondrial superoxide dismutase, MnSOD, whose overexpression has been widely shown to suppress tumor growth. Importantly, MnTnHex-2-PyP(5+) crosses blood brain barrier in sufficient amounts to demonstrate efficacy in treating CNS injuries. For those reasons we elected to test its effects in inhibiting brain tumor growth. This study is the first report of the antitumor properties of MnTnHex-2-PyP(5+) as a single agent in adult and pediatric glioblastoma multiforme (D-54 MG, D-245 MG, D-256 MG, D-456 MG) and pediatric medulloblastoma (D-341 MED), and is the first case where a redox-able metal complex has been used in glioma therapy. When given subcutaneously to mice bearing subcutaneous and intracranial xenografts, MnTnHex-2-PyP(5+) caused a significant (P ≤ 0.001) growth delay in D 245 MG, D-256 MG, D-341 MED, and D-456 MG tumors. Growth delay for mice bearing subcutaneous xenografts ranged from 3 days in D-54 MG to 34 days in D-341 MED. With mice bearing intracranial xenografts, MnTnHex-2-PyP(5+) increases median survival by 33% in adult glioblastoma multiforme (D-256 MG; p≤ 0.001) and 173% in pediatric medulloblastoma (D-341 MED, <0.001). The beneficial effects of MnTnHex-2-PyP(5+) are presumably achieved either (1) indirectly via elimination of signaling reactive oxygen and nitrogen species (in particular superoxide and peroxynitrite) which in turn would prevent activation of transcription factors; or (2) directly by coupling with cellular reductants and redox-sensitive signaling proteins. The former action is antioxidative while the latter action is presumably pro-oxidative in nature. Our findings suggest that the use of Mn porphyrin-based SOD mimics, and in particular lipophilic analogues such as MnTnHex-2-PyP(5+), is a promising approach for brain tumor therapy.

Authors
Keir, ST; Dewhirst, MW; Kirkpatrick, JP; Bigner, DD; Batinic-Haberle, I
MLA Citation
Keir, Stephen T., et al. “Cellular redox modulator, ortho Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP(5+) in the treatment of brain tumors..” Anticancer Agents Med Chem, vol. 11, no. 2, Feb. 2011, pp. 202–12.
PMID
21291403
Source
pubmed
Published In
Anticancer Agents Med Chem
Volume
11
Issue
2
Publish Date
2011
Start Page
202
End Page
212

Molecular imaging of hypoxia.

A wide variety of imaging approaches have been developed in the past few decades for monitoring tumor oxygenation and hypoxia in vivo. In particular, nuclear medicine has seen the development of several radiolabeled hypoxia markers and is the preferred method for imaging of tumor hypoxia. Hypoxia imaging is increasingly being used in the clinical setting and is progressing from a mere detection method to application in individualization of chemoradiotherapy.

Authors
Chitneni, SK; Palmer, GM; Zalutsky, MR; Dewhirst, MW
MLA Citation
Chitneni, Satish K., et al. “Molecular imaging of hypoxia..” J Nucl Med, vol. 52, no. 2, Feb. 2011, pp. 165–68. Pubmed, doi:10.2967/jnumed.110.075663.
PMID
21233176
Source
pubmed
Published In
Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
Volume
52
Issue
2
Publish Date
2011
Start Page
165
End Page
168
DOI
10.2967/jnumed.110.075663

Bioavailability of metalloporphyrin-based SOD mimics is greatly influenced by a single charge residing on a Mn site.

In the cell Mn porphyrins (MnPs) likely couple with cellular reductants which results in a drop of total charge from 5+ to 4+ and dramatically increases their lipophilicity by up to three orders of magnitude depending upon the length of alkylpyridyl chains and type of isomer. The effects result from the interplay of solvation, lipophilicit and stericity. Impact of ascorbate on accumulation of MnPs was measured in E. coli and in Balb/C mouse tumours and muscle; for the latter measurements, the LC/ESI-MS/MS method was developed. Accumulation was significantly enhanced when MnPs were co-administered with ascorbate in both prokaryotic and eukaryotic systems. Further, MnTnHex-2-PyP(5+) accumulates 5-fold more in the tumour than in a muscle. Such data increase our understanding of MnPs cellular and sub-cellular accumulation and remarkable in vivo effects. The work is in progress to understand how coupling of MnPs with ascorbate affects their mechanism of action, in particular with respect to cancer therapy.

Authors
Spasojevic, I; Kos, I; Benov, LT; Rajic, Z; Fels, D; Dedeugd, C; Ye, X; Vujaskovic, Z; Reboucas, JS; Leong, KW; Dewhirst, MW; Batinic-Haberle, I
MLA Citation
Spasojevic, Ivan, et al. “Bioavailability of metalloporphyrin-based SOD mimics is greatly influenced by a single charge residing on a Mn site..” Free Radic Res, vol. 45, no. 2, Feb. 2011, pp. 188–200. Pubmed, doi:10.3109/10715762.2010.522575.
PMID
20942564
Source
pubmed
Published In
Free Radic Res
Volume
45
Issue
2
Publish Date
2011
Start Page
188
End Page
200
DOI
10.3109/10715762.2010.522575

Nanoscale Drug Delivery and Hyperthermia: The Materials Design and Preclinical and Clinical Testing of Low Temperature-Sensitive Liposomes Used in Combination with Mild Hyperthermia in the Treatment of Local Cancer.

The overall objective of liposomal drug delivery is to selectively target drug delivery to diseased tissue, while minimizing drug delivery to critical normal tissues. The purpose of this review is to provide an overview of temperature-sensitive liposomes in general and the Low Temperature-Sensitive Liposome (LTSL) in particular. We give a brief description of the material design of LTSL and highlight the likely mechanism behind temperature-triggered drug release. A complete review of the progress and results of the latest preclinical and clinical studies that demonstrate enhanced drug delivery with the combined treatment of hyperthermia and liposomes is provided as well as a clinical perspective on cancers that would benefit from hyperthermia as an adjuvant treatment for temperature-triggered chemotherapeutics. This review discusses the ideas, goals, and processes behind temperature-sensitive liposome development in the laboratory to the current use in preclinical and clinical settings.

Authors
Landon, CD; Park, J-Y; Needham, D; Dewhirst, MW
MLA Citation
Landon, Chelsea D., et al. “Nanoscale Drug Delivery and Hyperthermia: The Materials Design and Preclinical and Clinical Testing of Low Temperature-Sensitive Liposomes Used in Combination with Mild Hyperthermia in the Treatment of Local Cancer..” Open Nanomed J, vol. 3, Jan. 2011, pp. 38–64. Pubmed, doi:10.2174/1875933501103010038.
PMID
23807899
Source
pubmed
Published In
The Open Nanomedicine Journal
Volume
3
Publish Date
2011
Start Page
38
End Page
64
DOI
10.2174/1875933501103010038

Individual responses to chemotherapy-induced oxidative stress.

Differences in redox homeostatic control between cancer patients may underlie predisposition to drug resistance and toxicities. To evaluate interindividual differences in redox response among newly diagnosed breast cancer patients undergoing standard chemotherapy, urine samples were collected before (T0), and at 1 (T1) and 24 h (T24) after chemotherapy administration. Oxidative status was assessed by urinary levels of allantoin and four F2-isoprostanes, quantified by LC-MS/MS. In all subjects, biomarker levels increased at T1 and returned to baseline at T24. Analyzing individual responses, two patterns were revealed: 10 subjects showed uniform increases of biomarker levels at T1 ("increase" pattern) and 8 subjects showed mixed (increase/unchanged/decrease) responses for different biomarkers ("mixed" pattern). The increase-pattern group had lower pre-treatment (T0) levels of the biomarkers and showed a sharp increase at T1 (64-141%) with a subsequent decrease at T24. The mixed-pattern group had higher pre-treatment biomarker levels and showed no change in biomarkers either at T1 or at T24. These findings indicate that there may be at least two distinct redox phenotypes with different homeostatic mechanisms balancing oxidative stress in humans. Recognizing redox phenotypes in human populations may lead to more precise assessment of health risks and benefits associated with individual redox make-up, and may also help to identify cancer patients who are especially susceptible to drug resistance and/or drug toxicity.

Authors
Il'yasova, D; Kennedy, K; Spasojevic, I; Wang, F; Tolun, AA; Base, K; Young, SP; Kelly Marcom, P; Marks, J; Millington, DS; Dewhirst, MW
MLA Citation
Il’yasova, Dora, et al. “Individual responses to chemotherapy-induced oxidative stress..” Breast Cancer Res Treat, vol. 125, no. 2, Jan. 2011, pp. 583–89. Pubmed, doi:10.1007/s10549-010-1158-7.
PMID
20830514
Source
pubmed
Published In
Breast Cancer Res Treat
Volume
125
Issue
2
Publish Date
2011
Start Page
583
End Page
589
DOI
10.1007/s10549-010-1158-7

Formulation and characterisation of magnetic resonance imageable thermally sensitive liposomes for use with magnetic resonance-guided high intensity focused ultrasound.

PURPOSE: Objectives of this study were to: 1) develop iLTSL, a low temperature sensitive liposome co-loaded with an MRI contrast agent (ProHance® Gd-HP-DO3A) and doxorubicin, 2) characterise doxorubicin and Gd-HP-DO3A release from iLTSL and 3) investigate the ability of magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) to induce and monitor iLTSL content release in phantoms and in vivo. METHODS: iLTSL was passively loaded with Gd-HP-DO3A and actively loaded with doxorubicin. Doxorubicin and Gd-HP-DO3A release was quantified by fluorescence and spectroscopic techniques, respectively. Release with MR-HIFU was examined in tissue-mimicking phantoms containing iLTSL and in a VX2 rabbit tumour model. RESULTS: iLTSL demonstrated consistent size and doxorubicin release kinetics after storage at 4°C for 7 days. Release of doxorubicin and Gd-HP-DO3A from iLTSL was minimal at 37°C but fast when heated to 41.3°C. The magnitude of release was not significantly different between doxorubicin and Gd-HP-DO3A over 10 min in HEPES buffer and plasma at 37°, 40° and 41.3°C (p > 0.05). Relaxivity of iLTSL increased significantly (p < 0.0001) from 1.95 ± 0.05 to 4.01 ± 0.1 mMs⁻¹ when heated above the transition temperature. Signal increase corresponded spatially and temporally to MR-HIFU-heated locations in phantoms. Signal increase was also observed in vivo after iLTSL injection and after each 10-min heating (41°C), with greatest increase in the heated tumour region. CONCLUSION: An MR imageable liposome formulation co-loaded with doxorubicin and an MR contrast agent was developed. Stability, imageability, and MR-HIFU monitoring and control of content release suggest that MR-HIFU combined with iLTSL may enable real-time monitoring and spatial control of content release.

Authors
Negussie, AH; Yarmolenko, PS; Partanen, A; Ranjan, A; Jacobs, G; Woods, D; Bryant, H; Thomasson, D; Dewhirst, MW; Wood, BJ; Dreher, MR
MLA Citation
Negussie, Ayele H., et al. “Formulation and characterisation of magnetic resonance imageable thermally sensitive liposomes for use with magnetic resonance-guided high intensity focused ultrasound..” Int J Hyperthermia, vol. 27, no. 2, 2011, pp. 140–55. Pubmed, doi:10.3109/02656736.2010.528140.
PMID
21314334
Source
pubmed
Published In
Int J Hyperthermia
Volume
27
Issue
2
Publish Date
2011
Start Page
140
End Page
155
DOI
10.3109/02656736.2010.528140

Thresholds for thermal damage to normal tissues: an update.

The purpose of this review is to summarise a literature survey on thermal thresholds for tissue damage. This review covers published literature for the consecutive years from 2002-2009. The first review on this subject was published in 2003. It included an extensive discussion of how to use thermal dosimetric principles to normalise all time-temperature data histories to a common format. This review utilises those same principles to address sensitivity of a variety of tissues, but with particular emphasis on brain and testis. The review includes new data on tissues that were not included in the original review. Several important observations have come from this review. First, a large proportion of the papers examined for this review were discarded because time-temperature history at the site of thermal damage assessment was not recorded. It is strongly recommended that future research on this subject include such data. Second, very little data is available examining chronic consequences of thermal exposure. On a related point, the time of assessment of damage after exposure is critically important for assessing whether damage is transient or permanent. Additionally, virtually no data are available for repeated thermal exposures which may occur in certain recreational or occupational activities. For purposes of regulatory guidelines, both acute and lasting effects of thermal damage should be considered.

Authors
Yarmolenko, PS; Moon, EJ; Landon, C; Manzoor, A; Hochman, DW; Viglianti, BL; Dewhirst, MW
MLA Citation
Yarmolenko, Pavel S., et al. “Thresholds for thermal damage to normal tissues: an update..” Int J Hyperthermia, vol. 27, no. 4, 2011, pp. 320–43. Pubmed, doi:10.3109/02656736.2010.534527.
PMID
21591897
Source
pubmed
Published In
Int J Hyperthermia
Volume
27
Issue
4
Publish Date
2011
Start Page
320
End Page
343
DOI
10.3109/02656736.2010.534527

Durable palliation of breast cancer chest wall recurrence with radiation therapy, hyperthermia, and chemotherapy.

BACKGROUND AND PURPOSE: Chest wall recurrences of breast cancer are a therapeutic challenge and durable local control is difficult to achieve. Our objective was to determine the local progression free survival (LPFS) and toxicity of thermochemoradiotherapy (ThChRT) for chest wall recurrence. METHODS: Twenty-seven patients received ThChRT for chest wall failure from 2/1995 to 6/2007 and make up this retrospective series. All received concurrent superficial hyperthermia twice weekly (median 8 sessions), chemotherapy (capecitabine in 21, vinorelbine in 2, and paclitaxel in 4), and radiation (median 45 Gy). Patients were followed up every 1.5-3 months and responses were graded with RECIST criteria and toxicities with the NCI CTC v4.0. RESULTS: Twenty-three (85%) patients were previously irradiated (median 60.4 Gy) and 22 (81%) patients received prior chemotherapy. Median follow-up was 11 months. Complete response (CR) was achieved in 16/20 (80%) of patients with follow-up data, and 1 year LPFS was 76%. Overall survival was 23 months for patients with CR, and 5.4 months in patients achieving a partial response (PR) (p=0.01). Twenty-two patients experienced acute grade 1/2 treatment related toxicities, primarily moist desquamation. Two patients experienced 3rd degree burns; all resolved with conservative measures. CONCLUSIONS: ThChRT offers durable palliation and prolonged LPFS with tolerable acute toxicity, especially if CR is achieved.

Authors
Zagar, TM; Higgins, KA; Miles, EF; Vujaskovic, Z; Dewhirst, MW; Clough, RW; Prosnitz, LR; Jones, EL
MLA Citation
Zagar, Timothy M., et al. “Durable palliation of breast cancer chest wall recurrence with radiation therapy, hyperthermia, and chemotherapy..” Radiother Oncol, vol. 97, no. 3, Dec. 2010, pp. 535–40. Pubmed, doi:10.1016/j.radonc.2010.10.020.
PMID
21074876
Source
pubmed
Published In
Radiother Oncol
Volume
97
Issue
3
Publish Date
2010
Start Page
535
End Page
540
DOI
10.1016/j.radonc.2010.10.020

NADPH oxidase-mediated reactive oxygen species production activates hypoxia-inducible factor-1 (HIF-1) via the ERK pathway after hyperthermia treatment.

Hyperthermia (HT) is a strong adjuvant treatment with radiotherapy and chemotherapy because it causes tumor reoxygenation. However, the detailed molecular mechanisms of how HT enhances tumor oxygenation have not been elucidated. Here we report that 1 h of HT activates hypoxia-inducible factor-1 (HIF-1) in tumors and its downstream targets, vascular endothelial growth factor (VEGF) and pyruvate dehydrogenase kinase 1 (PDK1). Consistent with HIF-1 activation and up-regulation of its downstream genes, HT also enhances tumor perfusion/vascularization and decreases oxygen consumption. As a result, tumor hypoxia is reduced after HT, suggesting that these physiological changes contribute to HT-induced tumor reoxygenation. Because HIF-1 is a potent regulator of tumor vascularization and metabolism, our findings suggest that HIF-1 plays a role in HT-induced tumor reoxygenation by transactivating its downstream targets. We demonstrate that NADPH oxidase-mediated reactive oxygen species production, as a mechanism, up-regulates HIF-1 after HT. Furthermore, we determine that this pathway is initiated by increased transcription of NADPH oxidase-1 through the ERK pathway. In conclusion, this study determines that, although HIF-1 is a good therapeutic target, the timing of its inhibition needs to be optimized to achieve the most beneficial outcome when it is combined with other treatments of HT, radiation, and chemotherapy.

Authors
Moon, EJ; Sonveaux, P; Porporato, PE; Danhier, P; Gallez, B; Batinic-Haberle, I; Nien, Y-C; Schroeder, T; Dewhirst, MW
MLA Citation
Moon, Eui Jung, et al. “NADPH oxidase-mediated reactive oxygen species production activates hypoxia-inducible factor-1 (HIF-1) via the ERK pathway after hyperthermia treatment..” Proc Natl Acad Sci U S A, vol. 107, no. 47, Nov. 2010, pp. 20477–82. Pubmed, doi:10.1073/pnas.1006646107.
PMID
21059928
Source
pubmed
Published In
Proc Natl Acad Sci U S A
Volume
107
Issue
47
Publish Date
2010
Start Page
20477
End Page
20482
DOI
10.1073/pnas.1006646107

Optical imaging of tumor hypoxia dynamics.

The influence of the tumor microenvironment and hypoxia plays a significant role in determining cancer progression, treatment response, and treatment resistance. That the tumor microenvironment is highly heterogeneous with significant intratumor and intertumor variability presents a significant challenge in developing effective cancer therapies. Critical to understanding the role of the tumor microenvironment is the ability to dynamically quantify oxygen levels in the vasculature and tissue in order to elucidate the roles of oxygen supply and consumption, spatially and temporally. To this end, we describe the use of hyperspectral imaging to characterize hemoglobin absorption to quantify hemoglobin content and oxygen saturation, as well as dual emissive fluorescent∕phosphorescent boron nanoparticles, which serve as ratiometric indicators of tissue oxygen tension. Applying these techniques to a window-chamber tumor model illustrates the role of fluctuations in hemoglobin saturation in driving changes in tissue oxygenation, the two being significantly correlated (r = 0.77). Finally, a green-fluorescence-protein reporter for hypoxia inducible factor-1 (HIF-1) provides an endpoint for hypoxic stress in the tumor, which is used to demonstrate a significant association between tumor hypoxia dynamics and HIF-1 activity in an in vivo demonstration of the technique.

Authors
Palmer, GM; Fontanella, AN; Zhang, G; Hanna, G; Fraser, CL; Dewhirst, MW
MLA Citation
Palmer, Gregory M., et al. “Optical imaging of tumor hypoxia dynamics..” J Biomed Opt, vol. 15, no. 6, Nov. 2010. Pubmed, doi:10.1117/1.3523363.
PMID
21198195
Source
pubmed
Published In
Journal of Biomedical Optics
Volume
15
Issue
6
Publish Date
2010
Start Page
066021
DOI
10.1117/1.3523363

Stereocomplexed poly(lactic acid)-poly(ethylene glycol) nanoparticles with dual-emissive boron dyes for tumor accumulation.

Responsive biomaterials play important roles in imaging, diagnostics, and therapeutics. Polymeric nanoparticles (NPs) containing hydrophobic and hydrophilic segments are one class of biomaterial utilized for these purposes. The incorporation of luminescent molecules into NPs adds optical imaging and sensing capability to these vectors. Here we report on the synthesis of dual-emissive, pegylated NPs with "stealth"-like properties, delivered intravenously (IV), for the study of tumor accumulation. The NPs were created by means of stereocomplexation using a methoxy-terminated polyethylene glycol and poly(D-lactide) (mPEG-PDLA) block copolymer combined with iodide-substituted difluoroboron dibenzoylmethane-poly(L-lactide) (BF2dbm(I)PLLA). Boron nanoparticles (BNPs) were fabricated in two different solvent compositions to study the effects on BNP size distribution. The physical and photoluminescent properties of the BNPs were studied in vitro over time to determine stability. Finally, preliminary in vivo results show that stereocomplexed BNPs injected IV are taken up by tumors, an important prerequisite to their use as hypoxia imaging agents in preclinical studies.

Authors
Kersey, FR; Zhang, G; Palmer, GM; Dewhirst, MW; Fraser, CL
MLA Citation
Kersey, Farrell R., et al. “Stereocomplexed poly(lactic acid)-poly(ethylene glycol) nanoparticles with dual-emissive boron dyes for tumor accumulation..” Acs Nano, vol. 4, no. 9, Sept. 2010, pp. 4989–96. Pubmed, doi:10.1021/nn901873t.
Website
http://hdl.handle.net/10161/4104
PMID
20704337
Source
pubmed
Published In
Acs Nano
Volume
4
Issue
9
Publish Date
2010
Start Page
4989
End Page
4996
DOI
10.1021/nn901873t

A feasibility study using radiochromic films for fast neutron 2D passive dosimetry.

The objective of this paper is threefold: (1) to establish sensitivity of XRQA and EBT radiochromic films to fast neutron exposure; (2) to develop a film response to radiation dose calibration curve and (3) to investigate a two-dimensional (2D) film dosimetry technique for use in establishing an experimental setup for a radiobiological irradiation of mice and to assess the dose to the mice in this setup. The films were exposed to a 10 MeV neutron beam via the (2)H(d,n)(3)He reaction. The XRQA film response was a factor of 1.39 greater than EBT film response to the 10 MeV neutron beam when exposed to a neutron dose of 165 cGy. A film response-to-soft tissue dose calibration function was established over a range of 0-10 Gy and had a goodness of fit of 0.9926 with the calibration data. The 2D film dosimetry technique estimated the neutron dose to the mice by measuring the dose using a mouse phantom and by placing a piece of film on the exterior of the experimental mouse setup. The film results were benchmarked using Monte Carlo and aluminum (Al) foil activation measurements. The radiochromic film, Monte Carlo and Al foil dose measurements were strongly correlated, and the film within the mouse phantom agreed to better than 7% of the externally mounted films. These results demonstrated the potential application of radiochromic films for passive 2D neutron dosimetry.

Authors
Brady, SL; Gunasingha, R; Yoshizumi, TT; Howell, CR; Crowell, AS; Fallin, B; Tonchev, AP; Dewhirst, MW
MLA Citation
Brady, Samuel L., et al. “A feasibility study using radiochromic films for fast neutron 2D passive dosimetry..” Phys Med Biol, vol. 55, no. 17, Sept. 2010, pp. 4977–92. Pubmed, doi:10.1088/0031-9155/55/17/007.
PMID
20693612
Source
pubmed
Published In
Phys Med Biol
Volume
55
Issue
17
Publish Date
2010
Start Page
4977
End Page
4992
DOI
10.1088/0031-9155/55/17/007

Low-carbohydrate diets and prostate cancer: how low is "low enough"?

Previous studies indicate that carbohydrate intake influences prostate cancer biology, as mice fed a no-carbohydrate ketogenic diet (NCKD) had significantly smaller xenograft tumors and longer survival than mice fed a Western diet. As it is nearly impossible for humans to consume and maintain NCKD, we determined whether diets containing 10% or 20% carbohydrate kcal showed similar tumor growth as NCKD. A total of 150 male severe combined immunodeficient mice were fed a Western diet ad libitum, injected with the human prostate cancer cell line LAPC-4, and then randomized 2 weeks later to one of three arms: NCKD, 10% carbohydrate, or 20% carbohydrate diets. Ten mice not injected were fed an ad libitum low-fat diet (12% fat kcal) serving as the reference in a modified-paired feeding protocol. Mice were sacrificed when tumors reached 1,000 mm(3). Despite consuming extra calories, all mice receiving low-carbohydrate diets were significantly lighter than those receiving a low-fat diet (P < 0.04). Among the low-carbohydrate arms, NCKD-fed mice were significantly lighter than the 10% or 20% carbohydrate groups (P < 0.05). Tumors were significantly larger in the 10% carbohydrate group on days 52 and 59 (P < 0.05), but at no other point during the study. Diet did not affect survival (P = 0.34). There were no differences in serum insulin-like growth factor-I or insulin-like growth factor binding protein-3 at sacrifice among the low-carbohydrate arms (P = 0.07 and P = 0.55, respectively). Insulin was significantly lower in the 20% carbohydrate arm (P = 0.03). LAPC-4 xenograft mice fed a low-carbohydrate diet (10-20% carbohydrate kcal) had similar survival as mice consuming NCKD (0% carbohydrate kcal).

Authors
Masko, EM; Thomas, JA; Antonelli, JA; Lloyd, JC; Phillips, TE; Poulton, SH; Dewhirst, MW; Pizzo, SV; Freedland, SJ
MLA Citation
Masko, Elizabeth M., et al. “Low-carbohydrate diets and prostate cancer: how low is "low enough"?.” Cancer Prev Res (Phila), vol. 3, no. 9, Sept. 2010, pp. 1124–31. Pubmed, doi:10.1158/1940-6207.CAPR-10-0071.
PMID
20716631
Source
pubmed
Published In
Cancer Prev Res (Phila)
Volume
3
Issue
9
Publish Date
2010
Start Page
1124
End Page
1131
DOI
10.1158/1940-6207.CAPR-10-0071

Establishing the Tumor Microenvironment

Authors
Betof, AS; Dewhirst, MW
MLA Citation
Betof, A. S., and M. W. Dewhirst. Establishing the Tumor Microenvironment. Aug. 2010, pp. 7–33. Scopus, doi:10.1002/9780470669891.ch2.
Source
scopus
Publish Date
2010
Start Page
7
End Page
33
DOI
10.1002/9780470669891.ch2

The shunt problem: control of functional shunting in normal and tumour vasculature.

Networks of blood vessels in normal and tumour tissues have heterogeneous structures, with widely varying blood flow pathway lengths. To achieve efficient blood flow distribution, mechanisms for the structural adaptation of vessel diameters must be able to inhibit the formation of functional shunts (whereby short pathways become enlarged and flow bypasses long pathways). Such adaptation requires information about tissue metabolic status to be communicated upstream to feeding vessels, through conducted responses. We propose that impaired vascular communication in tumour microvascular networks, leading to functional shunting, is a primary cause of dysfunctional microcirculation and local hypoxia in cancer. We suggest that anti-angiogenic treatment of tumours may restore vascular communication and thereby improve or normalize flow distribution in tumour vasculature.

Authors
Pries, AR; Höpfner, M; le Noble, F; Dewhirst, MW; Secomb, TW
MLA Citation
Pries, Axel R., et al. “The shunt problem: control of functional shunting in normal and tumour vasculature..” Nat Rev Cancer, vol. 10, no. 8, Aug. 2010, pp. 587–93. Pubmed, doi:10.1038/nrc2895.
PMID
20631803
Source
pubmed
Published In
Nat Rev Cancer
Volume
10
Issue
8
Publish Date
2010
Start Page
587
End Page
593
DOI
10.1038/nrc2895

A comprehensive method for optical-emission computed tomography.

Optical-computed tomography (CT) and optical-emission computed tomography (ECT) are recent techniques with potential for high-resolution multi-faceted 3D imaging of the structure and function in unsectioned tissue samples up to 1-4 cc. Quantitative imaging of 3D fluorophore distribution (e.g. GFP) using optical-ECT is challenging due to attenuation present within the sample. Uncorrected reconstructed images appear hotter near the edges than at the center. A similar effect is seen in SPECT/PET imaging, although an important difference is attenuation occurs for both emission and excitation photons. This work presents a way to implement not only the emission attenuation correction utilized in SPECT, but also excitation attenuation correction and source strength modeling which are unique to optical-ECT. The performance of the correction methods was investigated by the use of a cylindrical gelatin phantom whose central region was filled with a known distribution of attenuation and fluorophores. Uncorrected and corrected reconstructions were compared to a sectioned slice of the phantom imaged using a fluorescent dissecting microscope. Significant attenuation artifacts were observed in uncorrected images and appeared up to 80% less intense in the central regions due to attenuation and an assumed uniform light source. The corrected reconstruction showed agreement throughout the verification image with only slight variations ( approximately 5%). Final experiments demonstrate the correction in tissue as applied to a tumor with constitutive RFP.

Authors
Thomas, A; Bowsher, J; Roper, J; Oliver, T; Dewhirst, M; Oldham, M
MLA Citation
Thomas, Andrew, et al. “A comprehensive method for optical-emission computed tomography..” Phys Med Biol, vol. 55, no. 14, July 2010, pp. 3947–57. Pubmed, doi:10.1088/0031-9155/55/14/001.
PMID
20577042
Source
pubmed
Published In
Phys Med Biol
Volume
55
Issue
14
Publish Date
2010
Start Page
3947
End Page
3957
DOI
10.1088/0031-9155/55/14/001

Novel MRI and fluorescent probes responsive to the Factor XIII transglutaminase activity.

Transglutaminases, including factor XIII and tissue transglutaminase, participate in multiple extracellular processes associated with remodeling of the extracellular matrix during wound repair, blood clotting, tumor progression and fibrosis of ischemic injuries. The aim of this work was to evaluate a novel substrate analog for transglutaminase optimized by molecular modeling calculations (DCCP16), which can serve for molecular imaging of transglutaminase activity by magnetic resonance imaging and by near-infrared imaging. Experimental data showed covalent binding of Gd-DCCP16 and DCCP16-IRIS Blue to human clots, to basement membrane components and to casein in purified systems as well as in three-dimensional multicellular spheroids. In vivo, DCCP16 showed enhancement with a prolonged retention in clots and tumors, demonstrating the ability to detect both factor XIII and tissue transglutaminase mediated covalent binding of the contrast material.

Authors
Tei, L; Mazooz, G; Shellef, Y; Avni, R; Vandoorne, K; Barge, A; Kalchenko, V; Dewhirst, MW; Chaabane, L; Miragoli, L; Longo, D; Neeman, M; Aime, S
MLA Citation
Tei, Lorenzo, et al. “Novel MRI and fluorescent probes responsive to the Factor XIII transglutaminase activity..” Contrast Media Mol Imaging, vol. 5, no. 4, July 2010, pp. 213–22. Pubmed, doi:10.1002/cmmi.392.
PMID
20812289
Source
pubmed
Published In
Contrast Media Mol Imaging
Volume
5
Issue
4
Publish Date
2010
Start Page
213
End Page
222
DOI
10.1002/cmmi.392

Application of mixed spin iMQCs for temperature and chemical-selective imaging.

The development of accurate and non-invasive temperature imaging techniques has a wide variety of applications in fields such as medicine, chemistry and materials science. Accurate detection of temperature both in phantoms and in vivo can be obtained using iMQCs (intermolecular multiple quantum coherences), as demonstrated in a recent paper. This paper describes the underlying theory of iMQC temperature detection, as well as extensions of that work allowing not only for imaging of absolute temperature but also for imaging of analyte concentrations through chemically-selective spin density imaging.

Authors
Jenista, ER; Galiana, G; Branca, RT; Yarmolenko, PS; Stokes, AM; Dewhirst, MW; Warren, WS
MLA Citation
Jenista, Elizabeth R., et al. “Application of mixed spin iMQCs for temperature and chemical-selective imaging..” J Magn Reson, vol. 204, no. 2, June 2010, pp. 208–18. Pubmed, doi:10.1016/j.jmr.2010.02.021.
PMID
20303808
Source
pubmed
Published In
J Magn Reson
Volume
204
Issue
2
Publish Date
2010
Start Page
208
End Page
218
DOI
10.1016/j.jmr.2010.02.021

Effect of pazopanib on tumor microenvironment and liposome delivery.

Pathologic angiogenesis creates an abnormal microenvironment in solid tumors, characterized by elevated interstitial fluid pressure (IFP) and hypoxia. Emerging theories suggest that judicious downregulation of proangiogenic signaling pathways may transiently "normalize" the vascular bed, making it more suitable for drug delivery and radiotherapy. In this work, we investigate the role of pazopanib, a small-molecule inhibitor of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, on tumor IFP, angiogenesis, hypoxia, and liposomal drug delivery. Nude mice bearing A549 human non-small cell lung cancer xenografts were treated with 100 mg/kg pazopanib (n = 20) or vehicle (n = 20) through oral gavage for 8 days, followed by a one-time intravenous dose of 10 mg/kg Doxil (liposomal doxorubicin). Pazopanib treatment resulted in significant reduction of tumor IFP and decreased vessel density, assessed by CD31 staining. Despite these trends toward normalization, high-performance liquid chromatography revealed no differences in doxorubicin concentration between pazopanib-treated and control tumors, with Doxil penetration from microvessels being significantly reduced in the pazopanib group. Additionally, tumor hypoxia, evaluated by CA-IX immunostaining and confirmed in a second study by EF5 expression (n = 4, 100 mg/kg pazopanib; n = 4, vehicle), was increased in pazopanib-treated tumors. Our results suggest that the classic definition of tumor "normalization" may undermine the crucial role of vessel permeability and oncotic pressure gradients in liposomal drug delivery, and that functional measures of normalization, such as reduced IFP and hypoxia, may not occur in parallel temporal windows.

Authors
Tailor, TD; Hanna, G; Yarmolenko, PS; Dreher, MR; Betof, AS; Nixon, AB; Spasojevic, I; Dewhirst, MW
MLA Citation
Tailor, Tina D., et al. “Effect of pazopanib on tumor microenvironment and liposome delivery..” Mol Cancer Ther, vol. 9, no. 6, June 2010, pp. 1798–808. Pubmed, doi:10.1158/1535-7163.MCT-09-0856.
PMID
20515941
Source
pubmed
Published In
Mol Cancer Ther
Volume
9
Issue
6
Publish Date
2010
Start Page
1798
End Page
1808
DOI
10.1158/1535-7163.MCT-09-0856

39 Targeting the lactate transporter monocarboxylate transporter 1 constitutes a new therapeutic modality that disrupts a fundamental metabolic symbiosis in tumours

Authors
Sonveaux, P; Dewhirst, MW; Feron, O
MLA Citation
Sonveaux, P., et al. “39 Targeting the lactate transporter monocarboxylate transporter 1 constitutes a new therapeutic modality that disrupts a fundamental metabolic symbiosis in tumours.” European Journal of Cancer Supplements, vol. 8, no. 5, Elsevier BV, 2010, pp. 10–10. Crossref, doi:10.1016/s1359-6349(10)70848-x.
Source
crossref
Published In
European Journal of Cancer Supplements
Volume
8
Issue
5
Publish Date
2010
Start Page
10
End Page
10
DOI
10.1016/s1359-6349(10)70848-x

Erratum: Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer (Journal of Applied Physiology (2010) 108: (343-348) DOI: 10.1152/japplphysiol.00424.2009)

Authors
Jones, LW; Viglianti, BL; Tashjian, JA; Kothadia, SM; Keir, ST; Freedland, SJ; Potter, MQ; Moon, EJ; Schroeder, T; Herndon, JE; Dewhirst, MW
MLA Citation
Jones, L. W., et al. “Erratum: Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer (Journal of Applied Physiology (2010) 108: (343-348) DOI: 10.1152/japplphysiol.00424.2009).” Journal of Applied Physiology, vol. 108, no. 4, Apr. 2010. Scopus, doi:10.1152/japplphysiol.zdg-9024-corr.2010.
Source
scopus
Published In
Journal of Applied Physiology (Bethesda, Md. : 1985)
Volume
108
Issue
4
Publish Date
2010
Start Page
1021
DOI
10.1152/japplphysiol.zdg-9024-corr.2010

Theoretical simulation of angiogenesis and structural adaptation in microvascular networks

Authors
Secomb, TW; Alberding, JP; Dewhirst, MW; Pries, AR
MLA Citation
Secomb, Timothy W., et al. “Theoretical simulation of angiogenesis and structural adaptation in microvascular networks.” Faseb Journal, vol. 24, Apr. 2010.
Source
wos-lite
Published In
Faseb Journal
Volume
24
Publish Date
2010

Non-invasive monitoring of intra-tumor drug concentration and therapeutic response using optical spectroscopy.

Optical spectroscopy was used to monitor changes in tumor physiology with therapy, and its influence on drug delivery and treatment efficacy for hyperthermia treatment combined with free doxorubicin or a low-temperature sensitive liposomal formulation. Monte Carlo-based modeling techniques were used to characterize the intrinsic absorption, scattering, and fluorescence properties of tissue. Fluorescence assessment of drug concentration was validated against HPLC and found to be significantly linearly correlated (r=0.88). Cluster analysis on the physiologic data obtained by optical spectroscopy revealed two physiologic phenotypes prior to treatment. One of these was relatively hypoxic, with relatively low total hemoglobin content. This hypoxic group was found to have a significantly shorter time to reach 3 times pre-treatment volume, indicating a more treatment resistant phenotype (p=0.003). Influence of tumor physiology was assessed in more detail for the liposomal doxorubicin+hyperthermia group, which demonstrated a highly significant correlation between pre-treatment hemoglobin saturation and tumor growth delay, and also between post-hyperthermia total hemoglobin content and tumor drug delivery. Finally, it was found that the doxorubicin concentration, measured in vivo using fluorescence techniques significantly predicted for chemoresponse (hazard ratio: 0.34, p=0.0007). The ability to characterize drug delivery and tumor physiology in vivo makes this a potentially useful tool for evaluating the efficacy of targeted delivery systems in preclinical studies, and may be translatable for monitoring and predicting individual treatment responses in the clinic.

Authors
Palmer, GM; Boruta, RJ; Viglianti, BL; Lan, L; Spasojevic, I; Dewhirst, MW
MLA Citation
Palmer, Gregory M., et al. “Non-invasive monitoring of intra-tumor drug concentration and therapeutic response using optical spectroscopy..” J Control Release, vol. 142, no. 3, Mar. 2010, pp. 457–64. Pubmed, doi:10.1016/j.jconrel.2009.10.034.
PMID
19896999
Source
pubmed
Published In
J Control Release
Volume
142
Issue
3
Publish Date
2010
Start Page
457
End Page
464
DOI
10.1016/j.jconrel.2009.10.034

Phosphorylated epidermal growth factor receptor and cyclooxygenase-2 expression in localized non-small cell lung cancer.

PURPOSE: The prognostic significance of epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) expression remains unestablished, although EGFR and COX-2 are frequently overexpressed in non-small cell lung cancer (NSCLC). Considering the importance of EGFR activation after ligand binding, however, the expression of phosphorylated EGFR (p-EGFR) may have more significance in predicting tumor aggressiveness in NSCLC than either EGFR or COX-2 expression. PATIENTS AND METHODS: We studied the relationships between p-EGFR, EGFR, and COX-2 overexpression and examined their association with prognosis in localized NSCLC. The expression of p-EGFR, EGFR, and COX-2 was studied by immunohistochemistry in 77 surgically-resected stage I/II NSCLC cases. EGFR mutational status was determined by sequencing exons 18-21. Correlation of expression with clinical outcome and other biomarkers, including Ki-67 and microvessel density (MVD), was also examined. RESULTS: Out of the 77 patients, EGFR overexpression was observed in 37 (48.1%), p-EGFR expression was found in 22 (28.6%), and COX-2 overexpression was seen in 45 (58.4%). Expression of p-EGFR was associated with COX-2 overexpression (P = 0.047), but not EGFR overexpression or high Ki-67 (P = 0.087 and P = 0.092, respectively). COX-2 overexpression was significantly associated with high Ki-67 (P = 0.011). Expression of p-EGFR correlated with lower disease-free survival (P = 0.045), but not overall survival. Neither EGFR nor COX-2 overexpression was associated with prognosis. CONCLUSION: p-EGFR appears to be a better indicator for lower disease-free survival than EGFR overexpression itself in localized NSCLC. Pathways other than EGFR activation may influence COX-2 overexpression.

Authors
Kim, SJ; Rabbani, ZN; Dong, F; Vollmer, RT; Schreiber, E-G; Dewhirst, MW; Vujaskovic, Z; Kelley, MJ
MLA Citation
Kim, Seok Jin, et al. “Phosphorylated epidermal growth factor receptor and cyclooxygenase-2 expression in localized non-small cell lung cancer..” Med Oncol, vol. 27, no. 1, Mar. 2010, pp. 91–97. Pubmed, doi:10.1007/s12032-009-9178-z.
PMID
19235531
Source
pubmed
Published In
Med Oncol
Volume
27
Issue
1
Publish Date
2010
Start Page
91
End Page
97
DOI
10.1007/s12032-009-9178-z

Mathematical formulation and analysis of the nonlinear system reconstruction of the online image-guided adaptive control of hyperthermia.

PURPOSE: A nonlinear system reconstruction can theoretically provide timely system reconstruction when designing a real-time image-guided adaptive control for multisource heating for hyperthermia. This clinical need motivates an analysis of the essential mathematical characteristics and constraints of such an approach. METHODS: The implicit function theorem (IFT), the Karush-Kuhn-Tucker (KKT) necessary condition of optimality, and the Tikhonov-Phillips regularization (TPR) were used to analyze and determine the requirements of the optimal system reconstruction. Two mutually exclusive generic approaches were analyzed to reconstruct the physical system: The traditional full reconstruction and the recently suggested partial reconstruction. Rigorous mathematical analysis based on IFT, KKT, and TPR was provided for all four possible nonlinear reconstructions: (1) Nonlinear noiseless full reconstruction, (2) nonlinear noisy full reconstruction, (3) nonlinear noiseless partial reconstruction, and (4) nonlinear noisy partial reconstruction, when a class of nonlinear formulations of system reconstruction is employed. RESULTS: Effective numerical algorithms for solving each of the aforementioned four nonlinear reconstructions were introduced and formal derivations and analyses were provided. The analyses revealed the necessity of adding regularization when partial reconstruction is used. Regularization provides the theoretical support for one to uniquely reconstruct the optimal system. It also helps alleviate the negative influences of unavoidable measurement noise. Both theoretical analysis and numerical examples showed the importance of having a good initial guess for accomplishing nonlinear system reconstruction. CONCLUSIONS: Regularization is mandatory for partial reconstruction to make it well posed. The Tikhonov-Phillips regularized Gauss-Newton algorithm has nice theoretical performance for partial reconstruction of systems with and without noise. The Levenberg-Marquardt algorithm is a more robust algorithmic option compared to the Gauss-Newton algorithm for nonlinear full reconstruction. A severe limitation of nonlinear reconstruction is the time consuming calculations required for the derivatives of temperatures to unknowns. Developing a method of model reduction or implementing a parallel algorithm can resolve this. The results provided herein are applicable to hyperthermia with blood perfusion nonlinearly depending on temperature and in the presence of thermally significant blood vessels.

Authors
Cheng, K-S; Dewhirst, MW; Stauffer, PF; Das, S
MLA Citation
Cheng, Kung-Shan, et al. “Mathematical formulation and analysis of the nonlinear system reconstruction of the online image-guided adaptive control of hyperthermia..” Med Phys, vol. 37, no. 3, Mar. 2010, pp. 980–94. Pubmed, doi:10.1118/1.3298005.
PMID
20384234
Source
pubmed
Published In
Medical Physics
Volume
37
Issue
3
Publish Date
2010
Start Page
980
End Page
994
DOI
10.1118/1.3298005

Effective learning strategies for real-time image-guided adaptive control of multiple-source hyperthermia applicators.

PURPOSE: This paper investigates overall theoretical requirements for reducing the times required for the iterative learning of a real-time image-guided adaptive control routine for multiple-source heat applicators, as used in hyperthermia and thermal ablative therapy for cancer. METHODS: Methods for partial reconstruction of the physical system with and without model reduction to find solutions within a clinically practical timeframe were analyzed. A mathematical analysis based on the Fredholm alternative theorem (FAT) was used to compactly analyze the existence and uniqueness of the optimal heating vector under two fundamental situations: (1) noiseless partial reconstruction and (2) noisy partial reconstruction. These results were coupled with a method for further acceleration of the solution using virtual source (VS) model reduction. The matrix approximation theorem (MAT) was used to choose the optimal vectors spanning the reduced-order subspace to reduce the time for system reconstruction and to determine the associated approximation error. Numerical simulations of the adaptive control of hyperthermia using VS were also performed to test the predictions derived from the theoretical analysis. A thigh sarcoma patient model surrounded by a ten-antenna phased-array applicator was retained for this purpose. The impacts of the convective cooling from blood flow and the presence of sudden increase of perfusion in muscle and tumor were also simulated. RESULTS: By FAT, partial system reconstruction directly conducted in the full space of the physical variables such as phases and magnitudes of the heat sources cannot guarantee reconstructing the optimal system to determine the global optimal setting of the heat sources. A remedy for this limitation is to conduct the partial reconstruction within a reduced-order subspace spanned by the first few maximum eigenvectors of the true system matrix. By MAT, this VS subspace is the optimal one when the goal is to maximize the average tumor temperature. When more than 6 sources present, the steps required for a nonlinear learning scheme is theoretically fewer than that of a linear one, however, finite number of iterative corrections is necessary for a single learning step of a nonlinear algorithm. Thus, the actual computational workload for a nonlinear algorithm is not necessarily less than that required by a linear algorithm. CONCLUSIONS: Based on the analysis presented herein, obtaining a unique global optimal heating vector for a multiple-source applicator within the constraints of real-time clinical hyperthermia treatments and thermal ablative therapies appears attainable using partial reconstruction with minimum norm least-squares method with supplemental equations. One way to supplement equations is the inclusion of a method of model reduction.

Authors
Cheng, K-S; Dewhirst, MW; Stauffer, PR; Das, S
MLA Citation
Cheng, Kung-Shan, et al. “Effective learning strategies for real-time image-guided adaptive control of multiple-source hyperthermia applicators..” Med Phys, vol. 37, no. 3, Mar. 2010, pp. 1285–97. Pubmed, doi:10.1118/1.3302829.
PMID
20384266
Source
pubmed
Published In
Medical Physics
Volume
37
Issue
3
Publish Date
2010
Start Page
1285
End Page
1297
DOI
10.1118/1.3302829

SplicerAV: a tool for mining microarray expression data for changes in RNA processing.

BACKGROUND: Over the past two decades more than fifty thousand unique clinical and biological samples have been assayed using the Affymetrix HG-U133 and HG-U95 GeneChip microarray platforms. This substantial repository has been used extensively to characterize changes in gene expression between biological samples, but has not been previously mined en masse for changes in mRNA processing. We explored the possibility of using HG-U133 microarray data to identify changes in alternative mRNA processing in several available archival datasets. RESULTS: Data from these and other gene expression microarrays can now be mined for changes in transcript isoform abundance using a program described here, SplicerAV. Using in vivo and in vitro breast cancer microarray datasets, SplicerAV was able to perform both gene and isoform specific expression profiling within the same microarray dataset. Our reanalysis of Affymetrix U133 plus 2.0 data generated by in vitro over-expression of HRAS, E2F3, beta-catenin (CTNNB1), SRC, and MYC identified several hundred oncogene-induced mRNA isoform changes, one of which recognized a previously unknown mechanism of EGFR family activation. Using clinical data, SplicerAV predicted 241 isoform changes between low and high grade breast tumors; with changes enriched among genes coding for guanyl-nucleotide exchange factors, metalloprotease inhibitors, and mRNA processing factors. Isoform changes in 15 genes were associated with aggressive cancer across the three breast cancer datasets. CONCLUSIONS: Using SplicerAV, we identified several hundred previously uncharacterized isoform changes induced by in vitro oncogene over-expression and revealed a previously unknown mechanism of EGFR activation in human mammary epithelial cells. We analyzed Affymetrix GeneChip data from over 400 human breast tumors in three independent studies, making this the largest clinical dataset analyzed for en masse changes in alternative mRNA processing. The capacity to detect RNA isoform changes in archival microarray data using SplicerAV allowed us to carry out the first analysis of isoform specific mRNA changes directly associated with cancer survival.

Authors
Robinson, TJ; Dinan, MA; Dewhirst, M; Garcia-Blanco, MA; Pearson, JL
MLA Citation
Robinson, Timothy J., et al. “SplicerAV: a tool for mining microarray expression data for changes in RNA processing..” Bmc Bioinformatics, vol. 11, Feb. 2010. Pubmed, doi:10.1186/1471-2105-11-108.
Website
http://hdl.handle.net/10161/4332
PMID
20184770
Source
pubmed
Published In
Bmc Bioinformatics
Volume
11
Publish Date
2010
Start Page
108
DOI
10.1186/1471-2105-11-108

Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer.

Recent epidemiologic studies report that regular exercise may be associated with substantial reductions in cancer-specific and all-cause mortality following a breast cancer diagnosis. The mechanisms underlying this relationship have not been identified. We investigated the effects of long-term voluntary wheel running on growth and progression using an animal model of human breast cancer. We also examined effects on the central features of tumor physiology, including markers of tumor blood perfusion/vascularization, hypoxia, angiogenesis, and metabolism. Athymic female mice fed a high-fat diet were orthotopically (direct into the mammary fat pad) implanted with human breast cancer cells (MDA-MB-231 at 1 x 10(6)) into the right dorsal mammary fat pad and randomly assigned (1:1) to voluntary wheel running (n = 25) or a nonintervention (sedentary) control group (n = 25). Tumor volume was measured every three days using digital calipers. All experimental animals were killed when tumor volume reached > or = 1,500 mm(3). Kaplan-Meier (KM) analysis indicated that tumor growth (survival) was comparable between the experimental groups (exercise 44 days vs. control 48 days; KM proportional hazard ratio = 1.41, 95% confidence interval, 0.77-2.58, P = 0.14). However, tumors from exercising animals had significantly improved blood perfusion/vascularization relative to the sedentary control group (P < 0.05). Histological analyses indicated that intratumoral hypoxia levels (as assessed by hypoxia-inducible factor 1) were significantly higher in the exercise group relative to sedentary control (P < 0.05). Aerobic exercise can significantly increase intratumoral vascularization, leading to "normalization" of the tissue microenvironment in human breast tumors. Such findings may have important implications for inhibiting tumor metastasis and improving the efficacy of conventional cancer therapies.

Authors
Jones, LW; Viglianti, BL; Tashjian, JA; Kothadia, SM; Keir, ST; Freedland, SJ; Potter, MQ; Moon, EJ; Schroeder, T; Herndon, JE; Dewhirst, MW
MLA Citation
Jones, Lee W., et al. “Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer..” J Appl Physiol (1985), vol. 108, no. 2, Feb. 2010, pp. 343–48. Pubmed, doi:10.1152/japplphysiol.00424.2009.
PMID
19959769
Source
pubmed
Published In
J Appl Physiol (1985)
Volume
108
Issue
2
Publish Date
2010
Start Page
343
End Page
348
DOI
10.1152/japplphysiol.00424.2009

TU‐E‐201C‐06: Imaging the Biological Structure and Characteristics of Model Tumors Using Optical Computed Transmission and Emission Tomography

Purpose: To obtain the first co‐registered high resolution 3D images of an intact xenograft tumor showing (i) the vasculature network labeled with an absorbing vasculature contrast agent, and imaged with optical‐CT (ii) the distribution of red‐fluorescent‐protein (RFP) constitutively expressed by viable tumor cells, and (iii) the distribution of green‐fluorescent‐protein (GFP) endogenously expressed by tumor cells exhibiting HIF‐1 transcription (hypoxia‐inducible‐factor). Method and Materials: An in‐house prototype optical‐CT/ECT system was constructed incorporating specialized optics to facilitate accurate parallel beam tomographic imaging. Both transmission imaging (optical‐CT) and emission imaging (optical‐ECT) can be performed on the same sample, enabling very accurate multi‐modal image registration. A 4T1 tumor cell line with double fluorescent reporter labeling (GFP and RFP as described above) was grown in a window chamber (under IACUC approved protocol). The tumor was first imaged in‐vivo, with an epi‐fluorescent microscope. A tail vein injection of vascular contrast was then administered, and the tumor removed from the window and optically cleared, in preparation for optical‐CT/ECT imaging. Results: Comparison of the in‐vivo window chamber images with post clearing images revealed consistent areas of fluorescent signal but, importantly, new areas of signal were visible in the cleared images where signal had been obscured by overlying structures in the in‐vivo images. All 3 biological characteristics (vasculature, viable tumor‐sub‐volume, and HIF‐1 expressing sub‐volumes) were successfully imaged, and accurately co‐registered, enabling detailed analysis of inter‐relationships using overlay images. Quantitative metrics were derived from the images, including viable‐tumor‐volume=10.5mm3, GFP‐hypoxic sub‐volume=2.6mm3, vessel‐volume =1.7mm3, and hypoxic ratio=0.25. Conclusion: High resolution multi‐modal 3D co‐registered images can be acquired with optical‐CT/ECT techniques from optically cleared tissue samples. The unique capabilities of these techniques to image relatively large un‐sectioned samples offers a new low‐cost way to investigate biological processes and inter‐dependencies in whole samples. © 2010, American Association of Physicists in Medicine. All rights reserved.

Authors
Oldham, M; Thomas, A; Schroeder, T; Fontanella, A; Dewhirst, M
MLA Citation
Oldham, M., et al. “TU‐E‐201C‐06: Imaging the Biological Structure and Characteristics of Model Tumors Using Optical Computed Transmission and Emission Tomography.” Medical Physics, vol. 37, no. 6, 2010. Scopus, doi:10.1118/1.3469308.
Source
scopus
Published In
Medical Physics
Volume
37
Issue
6
Publish Date
2010
Start Page
3405
DOI
10.1118/1.3469308

Growth and Structural Adaptation of Blood Vessels in Normal and Tumor Tissues

Authors
Secomb, TW; Dewhirst, MW; Pries, AR
MLA Citation
Secomb, Timothy W., et al. “Growth and Structural Adaptation of Blood Vessels in Normal and Tumor Tissues.” New Perspectives in Mathematical Biology, edited by S. Sivaloganathan, vol. 57, AMER MATHEMATICAL SOC, 2010, pp. 21–35.
Source
wos
Published In
New Perspectives in Mathematical Biology
Volume
57
Publish Date
2010
Start Page
21
End Page
35

Tumor metabolism of lactate: the influence and therapeutic potential for MCT and CD147 regulation.

Tumor metabolism consists of complex interactions between oxygenation states, metabolites, ions, the vascular network and signaling cascades. Accumulation of lactate within tumors has been correlated with poor clinical outcomes. While its production has negative implications, potentially contributing to tumor progression, the implications of the ability of tumors to utilize lactate can offer new therapeutic targets for the future. Monocarboxylate transporters (MCTs) of the SLC16A gene family influence substrate availability, the metabolic path of lactate and pH balance within the tumor. CD147, a chaperone to some MCT subtypes, contributes to tumor progression and metastasis. The implications and consequences of lactate utilization by tumors are currently unknown; therefore future research is needed on the intricacies of tumor metabolism. The possibility of metabolic modification of the tumor microenvironment via regulation or manipulation of MCT1 and CD147 may prove to be promising avenues of therapeutic options.

Authors
Kennedy, KM; Dewhirst, MW
MLA Citation
Kennedy, Kelly M., and Mark W. Dewhirst. “Tumor metabolism of lactate: the influence and therapeutic potential for MCT and CD147 regulation..” Future Oncol, vol. 6, no. 1, Jan. 2010, pp. 127–48. Pubmed, doi:10.2217/fon.09.145.
PMID
20021214
Source
pubmed
Published In
Future Oncol
Volume
6
Issue
1
Publish Date
2010
Start Page
127
End Page
148
DOI
10.2217/fon.09.145

Longitudinal optical imaging of tumor metabolism and hemodynamics.

An important feature of tumor hypoxia is its temporal instability, or "cycling hypoxia." The primary consequence of cycling hypoxia is increased tumor aggressiveness and treatment resistance beyond that of chronic hypoxia. Longitudinal imaging of tumor metabolic demand, hemoglobin oxygen saturation, and blood flow would provide valuable insight into the mechanisms and distribution of cycling hypoxia in tumors. Fluorescence imaging of metabolic demand via the optical redox ratio (fluorescence intensity of FAD/NADH), absorption microscopy of hemoglobin oxygen saturation, and Doppler optical coherence tomography of vessel morphology and blood flow are combined to noninvasively monitor changes in oxygen supply and demand in the mouse dorsal skin fold window chamber tumor model (human squamous cell carcinoma) every 6 h for 36 h. Biomarkers for metabolic demand, blood oxygenation, and blood flow are all found to significantly change with time (p<0.05). These variations in oxygen supply and demand are superimposed on a significant (p<0.05) decline in metabolic demand with distance from the nearest vessel in tumors (this gradient was not observed in normal tissues). Significant (p<0.05), but weak (r

Authors
Skala, MC; Fontanella, A; Lan, L; Izatt, JA; Dewhirst, MW
MLA Citation
Skala, Melissa C., et al. “Longitudinal optical imaging of tumor metabolism and hemodynamics..” J Biomed Opt, vol. 15, no. 1, Jan. 2010. Pubmed, doi:10.1117/1.3285584.
PMID
20210438
Source
pubmed
Published In
Journal of Biomedical Optics
Volume
15
Issue
1
Publish Date
2010
Start Page
011112
DOI
10.1117/1.3285584

Utility of functional imaging in prediction or assessment of treatment response and prognosis following thermotherapy.

The purpose of this review is to examine the roles that functional imaging may play in prediction of treatment response and determination of overall prognosis in patients who are enrolled in thermotherapy trials, either in combination with radiotherapy, chemotherapy or both. Most of the historical work that has been done in this field has focused on magnetic resonance imaging/magnetic resonance spectroscopy (MRI/MRS) methods, so the emphasis will be there, although some discussion of the role that positron emission tomography (PET) might play will also be examined. New optical technologies also hold promise for obtaining low cost, yet valuable physiological data from optically accessible sites. The review is organised by traditional outcome parameters: local response, local control and progression-free or overall survival. Included in the review is a discussion of future directions for this type of translational work.

Authors
Dewhirst, MW; Thrall, DE; Palmer, G; Schroeder, T; Vujaskovic, Z; Cecil Charles, H; Macfall, J; Wong, T
MLA Citation
Dewhirst, Mark W., et al. “Utility of functional imaging in prediction or assessment of treatment response and prognosis following thermotherapy..” Int J Hyperthermia, vol. 26, no. 3, 2010, pp. 283–93. Pubmed, doi:10.3109/02656730903286214.
PMID
20170362
Source
pubmed
Published In
Int J Hyperthermia
Volume
26
Issue
3
Publish Date
2010
Start Page
283
End Page
293
DOI
10.3109/02656730903286214

Hyperthermia for locally advanced breast cancer.

Hyperthermia (HT) has a proven benefit for treating superficial malignancies, particularly chest wall recurrences of breast cancer. There has been less research utilising HT in patients with locally advanced breast cancer (LABC), but available data are promising. HT has been combined with chemotherapy and/or radiotherapy in the neoadjuvant, definitive and adjuvant setting, albeit in series with small numbers of patients. There is only one phase III trial that examines hyperthermia in LABC, also with relatively small numbers of patients. The goal of this review is to highlight important research utilising HT in patients with LABC as well as to suggest future directions for its use.

Authors
Zagar, TM; Oleson, JR; Vujaskovic, Z; Dewhirst, MW; Craciunescu, OI; Blackwell, KL; Prosnitz, LR; Jones, EL
MLA Citation
Zagar, Timothy M., et al. “Hyperthermia for locally advanced breast cancer..” Int J Hyperthermia, vol. 26, no. 7, 2010, pp. 618–24. Pubmed, doi:10.3109/02656736.2010.501051.
PMID
20849257
Source
pubmed
Published In
Int J Hyperthermia
Volume
26
Issue
7
Publish Date
2010
Start Page
618
End Page
624
DOI
10.3109/02656736.2010.501051

Comparative effects of thermosensitive doxorubicin-containing liposomes and hyperthermia in human and murine tumours.

PURPOSE: In previous reports, laboratory-made lysolecithin-containing thermosensitive liposome encapsulating doxorubicin (LTSL-DOX) showed potent anticancer effects in FaDu human squamous cell carcinoma. To further study the spectrum of LTSL-DOX activity, the efficacy of its commercial formulation was re-examined in FaDu and compared in HCT116, PC3, SKOV-3 and 4T07 cancer cell lines. Factors that may influence differences in HT-LTSL-DOX efficacy were also examined. METHODS: Anticancer effect was measured using standard growth delay methods. We measured doubling time and clonogenic survival after doxorubicin exposure in vitro, and interstitial pH and drug concentrations in vivo. RESULTS: In all five tumour types, HT-LTSL-DOX increased median tumour growth time compared with untreated controls (p < 0.0006) and HT alone (p < 0.01), and compared with LTSL-DOX alone in FaDu, PC-3 and HCT-116 (p < 0.0006). HT-LTSL-DOX yielded significantly higher drug concentrations than LTSL-DOX (p < 0.0001). FaDu was most sensitive (p < 0.0014) to doxorubicin (IC(50) = 90 nM) in vitro, compared to the other cell lines (IC(50) = 129-168 nM). Of the parameters tested for correlation with efficacy, only the correlation of in vitro doubling time and in vivo median growth time was significant (Pearson r = 0.98, p = 0.0035). Slower-growing SKOV-3 and PC-3 had the greatest numbers of complete regressions and longest tumour growth delays, which are clinically important parameters. CONCLUSIONS: These results strongly suggest that variations in anti-tumour effect of HT-LTSL-DOX are primarily related to in vitro doubling time. In the clinic, the rate of tumour progression must be considered in design of treatment regimens involving HT-LTSL-DOX.

Authors
Yarmolenko, PS; Zhao, Y; Landon, C; Spasojevic, I; Yuan, F; Needham, D; Viglianti, BL; Dewhirst, MW
MLA Citation
Yarmolenko, Pavel S., et al. “Comparative effects of thermosensitive doxorubicin-containing liposomes and hyperthermia in human and murine tumours..” Int J Hyperthermia, vol. 26, no. 5, 2010, pp. 485–98. Pubmed, doi:10.3109/02656731003789284.
PMID
20597627
Source
pubmed
Published In
Int J Hyperthermia
Volume
26
Issue
5
Publish Date
2010
Start Page
485
End Page
498
DOI
10.3109/02656731003789284

A phase I/II study of neoadjuvant liposomal doxorubicin, paclitaxel, and hyperthermia in locally advanced breast cancer.

PURPOSE: The prognosis for locally advanced breast cancer (LABC) patients continues to be poor, with an estimated five-year survival of only 50-60%. Preclinical data demonstrates enhanced therapeutic efficacy with liposomal encapsulation of doxorubicin combined with hyperthermia (HT). Therefore this phase I/II study was designed to evaluate the safety and efficacy of a novel neoadjuvant combination treatment of paclitaxel, liposomal doxorubicin, and hyperthermia. MATERIALS AND METHODS: Eligible patients received four cycles of neoadjuvant liposomal doxorubicin (30-75 mg/m(2)), paclitaxel (100-175 mg/m(2)), and hyperthermia. They subsequently underwent either a modified radical mastectomy or lumpectomy with axillary node dissection followed by radiation therapy and then eight cycles of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy. RESULTS: Forty-seven patients with stage IIB-III LABC were enrolled and 43 patients were evaluable. Fourteen patients (33%) had inflammatory breast cancer. Combined (partial + complete) clinical response rate was 72% and combined pathological response rate was 60%. Four patients achieved a pathologically complete response. Sixteen patients were eligible for breast-conserving surgery. The cumulative equivalent minutes (CEM 43) at T90 (tenth percentile of temperature distribution) was significantly greater for those with a pathological response. Four-year disease-free survival was 63% (95% CI, 46%-76%) and the four-year overall survival was 75% (95% CI, 58-86%). CONCLUSIONS: Neoadjuvant therapy using paclitaxel, liposomal doxorubicin and hyperthermia is a feasible and well tolerated treatment strategy in patients with LABC. The thermal dose parameter CEM 43 T90 was significantly correlated with attaining a pathological response.

Authors
Vujaskovic, Z; Kim, DW; Jones, E; Lan, L; McCall, L; Dewhirst, MW; Craciunescu, O; Stauffer, P; Liotcheva, V; Betof, A; Blackwell, K
MLA Citation
Vujaskovic, Zeljko, et al. “A phase I/II study of neoadjuvant liposomal doxorubicin, paclitaxel, and hyperthermia in locally advanced breast cancer..” Int J Hyperthermia, vol. 26, no. 5, 2010, pp. 514–21. Pubmed, doi:10.3109/02656731003639364.
PMID
20377362
Source
pubmed
Published In
Int J Hyperthermia
Volume
26
Issue
5
Publish Date
2010
Start Page
514
End Page
521
DOI
10.3109/02656731003639364

Hyperthermia combined with radiation therapy for superficial breast cancer and chest wall recurrence: a review of the randomised data.

Hyperthermia has long been used in combination with radiation for the treatment of superficial malignancies, in part due to its radiosensitising capabilities. Patients who suffer superficial recurrences of breast cancer, be it in their chest wall following mastectomy, or in their breast after breast conservation, typically have poor clinical outcomes. They often develop distant metastatic disease, but one must not overlook the problems associated with an uncontrolled local failure. Morbidity is enormous, and can significantly impair quality of life. There is no accepted standard of care in treating superficial recurrences of breast cancer, particularly in patients that have previously been irradiated. There is a substantial literature regarding the combined use of hyperthermia and radiotherapy for these superficial recurrences. Most of it is retrospective in nature, but there are several larger phase III randomised trials that show an improved rate of clinical complete response in patients treated with both modalities. In this review article, we will highlight the important prospective data that has been published regarding the combined use of hyperthermia and radiation.

Authors
Zagar, TM; Oleson, JR; Vujaskovic, Z; Dewhirst, MW; Craciunescu, OI; Blackwell, KL; Prosnitz, LR; Jones, EL
MLA Citation
Zagar, Timothy M., et al. “Hyperthermia combined with radiation therapy for superficial breast cancer and chest wall recurrence: a review of the randomised data..” Int J Hyperthermia, vol. 26, no. 7, 2010, pp. 612–17. Pubmed, doi:10.3109/02656736.2010.487194.
PMID
20849256
Source
pubmed
Published In
Int J Hyperthermia
Volume
26
Issue
7
Publish Date
2010
Start Page
612
End Page
617
DOI
10.3109/02656736.2010.487194

Magnetic resonance imaging: a potential tool in assessing the addition of hyperthermia to neoadjuvant therapy in patients with locally advanced breast cancer.

The poor overall survival for patients with locally advanced breast cancers has led over the past decade to the introduction of numerous neoadjuvant combined therapy regimens to down-stage the disease before surgery. At the same time, more evidence suggests the need for treatment individualisation with a wide variety of new targets for cancer therapeutics and also multi modality therapies. In this context, early determination of whether the patient will fail to respond can enable the use of alternative therapies that can be more beneficial. The purpose of this review is to examine the potential role of magnetic resonance imaging (MRI) in early prediction of treatment response and prognosis of overall survival in locally advanced breast cancer patients enrolled on multi modality therapy trials that include hyperthermia. The material is organised with a review of dynamic contrast (DCE)-MRI and diffusion weighted (DW)-MRI for characterisation of phenomenological parameters of tumour physiology and their potential role in estimating therapy response. Most of the work published in this field has focused on responses to neoadjuvant chemotherapy regimens alone, so the emphasis will be there, however the available data that involves the addition of hyperthermia to the regimen will be discussed The review will also include future directions that include the potential use of MRI imaging techniques in establishing the role of hyperthermia alone in modifying breast tumour microenvironment, together with specific challenges related to performing such studies.

Authors
Craciunescu, OI; Thrall, DE; Vujaskovic, Z; Dewhirst, MW
MLA Citation
Craciunescu, Oana I., et al. “Magnetic resonance imaging: a potential tool in assessing the addition of hyperthermia to neoadjuvant therapy in patients with locally advanced breast cancer..” Int J Hyperthermia, vol. 26, no. 7, 2010, pp. 625–37. Pubmed, doi:10.3109/02656736.2010.499526.
PMID
20849258
Source
pubmed
Published In
Int J Hyperthermia
Volume
26
Issue
7
Publish Date
2010
Start Page
625
End Page
637
DOI
10.3109/02656736.2010.499526

Erratum: Arrhenius relationships from the molecule and cell to the clinic (International Journal of Hyperthermia (2009) 25 (21-24))

Authors
Dewey, WC; Diederich, CJ; Dewhirst, MW
MLA Citation
Dewey, W. C., et al. “Erratum: Arrhenius relationships from the molecule and cell to the clinic (International Journal of Hyperthermia (2009) 25 (21-24)).” International Journal of Hyperthermia, vol. 25, no. 3, Dec. 2009. Scopus, doi:10.1080/02656730902841118.
Source
scopus
Published In
International Journal of Hyperthermia : the Official Journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group
Volume
25
Issue
3
Publish Date
2009
Start Page
248
DOI
10.1080/02656730902841118

Combined hyperspectral and optical coherence tomography microscope for non-invasive hemodynamic imaging

Hyperspectral microscopy of hemoglobin oxygenation and optical coherence microscopy of three-dimensional microvessel morphology and blood velocity was demonstrated in growing tumors in the mouse skin fold window chamber. © 2007 Optical Society of America.

Authors
Skala, M; Fontanella, A; Hendargo, H; Dewhirst, M; Izatt, J
MLA Citation
Skala, M., et al. “Combined hyperspectral and optical coherence tomography microscope for non-invasive hemodynamic imaging.” Optics Infobase Conference Papers, Dec. 2009.
Source
scopus
Published In
Optics Infobase Conference Papers
Publish Date
2009

Relationships between cycling hypoxia, HIF-1, angiogenesis and oxidative stress.

This Failla Lecture focused on the inter-relationships between tumor angiogenesis, HIF-1 expression and radiotherapy responses. A common thread that bonds all of these factors together is microenvironmental stress caused by reactive oxygen and nitrogen species formed during tumor growth and angiogenesis or in response to cytotoxic treatment. In this review we focus on one aspect of the crossroad between oxidative stress and angiogenesis, namely cycling hypoxia. Understanding of the relative importance of this feature of the tumor microenvironment has recently expanded; it influences tumor biology in ways that are separate from chronic hypoxia. Cycling hypoxia can influence angiogenesis, treatment responses and metastatic behavior. It represents an important and relatively less well understood feature of tumor biology that requires additional research.

Authors
Dewhirst, MW
MLA Citation
Dewhirst, Mark W. “Relationships between cycling hypoxia, HIF-1, angiogenesis and oxidative stress..” Radiat Res, vol. 172, no. 6, Dec. 2009, pp. 653–65. Pubmed, doi:10.1667/RR1926.1.
PMID
19929412
Source
pubmed
Published In
Radiat Res
Volume
172
Issue
6
Publish Date
2009
Start Page
653
End Page
665
DOI
10.1667/RR1926.1

Accuracy of real time noninvasive temperature measurements using magnetic resonance thermal imaging in patients treated for high grade extremity soft tissue sarcomas.

PURPOSE: To establish accuracy of real time noninvasive temperature measurements using magnetic resonance thermal imaging in patients treated for high grade extremity soft tissue sarcomas. METHODS: Protocol patients with advanced extremity sarcomas were treated with external beam radiation therapy and hyperthermia. Invasive temperature measures were compared to noninvasive magnetic resonance thermal imaging (MRTI) at 1.5 T performed during hyperthermia. Volumetric temperature rise images were obtained using the proton resonance frequency shift (PRFS) technique during heating in a 140 MHz miniannular phased array applicator. MRTI temperature changes were compared to invasive measurements of temperature with a multisensor fiber optic probe inside a #15 g catheter in the tumor. Since the PRFS technique is sensitive to drifts in the primary imaging magnetic field, temperature change distributions were corrected automatically during treatment using temperature-stable reference materials to characterize field changes in 3D. The authors analyzed MRT images and compared, in evaluable treatments, MR-derived temperatures to invasive temperatures measured in extremity sarcomas. Small regions of interest (ROIs) were specified near each invasive sensor identified on MR images. Temperature changes in the interstitial sensors were compared to the corresponding ROI PRFS-based temperature changes over the entire treatment and over the steady-state period. Nonevaluable treatments (motion/imaging artifacts, noncorrectable drifts) were not included in the analysis. RESULTS: The mean difference between MRTI and interstitial probe measurements was 0.91 degrees C for the entire heating time and 0.85 degrees C for the time at steady state. These values were obtained from both tumor and normal tissue ROIs. When the analysis is done on just the tumor ROIs, the mean difference for the whole power on time was 0.74 degrees C and during the period of steady state was 0.62 degrees C. CONCLUSIONS: The data show that for evaluable treatments, excellent correlation (deltaT < 1 degrees C) of MRTI-ROI and invasive measurements can be achieved, but that motion and other artifacts are still serious challenges that must be overcome in future work.

Authors
Craciunescu, OI; Stauffer, PR; Soher, BJ; Wyatt, CR; Arabe, O; Maccarini, P; Das, SK; Cheng, K-S; Wong, TZ; Jones, EL; Dewhirst, MW; Vujaskovic, Z; MacFall, JR
MLA Citation
Craciunescu, Oana I., et al. “Accuracy of real time noninvasive temperature measurements using magnetic resonance thermal imaging in patients treated for high grade extremity soft tissue sarcomas..” Med Phys, vol. 36, no. 11, Nov. 2009, pp. 4848–58. Pubmed, doi:10.1118/1.3227506.
PMID
19994492
Source
pubmed
Published In
Medical Physics
Volume
36
Issue
11
Publish Date
2009
Start Page
4848
End Page
4858
DOI
10.1118/1.3227506

Synchronous Chemoradiation and Multiple Targeted Drugs for Advanced Head and Neck Cancer

Authors
Brizel, DM; Yoo, DS; Ready, N; Kirkpatrick, JP; Dewhirst, MW; Scher, RL; Cleland, E; MacFall, J; Barboriak, D; Craciunescu, O
MLA Citation
Brizel, D. M., et al. “Synchronous Chemoradiation and Multiple Targeted Drugs for Advanced Head and Neck Cancer.” International Journal of Radiation Oncology*Biology*Physics, vol. 75, no. 3, Elsevier BV, 2009, pp. S175–76. Crossref, doi:10.1016/j.ijrobp.2009.07.409.
Source
crossref
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
75
Issue
3
Publish Date
2009
Start Page
S175
End Page
S176
DOI
10.1016/j.ijrobp.2009.07.409

Antiangiogenic action of redox-modulating Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP(5+), via suppression of oxidative stress in a mouse model of breast tumor.

MnTE-2-PyP(5+) is a potent catalytic scavenger of reactive oxygen and nitrogen species, primarily superoxide and peroxynitrite. It therefore not only attenuates primary oxidative damage, but was found to modulate redox-based signaling pathways (HIF-1alpha, NF-kappaB, SP-1, and AP-1) and thus, in turn, secondary oxidative injury also. Cancer has been widely considered an oxidative stress condition. The goal of this study was to prove if and why a catalytic SOD mimic/peroxynitrite scavenger would exert anti-cancer effects, i.e., to evaluate whether the attenuation of the oxidative stress by MnTE-2-PyP(5+) could suppress tumor growth in a 4T1 mouse breast tumor model. Tumor cells were implanted into Balb/C mouse flanks. Three groups of mice (n=25) were studied: control (PBS) and 2 and 15 mg/kg/day of MnTE-2-PyP(5+) given subcutaneously twice daily starting when the tumors averaged 200 mm(3) (until they reached approximately 5-fold the initial volume). Intratumoral hypoxia (pimonidazole, carbonic anhydrase), HIF-1alpha, VEGF, proliferating capillary index (CD105), microvessel density (CD31), protein nitration, DNA oxidation (8-OHdG), NADPH oxidase (Nox-4), apoptosis (CD31), macrophage infiltration (CD68), and tumor drug levels were assessed. With 2 mg/kg/day a trend toward tumor growth delay was observed, and a significant trend was observed with 15 mg/kg/day. The 7.5-fold increase in drug dose was accompanied by a similar (6-fold) increase in tumor drug levels. Oxidative stress was largely attenuated as observed through the decreased levels of DNA damage, protein 3-nitrotyrosine, macrophage infiltration, and NADPH oxidase. Further, hypoxia was significantly decreased as were the levels of HIF-1alpha and VEGF. Consequently, suppression of angiogenesis was observed; both the microvessel density and the endothelial cell proliferation were markedly decreased. Our study indicates for the first time that MnTE-2-PyP(5+) has anti-cancer activity in its own right. The anti-cancer activity via HIF/VEGF pathways probably arises from the impact of the drug on the oxidative stress. Therefore, the catalytic scavenging of ROS/RNS by antioxidants, which in turn suppresses cellular transcriptional activity, could be an appropriate strategy for anti-cancer therapy. Enhancement of the anti-cancer effects may be achieved by optimizing the dosing regime, utilizing more bioavailable Mn porphyrins (MnP), and combining MnP treatment with irradiation, hyperthermia, and chemotherapy. Mn porphyrins may be advantageous compared to other anti-cancer drugs, owing to their radioprotection of normal tissue and the ability to afford pain management in cancer patients via prevention of chronic morphine tolerance.

Authors
Rabbani, ZN; Spasojevic, I; Zhang, X; Moeller, BJ; Haberle, S; Vasquez-Vivar, J; Dewhirst, MW; Vujaskovic, Z; Batinic-Haberle, I
MLA Citation
Rabbani, Zahid N., et al. “Antiangiogenic action of redox-modulating Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP(5+), via suppression of oxidative stress in a mouse model of breast tumor..” Free Radic Biol Med, vol. 47, no. 7, Oct. 2009, pp. 992–1004. Pubmed, doi:10.1016/j.freeradbiomed.2009.07.001.
PMID
19591920
Source
pubmed
Published In
Free Radic Biol Med
Volume
47
Issue
7
Publish Date
2009
Start Page
992
End Page
1004
DOI
10.1016/j.freeradbiomed.2009.07.001

Increased skin carcinogenesis in caspase-activated DNase knockout mice.

Caspase-activated DNase (CAD), also called DNA fragmentation factor (DFF), is the enzyme responsible for DNA fragmentation during apoptosis, a hallmark of programmed cell death. CAD/DFF has been shown to suppress radiation-induced carcinogenesis by preventing genomic instability in cells. In this study, we have investigated the role of CAD in chemical carcinogenesis using CAD-null mice and two-stage model of skin carcinogenesis. After topical treatment of mouse skin with dimethylbenz[a]anthracene (DMBA) as an initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoting agent, there was a 4-fold increase in the number of papillomas per mouse and 50.8% increase in the incidence of papilloma formation in the CAD knockout mice compared with wild-type littermates. The papillomas in CAD-null mice grew faster and reached larger sizes. These data indicate that loss of CAD function enhances tumorigenesis induced by a chemical carcinogen in the DMBA/TPA two-stage model of skin carcinogenesis in mice.

Authors
Yan, B; Wang, H; Xie, D; Wakamatsu, N; Anscher, MS; Dewhirst, MW; Mitchel, REJ; Chen, BJ; Li, C-Y
MLA Citation
Yan, Bin, et al. “Increased skin carcinogenesis in caspase-activated DNase knockout mice..” Carcinogenesis, vol. 30, no. 10, Oct. 2009, pp. 1776–80. Pubmed, doi:10.1093/carcin/bgp146.
PMID
19541853
Source
pubmed
Published In
Carcinogenesis
Volume
30
Issue
10
Publish Date
2009
Start Page
1776
End Page
1780
DOI
10.1093/carcin/bgp146

Using optical spectroscopy to longitudinally monitor physiological changes within solid tumors.

The feasibility of using quantitative diffuse reflectance spectroscopy to longitudinally monitor physiological response to cancer therapy was evaluated in a preclinical model. This study included two groups of nude mice bearing 4T1 flank tumors (N = 50), half of which were treated with a maximum tolerated dose of doxorubicin (DOX). Diffuse reflectance spectra were collected from tumors during a period of 2 weeks using a fiber-optic probe coupled to a spectrometer. These spectra were quantified using an inverse scalable Monte Carlo model of light transport in tissue to extract the concentrations of oxygenated, deoxygenated hemoglobin (dHb), and a wavelength mean reduced scattering coefficient (). The tumor growth rates of the treated and control groups were nearly identical, as were changes in the scattering parameter during this time frame. However, tumors treated with DOX showed a transient but significant increase in blood oxygen saturation. A comparison between the optically derived and immunohistochemical end points in a subset of the 50 animals showed that the temporal kinetics of dHb concentration and were highly concordant with those of hypoxic and necrotic fractions, respectively. In conclusion, optical methods could function as a "screening" technology in longitudinal studies of small animal tumor models to accelerate development and testing of new anticancer drugs. This technique could isolate specific landmark time points at which more expensive and sophisticated imaging methods or immunohistochemistry could be performed.

Authors
Vishwanath, K; Yuan, H; Barry, WT; Dewhirst, MW; Ramanujam, N
MLA Citation
Vishwanath, Karthik, et al. “Using optical spectroscopy to longitudinally monitor physiological changes within solid tumors..” Neoplasia, vol. 11, no. 9, Sept. 2009, pp. 889–900. Pubmed, doi:10.1593/neo.09580.
PMID
19724683
Source
pubmed
Published In
Neoplasia
Volume
11
Issue
9
Publish Date
2009
Start Page
889
End Page
900
DOI
10.1593/neo.09580

Quantitative optical spectroscopy can identify long-term local tumor control in irradiated murine head and neck xenografts.

Noninvasive and longitudinal monitoring of tumor oxygenation status using quantitative diffuse reflectance spectroscopy is used to test whether a final treatment outcome could be estimated from early optical signatures in a murine model of head and neck cancer when treated with radiation. Implanted tumors in the flank of 23 nude mice are exposed to 39 Gy of radiation, while 11 animals exposed to sham irradiation serve as controls. Diffuse optical reflectance is measured from the tumors at baseline (prior to irradiation) and then serially until 17 days posttreatment. The fastest and greatest increase in baseline-corrected blood oxygen saturation levels are observed from the animals that show complete tumor regression with no recurrence 90 days postirradiation, relative to both untreated and treated animals with local recurrences. These increases in saturation are observed starting 5 days posttreatment and last up to 17 days posttreatment. This preclinical study demonstrates that diffuse reflectance spectroscopy could provide a practical method far more effective than the growth delay assay to prognosticate treatment outcome in solid tumors and may hold significant translational promise.

Authors
Vishwanath, K; Klein, D; Chang, K; Schroeder, T; Dewhirst, MW; Ramanujam, N
MLA Citation
Vishwanath, Karthik, et al. “Quantitative optical spectroscopy can identify long-term local tumor control in irradiated murine head and neck xenografts..” J Biomed Opt, vol. 14, no. 5, Sept. 2009. Pubmed, doi:10.1117/1.3251013.
PMID
19895152
Source
pubmed
Published In
Journal of Biomedical Optics
Volume
14
Issue
5
Publish Date
2009
Start Page
054051
DOI
10.1117/1.3251013

A dual-emissive-materials design concept enables tumour hypoxia imaging.

Luminescent materials are widely used for imaging and sensing owing to their high sensitivity, rapid response and facile detection by many optical technologies. Typically materials must be chemically tailored to achieve intense, photostable fluorescence, oxygen-sensitive phosphorescence or dual emission for ratiometric sensing, often by blending two dyes in a matrix. Dual-emissive materials combining all of these features in one easily tunable molecular platform are desirable, but when fluorescence and phosphorescence originate from the same dye, it can be challenging to vary relative fluorescence/phosphorescence intensities for practical sensing applications. Heavy-atom substitution alone increases phosphorescence by a given, not variable amount. Here, we report a strategy for modulating fluorescence/phosphorescence for a single-component, dual-emissive, iodide-substituted difluoroboron dibenzoylmethane-poly(lactic acid) (BF(2)dbm(I)PLA) solid-state sensor material. This is accomplished through systematic variation of the PLA chain length in controlled solvent-free lactide polymerization combined with heavy-atom substitution. We demonstrate the versatility of this approach by showing that films made from low-molecular-weight BF(2)dbm(I)PLA with weak fluorescence and strong phosphorescence are promising as 'turn on' sensors for aerodynamics applications, and that nanoparticles fabricated from a higher-molecular-weight polymer with balanced fluorescence and phosphorescence intensities serve as ratiometric tumour hypoxia imaging agents.

Authors
Zhang, G; Palmer, GM; Dewhirst, MW; Fraser, CL
MLA Citation
Zhang, Guoqing, et al. “A dual-emissive-materials design concept enables tumour hypoxia imaging..” Nat Mater, vol. 8, no. 9, Sept. 2009, pp. 747–51. Pubmed, doi:10.1038/nmat2509.
PMID
19668206
Source
pubmed
Published In
Nature Materials
Volume
8
Issue
9
Publish Date
2009
Start Page
747
End Page
751
DOI
10.1038/nmat2509

Characterization of a 137Cs irradiator from a new perspective with modern dosimetric tools.

To provide for accurate dosimetry in a 137Cs irradiator, the following were investigated: (1) correct mapping of the irradiator cavity's dose distribution, (2) rotated versus stationary dose rate measurements, (3) exposure-to-dose calibration selection for exposure time calculation, and (4) irradiator-timer error correction. This work introduces techniques to map dose distributions and measure dose rates with new high-sensitivity radiochromic films and a small-volume ion chamber constructed for in-beam, high-intensity gamma irradiation. Measured film distributions were compared to manufacturer-provided data and independent measurements from an ion chamber and TLD-100 chips. Measured film distributions agreed with the manufacturer-provided data in the central-vertical region, but disagreed by as much as 95% in surrounding regions. The independent measurements agreed within 96% with the measured dose distribution. Dose rates varied by approximately 11% for a rotational versus stationary setup, by approximately 10% for the dose-to-medium correction between air and soft tissue, and by approximately 4-12% for irradiation times from 0.2-0.7 min due to timer error. In conclusion, a critical irradiator characterization should be performed, initially, as a part of the acceptance testing of a newly installed irradiator, and periodically as an ongoing quality assurance protocol. We investigated, and recommend as part of a comprehensive irradiator verification protocol, the inclusion of radiochromic film-measured dose distributions, dose rates measured during rotation when samples are likewise rotated for exposure, timer error corrections for short-time irradiation, and exposure-to-dose corrections that reflect typical sample compositions, e.g., soft tissue or air.

Authors
Brady, SL; Toncheva, G; Dewhirst, MW; Yoshizumi, TT
MLA Citation
Brady, Samuel L., et al. “Characterization of a 137Cs irradiator from a new perspective with modern dosimetric tools..” Health Phys, vol. 97, no. 3, Sept. 2009, pp. 195–205. Pubmed, doi:10.1097/HP.0b013e3181a9bd42.
PMID
19667802
Source
pubmed
Published In
Health Phys
Volume
97
Issue
3
Publish Date
2009
Start Page
195
End Page
205
DOI
10.1097/HP.0b013e3181a9bd42

POLY 216-Boron biomaterials for imaging and oxygen sensing

Authors
Zhang, G; Fraser, CL; Hamm-Alvarez, S; Xie, J; Price, RJ; Palmer, GM; Dewhirst, MW
MLA Citation
Zhang, Guoqing, et al. “POLY 216-Boron biomaterials for imaging and oxygen sensing.” Abstracts of Papers of the American Chemical Society, vol. 238, AMER CHEMICAL SOC, Aug. 2009.
Source
wos
Published In
Abstracts of Papers of the American Chemical Society
Volume
238
Publish Date
2009

Dynamic contrast-enhanced magnetic resonance imaging as a predictor of clinical outcome in canine spontaneous soft tissue sarcomas treated with thermoradiotherapy.

PURPOSE: This study tests whether dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters obtained from canine patients with soft tissue sarcomas, treated with hyperthermia and radiotherapy, are predictive of therapeutic outcome. EXPERIMENTAL DESIGN: Thirty-seven dogs with soft tissue sarcomas had DCE-MRI done before and following the first hyperthermia. Signal enhancement for tumor and reference muscle were fitted empirically, yielding a washin/washout rate for the contrast agent and tumor area under the signal enhancement curve (AUC) calculated from 0 to 60 seconds, 90 seconds, and the time of maximal enhancement in the reference muscle. These parameters were then compared with local tumor control, metastasis-free survival, and overall survival. RESULTS: Pretherapy rate of contrast agent washout was positively predictive of improved overall and metastasis-free survival with hazard ratio of 0.67 (P = 0.015) and 0.68 (P = 0.012), respectively. After the first hyperthermia washin rate, AUC60, AUC90, and AUCt-max were predictive of improved overall and metastasis-free survival with hazard ratio ranging from 0.46 to 0.53 (P < 0.002) and 0.44 to 0.55 (P < 0.004), respectively. DCE-MRI parameters were compared with extracellular pH and (31)P MR spectroscopy results (previously published) in the same patients showing a correlation. This suggested that an increase in perfusion after therapy was effective in eliminating excess acid from the tumor. CONCLUSIONS: This study shows that DCE-MRI has utility predicting overall and metastasis-free survival in canine patients with soft tissue sarcomas. To our knowledge, this is the first time that DCE-MRI parameters are predictive of clinical outcome for soft tissue sarcomas.

Authors
Viglianti, BL; Lora-Michiels, M; Poulson, JM; Lan, L; Yu, D; Sanders, L; Craciunescu, O; Vujaskovic, Z; Thrall, DE; Macfall, J; Charles, CH; Wong, T; Dewhirst, MW
MLA Citation
Viglianti, Benjamin L., et al. “Dynamic contrast-enhanced magnetic resonance imaging as a predictor of clinical outcome in canine spontaneous soft tissue sarcomas treated with thermoradiotherapy..” Clin Cancer Res, vol. 15, no. 15, Aug. 2009, pp. 4993–5001. Pubmed, doi:10.1158/1078-0432.CCR-08-2222.
PMID
19622579
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
15
Issue
15
Publish Date
2009
Start Page
4993
End Page
5001
DOI
10.1158/1078-0432.CCR-08-2222

Analysis of HIF-1 inhibition by manassantin A and analogues with modified tetrahydrofuran configurations.

We have shown that manassantin A downregulated the HIF-1alpha expression and inhibited the secretion of VEGF. We have also demonstrated that the 2,3-cis-3,4-trans-4,5-cis-configuration of the tetrahydrofuran is critical to the HIF-1 inhibition of manassantin A.

Authors
Kasper, AC; Moon, EJ; Hu, X; Park, Y; Wooten, CM; Kim, H; Yang, W; Dewhirst, MW; Hong, J
MLA Citation
Kasper, Amanda C., et al. “Analysis of HIF-1 inhibition by manassantin A and analogues with modified tetrahydrofuran configurations..” Bioorg Med Chem Lett, vol. 19, no. 14, July 2009, pp. 3783–86. Pubmed, doi:10.1016/j.bmcl.2009.04.071.
PMID
19423348
Source
pubmed
Published In
Bioorg Med Chem Lett
Volume
19
Issue
14
Publish Date
2009
Start Page
3783
End Page
3786
DOI
10.1016/j.bmcl.2009.04.071

Lipophilicity of potent porphyrin-based antioxidants: comparison of ortho and meta isomers of Mn(III) N-alkylpyridylporphyrins.

Mn(III) N-alkylpyridylporphyrins are among the most potent known SOD mimics and catalytic peroxynitrite scavengers and modulators of redox-based cellular transcriptional activity. In addition to their intrinsic antioxidant capacity, bioavailability plays a major role in their in vivo efficacy. Although of identical antioxidant capacity, lipophilic MnTnHex-2-PyP is up to 120-fold more efficient in reducing oxidative stress injuries than hydrophilic MnTE-2-PyP. Owing to limitations of an analytical nature, porphyrin lipophilicity has been often estimated by the thin-layer chromatographic R(f) parameter, instead of the standard n-octanol/water partition coefficient, P(OW). Herein we used a new methodological approach to finally describe the MnP lipophilicity, using the conventional log P(OW) means, for a series of biologically active ortho and meta isomers of Mn(III) N-alkylpyridylporphyrins. Three new porphyrins (MnTnBu-3-PyP, MnTnHex-3-PyP, and MnTnHep-2-PyP) were synthesized to strengthen the conclusions. The log P(OW) was linearly related to R(f) and to the number of carbons in the alkyl chain (n(C)) for both isomer series, the meta isomers being 10-fold more lipophilic than the analogous ortho porphyrins. Increasing the length of the alkyl chain by one carbon atom increases the log P(OW) value approximately 1 log unit with both isomers. Dramatic approximately 4 and approximately 5 orders of magnitude increases in the lipophilicity of the ortho isomers, by extending the pyridyl alkyl chains from two (MnTE-2-PyP, log P(OW)=-6.89) to six (MnTnHex-2-PyP, log P(OW)=-2.76) and eight carbon atoms (MnTnOct-2-PyP, log P(OW)=-1.24), parallels the increased efficacy in several oxidative-stress injury models, particularly those of the central nervous system, in which transport across the blood-brain barrier is critical. Although meta isomers are only slightly less potent SOD mimics and antioxidants than their ortho analogues, their higher lipophilicity and smaller bulkiness may lead to a higher cellular uptake and overall similar effectiveness in vivo.

Authors
Kos, I; Rebouças, JS; DeFreitas-Silva, G; Salvemini, D; Vujaskovic, Z; Dewhirst, MW; Spasojević, I; Batinić-Haberle, I
MLA Citation
Kos, Ivan, et al. “Lipophilicity of potent porphyrin-based antioxidants: comparison of ortho and meta isomers of Mn(III) N-alkylpyridylporphyrins..” Free Radic Biol Med, vol. 47, no. 1, July 2009, pp. 72–78. Pubmed, doi:10.1016/j.freeradbiomed.2009.04.002.
PMID
19361553
Source
pubmed
Published In
Free Radic Biol Med
Volume
47
Issue
1
Publish Date
2009
Start Page
72
End Page
78
DOI
10.1016/j.freeradbiomed.2009.04.002

Novel imaging provides new insights into mechanisms of oxygen transport in tumors.

Hypoxia is a common feature of solid tumors, and abnormal tumor oxygen transport is a key factor in the imbalance between tumor oxygen supply and demand. Novel advanced imaging techniques can enable new insights into the complexities of tumor oxygen transport and hypoxia that were not previously known or fully appreciated. In this paper, we document new insights into tumor oxygen transport enabled by spectral imaging of microvascular hemoglobin saturation.

Authors
Hardee, ME; Dewhirst, MW; Agarwal, N; Sorg, BS
MLA Citation
Hardee, Matthew E., et al. “Novel imaging provides new insights into mechanisms of oxygen transport in tumors..” Curr Mol Med, vol. 9, no. 4, May 2009, pp. 435–41.
PMID
19519401
Source
pubmed
Published In
Current Molecular Medicine
Volume
9
Issue
4
Publish Date
2009
Start Page
435
End Page
441

Structural adaptation and heterogeneity of normal and tumor microvascular networks.

Relative to normal tissues, tumor microcirculation exhibits high structural and functional heterogeneity leading to hypoxic regions and impairing treatment efficacy. Here, computational simulations of blood vessel structural adaptation are used to explore the hypothesis that abnormal adaptive responses to local hemodynamic and metabolic stimuli contribute to aberrant morphological and hemodynamic characteristics of tumor microcirculation. Topology, vascular diameter, length, and red blood cell velocity of normal mesenteric and tumor vascular networks were recorded by intravital microscopy. Computational models were used to estimate hemodynamics and oxygen distribution and to simulate vascular diameter adaptation in response to hemodynamic, metabolic and conducted stimuli. The assumed sensitivity to hemodynamic and conducted signals, the vascular growth tendency, and the random variability of vascular responses were altered to simulate 'normal' and 'tumor' adaptation modes. The heterogeneous properties of vascular networks were characterized by diameter mismatch at vascular branch points (d(3) (var)) and deficit of oxygen delivery relative to demand (O(2def)). In the tumor, d(3) (var) and O(2def) were higher (0.404 and 0.182) than in normal networks (0.278 and 0.099). Simulated remodeling of the tumor network with 'normal' parameters gave low values (0.288 and 0.099). Conversely, normal networks attained tumor-like characteristics (0.41 and 0.179) upon adaptation with 'tumor' parameters, including low conducted sensitivity, increased growth tendency, and elevated random biological variability. It is concluded that the deviant properties of tumor microcirculation may result largely from defective structural adaptation, including strongly reduced responses to conducted stimuli.

Authors
Pries, AR; Cornelissen, AJM; Sloot, AA; Hinkeldey, M; Dreher, MR; Höpfner, M; Dewhirst, MW; Secomb, TW
MLA Citation
Pries, Axel R., et al. “Structural adaptation and heterogeneity of normal and tumor microvascular networks..” Plos Comput Biol, vol. 5, no. 5, May 2009. Pubmed, doi:10.1371/journal.pcbi.1000394.
PMID
19478883
Source
pubmed
Published In
Plos Computational Biology
Volume
5
Issue
5
Publish Date
2009
Start Page
e1000394
DOI
10.1371/journal.pcbi.1000394

The performance of a reduced-order adaptive controller when used in multi-antenna hyperthermia treatments with nonlinear temperature-dependent perfusion.

In large multi-antenna systems, adaptive controllers can aid in steering the heat focus toward the tumor. However, the large number of sources can greatly increase the steering time. Additionally, controller performance can be degraded due to changes in tissue perfusion which vary non-linearly with temperature, as well as with time and spatial position. The current work investigates whether a reduced-order controller with the assumption of piecewise constant perfusion is robust to temperature-dependent perfusion and achieves steering in a shorter time than required by a full-order controller. The reduced-order controller assumes that the optimal heating setting lies in a subspace spanned by the best heating vectors (virtual sources) of an initial, approximate, patient model. An initial, approximate, reduced-order model is iteratively updated by the controller, using feedback thermal images, until convergence of the heat focus to the tumor. Numerical tests were conducted in a patient model with a right lower leg sarcoma, heated in a 10-antenna cylindrical mini-annual phased array applicator operating at 150 MHz. A half-Gaussian model was used to simulate temperature-dependent perfusion. Simulated magnetic resonance temperature images were used as feedback at each iteration step. Robustness was validated for the controller, starting from four approximate initial models: (1) a 'standard' constant perfusion lower leg model ('standard' implies a model that exactly models the patient with the exception that perfusion is considered constant, i.e., not temperature dependent), (2) a model with electrical and thermal tissue properties varied from 50% higher to 50% lower than the standard model, (3) a simplified constant perfusion pure-muscle lower leg model with +/-50% deviated properties and (4) a standard model with the tumor position in the leg shifted by 1.5 cm. Convergence to the desired focus of heating in the tumor was achieved for all four simulated models. The controller accomplished satisfactory therapeutic outcomes: approximately 80% of the tumor was heated to temperatures 43 degrees C and approximately 93% was maintained at temperatures <41 degrees C. Compared to the controller without model reduction, a approximately 9-25 fold reduction in convergence time was accomplished using approximately 2-3 orthonormal virtual sources. In the situations tested, the controller was robust to the presence of temperature-dependent perfusion. The results of this work can help to lay the foundation for real-time thermal control of multi-antenna hyperthermia systems in clinical situations where perfusion can change rapidly with temperature.

Authors
Cheng, K-S; Yuan, Y; Li, Z; Stauffer, PR; Maccarini, P; Joines, WT; Dewhirst, MW; Das, SK
MLA Citation
Cheng, Kung-Shan, et al. “The performance of a reduced-order adaptive controller when used in multi-antenna hyperthermia treatments with nonlinear temperature-dependent perfusion..” Phys Med Biol, vol. 54, no. 7, Apr. 2009, pp. 1979–95. Pubmed, doi:10.1088/0031-9155/54/7/008.
PMID
19265209
Source
pubmed
Published In
Physics in Medicine and Biology
Volume
54
Issue
7
Publish Date
2009
Start Page
1979
End Page
1995
DOI
10.1088/0031-9155/54/7/008

Real-time MRI-guided hyperthermia treatment using a fast adaptive algorithm.

Magnetic resonance (MR) imaging is promising for monitoring and guiding hyperthermia treatments. The goal of this work is to investigate the stability of an algorithm for online MR thermal image guided steering and focusing of heat into the target volume. The control platform comprised a four-antenna mini-annular phased array (MAPA) applicator operating at 140 MHz (used for extremity sarcoma heating) and a GE Signa Excite 1.5 T MR system, both of which were driven by a control workstation. MR proton resonance frequency shift images acquired during heating were used to iteratively update a model of the heated object, starting with an initial finite element computed model estimate. At each iterative step, the current model was used to compute a focusing vector, which was then used to drive the next iteration, until convergence. Perturbation of the driving vector was used to prevent the process from stalling away from the desired focus. Experimental validation of the performance of the automatic treatment platform was conducted with two cylindrical phantom studies, one homogeneous and one muscle equivalent with tumor tissue (conductivity 50% higher) inserted, with initial focal spots being intentionally rotated 90 degrees and 50 degrees away from the desired focus, mimicking initial setup errors in applicator rotation. The integrated MR-HT treatment platform steered the focus of heating into the desired target volume in two quite different phantom tissue loads which model expected patient treatment configurations. For the homogeneous phantom test where the target was intentionally offset by 90 degrees rotation of the applicator, convergence to the proper phase focus in the target occurred after 16 iterations of the algorithm. For the more realistic test with a muscle equivalent phantom with tumor inserted with 50 degrees applicator displacement, only two iterations were necessary to steer the focus into the tumor target. Convergence improved the heating efficacy (the ratio of integral temperature in the tumor to integral temperature in normal tissue) by up to six-fold, compared to the first iteration. The integrated MR-HT treatment algorithm successfully steered the focus of heating into the desired target volume for both the simple homogeneous and the more challenging muscle equivalent phantom with tumor insert models of human extremity sarcomas after 16 and 2 iterations, correspondingly. The adaptive method for MR thermal image guided focal steering shows promise when tested in phantom experiments on a four-antenna phased array applicator.

Authors
Stakhursky, VL; Arabe, O; Cheng, K-S; Macfall, J; Maccarini, P; Craciunescu, O; Dewhirst, M; Stauffer, P; Das, SK
MLA Citation
Stakhursky, Vadim L., et al. “Real-time MRI-guided hyperthermia treatment using a fast adaptive algorithm..” Phys Med Biol, vol. 54, no. 7, Apr. 2009, pp. 2131–45. Pubmed, doi:10.1088/0031-9155/54/7/019.
PMID
19287081
Source
pubmed
Published In
Physics in Medicine and Biology
Volume
54
Issue
7
Publish Date
2009
Start Page
2131
End Page
2145
DOI
10.1088/0031-9155/54/7/019

Nucleophilic Addition of Organozinc Reagents to 2-Sulfonyl Cyclic Ethers: Stereoselective Synthesis of Manassantins A and B (Org. Lett., (2009) 11:7 (1671-1671)

Authors
Kim, H; Kasper, AC; Moon, EJ; Park, Y; Wooten, CM; Dewhirst, MW; Hong, J
MLA Citation
Kim, H., et al. “Nucleophilic Addition of Organozinc Reagents to 2-Sulfonyl Cyclic Ethers: Stereoselective Synthesis of Manassantins A and B (Org. Lett., (2009) 11:7 (1671-1671).” Organic Letters, vol. 11, no. 7, Apr. 2009. Scopus, doi:10.1021/ol900421x.
Source
scopus
Published In
Organic Letters
Volume
11
Issue
7
Publish Date
2009
Start Page
1671
DOI
10.1021/ol900421x

Light emitting boron biomaterials for imaging and oxygen sensing

Authors
Zhang, G; Evans, RE; Palmer, GM; Dewhirst, MW; Xie, J; Hamm-Alvarez, S; Price, RJ; Fraser, CL
MLA Citation
Zhang, Guoqing, et al. “Light emitting boron biomaterials for imaging and oxygen sensing.” Abstracts of Papers of the American Chemical Society, vol. 237, AMER CHEMICAL SOC, Mar. 2009.
Source
wos
Published In
Abstracts of Papers of the American Chemical Society
Volume
237
Publish Date
2009

Quantitative diffuse reflectance and fluorescence spectroscopy: tool to monitor tumor physiology in vivo.

This study demonstrates the use of optical spectroscopy for monitoring tumor oxygenation and metabolism in response to hyperoxic gas breathing. Hemoglobin saturation and redox ratio were quantified for a set of 14 and 9 mice, respectively, measured at baseline and during carbogen breathing (95% O(2), 5% CO(2)). In particular, significant increases in hemoglobin saturation and fluorescence redox ratio were observed upon carbogen breathing. These data were compared with data obtained concurrently using an established invasive technique, the OxyLite partial oxygen pressure (pO(2)) system, which also showed a significant increase in pO(2). It was found that the direction of changes were generally the same between all of the methods, but that the OxyLite system was much more variable in general, suggesting that optical techniques may provide a better assessment of global tumor physiology. Optical spectroscopy measurements are demonstrated to provide a reliable, reproducible indication of changes in tumor physiology in response to physiologic manipulation.

Authors
Palmer, GM; Viola, RJ; Schroeder, T; Yarmolenko, PS; Dewhirst, MW; Ramanujam, N
MLA Citation
Palmer, Gregory M., et al. “Quantitative diffuse reflectance and fluorescence spectroscopy: tool to monitor tumor physiology in vivo..” J Biomed Opt, vol. 14, no. 2, Mar. 2009. Pubmed, doi:10.1117/1.3103586.
PMID
19405740
Source
pubmed
Published In
Journal of Biomedical Optics
Volume
14
Issue
2
Publish Date
2009
Start Page
024010
DOI
10.1117/1.3103586

The International Journal of Hyperthermia - The first 25 years

Authors
Dewhirst, MW
MLA Citation
Dewhirst, M. W. “The International Journal of Hyperthermia - The first 25 years.” International Journal of Hyperthermia, vol. 25, no. 1, Feb. 2009, pp. 1–2. Scopus, doi:10.1080/02656730802691217.
Source
scopus
Published In
International Journal of Hyperthermia : the Official Journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group
Volume
25
Issue
1
Publish Date
2009
Start Page
1
End Page
2
DOI
10.1080/02656730802691217

Clinical Utility of Magnetic Resonance Thermal Imaging (MRTI) For Realtime Guidance of Deep Hyperthermia.

A critical need has emerged for volumetric thermometry to visualize 3D temperature distributions in real time during deep hyperthermia treatments used as an adjuvant to radiation or chemotherapy for cancer. For the current effort, magnetic resonance thermal imaging (MRTI) is used to measure 2D temperature rise distributions in four cross sections of large extremity soft tissue sarcomas during hyperthermia treatments. Novel hardware and software techniques are described which improve the signal to noise ratio of MR images, minimize motion artifact from circulating coupling fluids, and provide accurate high resolution volumetric thermal dosimetry. For the first 10 extremity sarcoma patients, the mean difference between MRTI region of interest and adjacent interstitial point measurements during the period of steady state temperature was 0.85°C. With 1min temporal resolution of measurements in four image planes, this non-invasive MRTI approach has demonstrated its utility for accurate monitoring and realtime steering of heat into tumors at depth in the body.

Authors
Stauffer, P; Craciunescu, O; Maccarini, P; Wyatt, C; Arunachalam, K; Arabe, O; Stakhursky, V; Li, Z; Soher, B; Macfall, J; Rangarao, S; Cheng, K; Das, S; Martins, C; Charles, C; Dewhirst, M; Wong, T; Jones, E; Vujaskovic, Z
MLA Citation
Stauffer, Pr, et al. “Clinical Utility of Magnetic Resonance Thermal Imaging (MRTI) For Realtime Guidance of Deep Hyperthermia..” Proc Spie Int Soc Opt Eng, vol. 7181, Feb. 2009. Pubmed, doi:10.1117/12.812188.
PMID
24224074
Source
pubmed
Published In
Smart Structures and Materials 2005: Active Materials: Behavior and Mechanics
Volume
7181
Publish Date
2009
DOI
10.1117/12.812188

Control time reduction using virtual source projection for treating a leg sarcoma with nonlinear perfusion.

PURPOSE: Blood perfusion is a well-known factor that complicates accurate control of heating during hyperthermia treatments of cancer. Since blood perfusion varies as a function of time, temperature and location, determination of appropriate power deposition pattern from multiple antenna array Hyperthermia systems and heterogeneous tissues is a difficult control problem. Therefore, we investigate the applicability of a real-time eigenvalue model reduction (virtual source - VS) reduced-order controller for hyperthermic treatments of tissue with nonlinearly varying perfusion. METHODS: We impose a piecewise linear approximation to a set of heat pulses, each consisting of a 1-min heat-up, followed by a 2-min cool-down. The controller is designed for feedback from magnetic resonance temperature images (MRTI) obtained after each iteration of heat pulses to adjust the projected optimal setting of antenna phase and magnitude for selective tumor heating. Simulated temperature patterns with additive Gaussian noise with a standard deviation of 1.0°C and zero mean were used as a surrogate for MRTI. Robustness tests were conducted numerically for a patient's right leg placed at the middle of a water bolus surrounded by a 10-antenna applicator driven at 150 MHz. Robustness tests included added discrepancies in perfusion, electrical and thermal properties, and patient model simplifications. RESULTS: The controller improved selective tumor heating after an average of 4-9 iterative adjustments of power and phase, and fulfilled satisfactory therapeutic outcomes with approximately 75% of tumor volumes heated to temperatures >43°C while maintaining about 93% of healthy tissue volume < 41°C. Adequate sarcoma heating was realized by using only 2 to 3 VSs rather than a much larger number of control signals for all 10 antennas, which reduced the convergence time to only 4 to 9% of the original value. CONCLUSIONS: Using a piecewise linear approximation to a set of heat pulses in a VS reduced-order controller, the proposed algorithm greatly improves the efficiency of hyperthermic treatment of leg sarcomas while accommodating practical nonlinear variation of tissue properties such as perfusion.

Authors
Cheng, K-S; Yuan, Y; Li, Z; Stauffer, PR; Joines, WT; Dewhirst, MW; Das, SK
MLA Citation
Cheng, Kung-Shan, et al. “Control time reduction using virtual source projection for treating a leg sarcoma with nonlinear perfusion..” Proc Spie Int Soc Opt Eng, vol. 7181, Feb. 2009. Pubmed, doi:10.1117/12.808499.
PMID
24392195
Source
pubmed
Published In
Smart Structures and Materials 2005: Active Materials: Behavior and Mechanics
Volume
7181
Publish Date
2009
DOI
10.1117/12.808499

Combined hyperspectral and spectral domain optical coherence tomography microscope for noninvasive hemodynamic imaging.

We have combined hyperspectral imaging with spectral domain optical coherence tomography (SDOCT) to noninvasively image changes in hemoglobin saturation, blood flow, microvessel morphology, and sheer rate on the vessel wall with tumor growth. Changes in these hemodynamic variables were measured over 24 h in dorsal skin fold window chamber tumors. There was a strong correlation between volumetric flow and hemoglobin saturation (rho=0.89, p=9x10(-6), N=15) and a moderate correlation between shear rate on the vessel wall and hemoglobin saturation (rho=0.56, p=0.03, N=15).

Authors
Skala, MC; Fontanella, A; Hendargo, H; Dewhirst, MW; Izatt, JA
MLA Citation
Skala, Melissa C., et al. “Combined hyperspectral and spectral domain optical coherence tomography microscope for noninvasive hemodynamic imaging..” Opt Lett, vol. 34, no. 3, Feb. 2009, pp. 289–91.
PMID
19183634
Source
pubmed
Published In
Optics Letters
Volume
34
Issue
3
Publish Date
2009
Start Page
289
End Page
291

Combined hyperspectral and spectral domain optical coherence tomography microscope for noninvasive hemodynamic imaging

We have combined hyperspectral imaging with spectral domain optical coherence tomography (SDOCT) to noninvasivel image changes in hemoglobin saturation, blood flow, microvessel morphology, and sheer rate on the vessel wall with tumor growth. Changes in these hemodynamic variables were measured over 24 h in dorsal skin fold window chamber tumors. There was a strong correlation between volumetric flow and hemoglobin saturation (p=0.89, p=9 × 10-6, N= 15) and a moderate correlation between shear rate on the vessel wall and hemoglobin saturation (p=0.56, p=0.03, N=15). ©2009 Optical Society of America.

Authors
Skala, MC; Fontanella, A; Hendargo, H; Dewhirst, MW; Izatt, JA
MLA Citation
Skala, M. C., et al. “Combined hyperspectral and spectral domain optical coherence tomography microscope for noninvasive hemodynamic imaging.” Optics Letters, vol. 34, no. 3, Feb. 2009, pp. 289–91. Scopus, doi:10.1364/OL.34.000289.
Source
scopus
Published In
Optics Letters
Volume
34
Issue
3
Publish Date
2009
Start Page
289
End Page
291
DOI
10.1364/OL.34.000289

Hyperthermia classic commentary: 'Arrhenius relationships from the molecule and cell to the clinic' by William Dewey, Int. J. Hyperthermia, 10:457-483, 1994.

Authors
Dewey, WC; Diederich, CJ; Dewhirst, MW
MLA Citation
Dewey, William C., et al. “Hyperthermia classic commentary: 'Arrhenius relationships from the molecule and cell to the clinic' by William Dewey, Int. J. Hyperthermia, 10:457-483, 1994..” Int J Hyperthermia, vol. 25, no. 1, Feb. 2009, pp. 21–24. Pubmed, doi:10.1080/02656730902733695.
PMID
19219696
Source
pubmed
Published In
Int J Hyperthermia
Volume
25
Issue
1
Publish Date
2009
Start Page
21
End Page
24
DOI
10.1080/02656730902733695

WE‐C‐BRC‐02: Combined Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE‐MRI) and Magnetic Resonance Thermal Imaging (MRTI) for Optimal Hyperthermia Treatment of Advanced Extremity Sarcomas: Fifteen Patients Update

Purpose: To deliver optimal hyperthermia (HT) treatments for patients with advanced extremity sarcomas using DCE‐MRI and MRTI Method and Materials: Patients were treated on a protocol using radiotherapy consisting of 45 Gy and once a week HT for 5 weeks in a setting that allows the use of a 1.5 T GE magnet for imaging. Pre‐ and post first HT treatment DCE‐MR images were acquired and analyzed with software from iCAD Inc. (Nashua, NH) based on a full time point pharmacokinetics (PK) analysis that measures tumor's permeability (Ktrans) and extracellular volume fraction (Ve). Multi‐slice temperature rise images were obtained using the proton resonance frequency shift technique during heating in a 140 MHz phased array HT applicator and compared to invasive temperature measurements. Thermal dose metrics were calculated and correlated with response and with the PK parameters. Results: Fifteen patients were enrolled on this protocol; ten patients were heated. Permeability maps derived from DCE‐MR images were used to guide the placement of the invasive catheter to span regions varying from high to low perfusion. The MRTI images were used to steer the power, with the intent of heating the tumor uniformly while maintaining surrounding normal tissue at lower temperatures. From the evaluable HT treatments, we achieved excellent correlation (ΔT<1°C) between the MRTI and invasive measurements. As a trend, patients that were either pathological complete or partial responders had a decrease in Ktrans. The Ve parameter showed no clear trend with pathological response or % necrosis. As expected, tumors that were more vascularized (higher Ktrans) heated less than tumors with a high degree of necrosis or fluid pockets. Conclusion: DCE‐MRI coupled with MRTI provides information on tumor environment that can improve planning, delivery, and evaluation of HT treatments. Supported by a grant from the NCI CA42745. © 2009, American Association of Physicists in Medicine. All rights reserved.

Authors
Craciunescu, O; Macfall, J; Soher, B; Stauffer, P; Maccarini, P; Jones, E; Larrier, N; Wong, T; Carroll, M; Dewhirst, M; Vujaskovic, Z
MLA Citation
Craciunescu, O., et al. “WE‐C‐BRC‐02: Combined Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE‐MRI) and Magnetic Resonance Thermal Imaging (MRTI) for Optimal Hyperthermia Treatment of Advanced Extremity Sarcomas: Fifteen Patients Update.” Medical Physics, vol. 36, no. 6, 2009. Scopus, doi:10.1118/1.3182470.
Source
scopus
Published In
Medical Physics
Volume
36
Issue
6
Publish Date
2009
Start Page
2760
DOI
10.1118/1.3182470

Nucleophilic addition of organozinc reagents to 2-sulfonyl cyclic ethers: stereoselective synthesis of manassantins A and B.

A convergent route to the synthesis of manassantins A and B, potent inhibitors of HIF-1, is described. Central to the synthesis is a stereoselective addition of an organozinc reagent to a 2-benzenesulfonyl cyclic ether to achieve the 2,3-cis-3,4-trans-4,5-cis-tetrahydrofuran of the natural products. Preliminary structure-activity relationships suggested that the (R)-configuration at C-7 and C-7''' is not critical for HIF-1 inhibition. In addition, the hydroxyl group at C-7 and C-7''' can be replaced with a carbonyl group without loss of activity.

Authors
Kim, H; Kasper, AC; Moon, EJ; Park, Y; Wooten, CM; Dewhirst, MW; Hong, J
MLA Citation
Kim, Hyoungsu, et al. “Nucleophilic addition of organozinc reagents to 2-sulfonyl cyclic ethers: stereoselective synthesis of manassantins A and B..” Org Lett, vol. 11, no. 1, Jan. 2009, pp. 89–92. Pubmed, doi:10.1021/ol8024617.
PMID
19111058
Source
pubmed
Published In
Org Lett
Volume
11
Issue
1
Publish Date
2009
Start Page
89
End Page
92
DOI
10.1021/ol8024617

The in vitro Cytotoxic Effects of Mn(III) Alkylpyridylporphyrin/ascorbate system on Four Tumor Cell Lines

Authors
Ye, X; Fels, D; Dedeugd, C; Dewhirst, MW; Leong, K; Batinic-Haberle, I
MLA Citation
Ye, Xiaodong, et al. “The in vitro Cytotoxic Effects of Mn(III) Alkylpyridylporphyrin/ascorbate system on Four Tumor Cell Lines.” Free Radical Biology and Medicine, vol. 47, ELSEVIER SCIENCE INC, 2009, pp. S136–S136.
Source
wos
Published In
Free Radical Biology and Medicine
Volume
47
Publish Date
2009
Start Page
S136
End Page
S136

Her2/neu signaling blockade improves tumor oxygenation in a multifactorial fashion in Her2/neu+ tumors.

PURPOSE: Tumor hypoxia reduces the efficacy of radiation and chemotherapy as well as altering gene expression that promotes cell survival and metastasis. The growth factor receptor, Her2/neu, is overexpressed in 25-30% of breast tumors. Tumors that are Her2(+) may have an altered state of oxygenation, relative to Her2(-) tumors, due to differences in tumor growth rate and angiogenesis. METHODS: Her2 blockade was accomplished using an antibody to the receptor (trastuzumab; Herceptin). This study examined the effects of Her2 blockade on tumor angiogenesis, vascular architecture, and hypoxia in Her2(+) and Her2(-) MCF7 xenograft tumors. RESULTS: Treatment with trastuzumab in Her2(+) tumors significantly improved tumor oxygenation, increased microvessel density, and improved vascular architecture compared with the control-treated Her2(+) tumors. The Her2(+) xenografts treated with trastuzumab also demonstrated decreased proliferation indices when compared with control-treated xenografts. These results indicate that Her2 blockade can improve tumor oxygenation by decreasing oxygen consumption (reducing tumor cell proliferation and inducing necrosis) and increasing oxygen delivery (vascular density and architecture). CONCLUSIONS: These results support the use of trastuzumab as an adjunct in the treatment of breast tumors with chemotherapy or radiotherapy, as improvements in tumor oxygenation should translate into improved treatment response.

Authors
Hardee, ME; Eapen, RJ; Rabbani, ZN; Dreher, MR; Marks, J; Blackwell, KL; Dewhirst, MW
MLA Citation
Hardee, Matthew E., et al. “Her2/neu signaling blockade improves tumor oxygenation in a multifactorial fashion in Her2/neu+ tumors..” Cancer Chemother Pharmacol, vol. 63, no. 2, Jan. 2009, pp. 219–28. Pubmed, doi:10.1007/s00280-008-0729-3.
PMID
18365198
Source
pubmed
Published In
Cancer Chemother Pharmacol
Volume
63
Issue
2
Publish Date
2009
Start Page
219
End Page
228
DOI
10.1007/s00280-008-0729-3

DCE-MRI parameters have potential to predict response of locally advanced breast cancer patients to neoadjuvant chemotherapy and hyperthermia: a pilot study.

UNLABELLED: Combined therapies represent a staple of modern medicine. For women treated with neoadjuvant chemotherapy (NA ChT) for locally advanced breast cancer (LABC), early determination of whether the patient will fail to respond can enable the use of alternative, more beneficial therapies. This is even more desirable when the combined therapy includes hyperthermia (HT), an efficient way to improve drug delivery, however, more costly and time consuming. There is data showing that this goal can be achieved using magnetic resonance imaging (MRI) with contrast agent (CA) enhancement. This work for the first time proposes combining the information extracted from pre-treatment MR imaging into a morpho-physiological tumour score (MPTS) with the hypothesis that this score will increase the prognostic efficacy, compared to each of its MR-derived components: morphological (derived from the shape of the tumour enhancement) and physiological (derived from the CA enhancement variance dynamics parameters). The MPTS was correlated with response as determined by both pathologic residual tumour and MRI imaging, and was shown to have potential to predict response. The MPTS was extracted from pre-treatment MRI parameters, so independent of the combined therapy used. PURPOSE: To use a novel morpho-physiological tumour score (MPTS) generated from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict response to treatment. MATERIALS AND METHODS: A protocol was designed to acquire DCE-MRI images of 20 locally advanced breast cancer (LABC) patients treated with neoadjuvant chemotherapy (NA ChT) and hyperthermia (HT). Imaging was done over 30 min following bolus injection of gadopentetate-based contrast agent. Parametric maps were generated by fitting the signal intensity to a double exponential curve and were used to derive a morphological characterisation of the lesions. Enhancement-variance dynamics parameters, wash-in and wash-out parameters (WiP, WoP), were extracted. The morphological characterisation and the WiP and WoP were combined into a MPTS with the intent of achieving better prognostic efficacy. The MPTS was correlated with response to NA therapy as determined by pathological residual tumour and MRI imaging. RESULTS: The contrast agent in all tumours typically peaked in the first 1-4 min. The tumours' WiP and WoP varied considerably. The MPTS was highly correlated with whether the patients had a pathological response. This scoring system has a specificity of 78% and a sensitivity of 91% for predicting response to NA chemotherapy. The kappa was 0.69 with a 95% confidence interval of [0.38, 1] and a p-value of 0.002. CONCLUSIONS: This pilot study shows that the MPTS derived using pre-treatment MRI images has the potential to predict response to NA ChT and HT in LABC patients. Further prospective studies are needed to confirm the validity of these results.

Authors
Craciunescu, OI; Blackwell, KL; Jones, EL; Macfall, JR; Yu, D; Vujaskovic, Z; Wong, TZ; Liotcheva, V; Rosen, EL; Prosnitz, LR; Samulski, TV; Dewhirst, MW
MLA Citation
Craciunescu, Oana I., et al. “DCE-MRI parameters have potential to predict response of locally advanced breast cancer patients to neoadjuvant chemotherapy and hyperthermia: a pilot study..” Int J Hyperthermia, vol. 25, no. 6, 2009, pp. 405–15. Pubmed, doi:10.1080/02656730903022700.
PMID
19657852
Source
pubmed
Published In
Int J Hyperthermia
Volume
25
Issue
6
Publish Date
2009
Start Page
405
End Page
415
DOI
10.1080/02656730903022700

Longitudinal monitoring of 4t1-tumor physiology in vivo with doxorubicin treatment via diffuse optical spectroscopy

A diffuse optical spectrometer was used to monitor 4T1 breast carcinoma tumors implanted in mice. Animals treated with doxorubicin showed relative increased oxygen saturation and decreased blood volume vs. Controls, over a 10 day period. © 2008 Optical Society of America.

Authors
Vishwanath, K; Yuan, H; Moore, L; Bender, J; Dewhirst, M; Ramanujam, N
MLA Citation
Vishwanath, K., et al. “Longitudinal monitoring of 4t1-tumor physiology in vivo with doxorubicin treatment via diffuse optical spectroscopy.” Biomedical Optics, Biomed 2008, Dec. 2008.
Source
scopus
Published In
Biomedical Optics, Biomed 2008
Publish Date
2008

Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice.

Tumors contain oxygenated and hypoxic regions, so the tumor cell population is heterogeneous. Hypoxic tumor cells primarily use glucose for glycolytic energy production and release lactic acid, creating a lactate gradient that mirrors the oxygen gradient in the tumor. By contrast, oxygenated tumor cells have been thought to primarily use glucose for oxidative energy production. Although lactate is generally considered a waste product, we now show that it is a prominent substrate that fuels the oxidative metabolism of oxygenated tumor cells. There is therefore a symbiosis in which glycolytic and oxidative tumor cells mutually regulate their access to energy metabolites. We identified monocarboxylate transporter 1 (MCT1) as the prominent path for lactate uptake by a human cervix squamous carcinoma cell line that preferentially utilized lactate for oxidative metabolism. Inhibiting MCT1 with alpha-cyano-4-hydroxycinnamate (CHC) or siRNA in these cells induced a switch from lactate-fueled respiration to glycolysis. A similar switch from lactate-fueled respiration to glycolysis by oxygenated tumor cells in both a mouse model of lung carcinoma and xenotransplanted human colorectal adenocarcinoma cells was observed after administration of CHC. This retarded tumor growth, as the hypoxic/glycolytic tumor cells died from glucose starvation, and rendered the remaining cells sensitive to irradiation. As MCT1 was found to be expressed by an array of primary human tumors, we suggest that MCT1 inhibition has clinical antitumor potential.

Authors
Sonveaux, P; Végran, F; Schroeder, T; Wergin, MC; Verrax, J; Rabbani, ZN; De Saedeleer, CJ; Kennedy, KM; Diepart, C; Jordan, BF; Kelley, MJ; Gallez, B; Wahl, ML; Feron, O; Dewhirst, MW
MLA Citation
Sonveaux, Pierre, et al. “Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice..” J Clin Invest, vol. 118, no. 12, Dec. 2008, pp. 3930–42. Pubmed, doi:10.1172/JCI36843.
PMID
19033663
Source
pubmed
Published In
The Journal of Clinical Investigation
Volume
118
Issue
12
Publish Date
2008
Start Page
3930
End Page
3942
DOI
10.1172/JCI36843

The role of hypoxia in canine cancer.

Human oncology has clearly demonstrated the existence of hypoxic tumours and the problematic nature of those tumours. Hypoxia is a significant problem in the treatment of all types of solid tumours and a common reason for treatment failure. Hypoxia is a negative prognostic indicator of survival and is correlated with the development of metastatic disease. Resistance to radiation therapy and chemotherapy can be because of hypoxia. There are two dominant types of hypoxia recognized in tumours, static and intermittent. Both types of hypoxia are important in terms of resistance. A variety of physiological factors cause hypoxia, and in turn, hypoxia can induce genetic and physiological changes. A limited number of studies have documented that hypoxia exists in spontaneous canine tumours. The knowledge from the human literature of problematic nature of hypoxic tumours combined with the rapid growth of veterinary oncology has necessitated a better understanding of hypoxia in canine tumours.

Authors
Snyder, SA; Dewhirst, MW; Hauck, ML
MLA Citation
Snyder, S. A., et al. “The role of hypoxia in canine cancer..” Vet Comp Oncol, vol. 6, no. 4, Dec. 2008, pp. 213–23. Pubmed, doi:10.1111/j.1476-5829.2008.00163.x.
PMID
19178681
Source
pubmed
Published In
Vet Comp Oncol
Volume
6
Issue
4
Publish Date
2008
Start Page
213
End Page
223
DOI
10.1111/j.1476-5829.2008.00163.x

In vivo bioluminescence imaging monitoring of hypoxia-inducible factor 1alpha, a promoter that protects cells, in response to chemotherapy.

OBJECTIVE: Bioluminescence imaging is a powerful technique that has shown that hypoxia-inducible factor 1 (HIF-1), a transcription factor that protects tumor cells from hypoxia, is up-regulated in tumors after radiation therapy. We tested the hypothesis that bioluminescence imaging would successfully and noninvasively depict an increase in HIF-1 in the novel therapeutic environment of chemotherapy and that, as in radiation therapy, the underlying mechanism involves inducible nitric oxide synthase originating in macrophages. Active HIF-1 consists of alpha and beta subunits that bind to promoter sequences in many genes, including those that protect endothelial cells, promote angiogenesis, and alter metastasis and tumor cell metabolism. MATERIALS AND METHODS: We grew 4T1 murine breast carcinoma cells with an HIF-1alpha luciferase reporter construct to 7 mm in the right rear flanks of 18 Balb-C mice. The mice were evenly randomized to receive one of the following single intraperitoneal doses: maximum tolerated dose cyclophosphamide (231.5 mg/kg), maximum tolerated dose paclitaxel (10 mg/kg), or control saline solution. Immunohistochemical analysis of tumor sections from the cyclophosphamide and control groups was performed 10 days after treatment to assess the intensity and distribution of HIF-1alpha expression, hypoxia, macrophage infiltration, and expression of macrophage-derived inducible nitric oxide synthase in tumor tissues treated with maximum tolerated dose cyclophosphamide compared with control tumors. RESULTS: Cyclophosphamide, but not paclitaxel, significantly inhibited tumor growth and caused a significant increase in HIF-1alpha protein levels, which peaked at a 10-fold increase from baseline on day 10 after administration. In contrast, paclitaxel did not have an antitumor effect in this model and did not cause a significant increase in HIF-1alpha. Immunohistochemical analysis showed increased and more evenly dispersed levels of HIF-1alpha protein, macrophage infiltration, and expression of inducible nitric oxide synthase originating in macrophages after cyclophosphamide treatment. CONCLUSION: We successfully monitored increased expression of a tumor protective protein in a noninvasive manner. Such monitoring may be a means of detection of resistance to therapy, and it may be possible to use the monitoring findings to alter treatment strategies in real time. The tumor microenvironment seen at immunohistochemical analysis supports the hypothesized mechanism that the cytotoxic effects of radiation therapy that attract macrophages, causing the release of macrophage-derived inducible nitric oxide synthase and production of HIF-1alpha under aerobic conditions, also underlie chemotherapy. Such noninvasive imaging may be a means to development of therapeutic strategies that prevent HIF-1 up-regulation after chemotherapy treatments.

Authors
Viola, RJ; Provenzale, JM; Li, F; Li, C-Y; Yuan, H; Tashjian, J; Dewhirst, MW
MLA Citation
Viola, Ronald J., et al. “In vivo bioluminescence imaging monitoring of hypoxia-inducible factor 1alpha, a promoter that protects cells, in response to chemotherapy..” Ajr Am J Roentgenol, vol. 191, no. 6, Dec. 2008, pp. 1779–84. Pubmed, doi:10.2214/AJR.07.4060.
PMID
19020250
Source
pubmed
Published In
Ajr. American Journal of Roentgenology
Volume
191
Issue
6
Publish Date
2008
Start Page
1779
End Page
1784
DOI
10.2214/AJR.07.4060

The genomic analysis of lactic acidosis and acidosis response in human cancers.

The tumor microenvironment has a significant impact on tumor development. Two important determinants in this environment are hypoxia and lactic acidosis. Although lactic acidosis has long been recognized as an important factor in cancer, relatively little is known about how cells respond to lactic acidosis and how that response relates to cancer phenotypes. We develop genome-scale gene expression studies to dissect transcriptional responses of primary human mammary epithelial cells to lactic acidosis and hypoxia in vitro and to explore how they are linked to clinical tumor phenotypes in vivo. The resulting experimental signatures of responses to lactic acidosis and hypoxia are evaluated in a heterogeneous set of breast cancer datasets. A strong lactic acidosis response signature identifies a subgroup of low-risk breast cancer patients having distinct metabolic profiles suggestive of a preference for aerobic respiration. The association of lactic acidosis response with good survival outcomes may relate to the role of lactic acidosis in directing energy generation toward aerobic respiration and utilization of other energy sources via inhibition of glycolysis. This "inhibition of glycolysis" phenotype in tumors is likely caused by the repression of glycolysis gene expression and Akt inhibition. Our study presents a genomic evaluation of the prognostic information of a lactic acidosis response independent of the hypoxic response. Our results identify causal roles of lactic acidosis in metabolic reprogramming, and the direct functional consequence of lactic acidosis pathway activity on cellular responses and tumor development. The study also demonstrates the utility of genomic analysis that maps expression-based findings from in vitro experiments to human samples to assess links to in vivo clinical phenotypes.

Authors
Chen, JL-Y; Lucas, JE; Schroeder, T; Mori, S; Wu, J; Nevins, J; Dewhirst, M; West, M; Chi, J-T
MLA Citation
Chen, Julia Ling-Yu, et al. “The genomic analysis of lactic acidosis and acidosis response in human cancers..” Plos Genet, vol. 4, no. 12, Dec. 2008. Pubmed, doi:10.1371/journal.pgen.1000293.
PMID
19057672
Source
pubmed
Published In
Plos Genet
Volume
4
Issue
12
Publish Date
2008
Start Page
e1000293
DOI
10.1371/journal.pgen.1000293

Estrogen-related receptor alpha is critical for the growth of estrogen receptor-negative breast cancer.

Expression of estrogen-related receptor alpha (ERRalpha) has recently been shown to carry negative prognostic significance in breast and ovarian cancers. The specific role of this orphan nuclear receptor in tumor growth and progression, however, is yet to be fully understood. The significant homology between estrogen receptor alpha (ERalpha) and ERRalpha initially suggested that these receptors may have similar transcriptional targets. Using the well-characterized ERalpha-positive MCF-7 breast cancer cell line, we sought to gain a genome-wide picture of ERalpha-ERRalpha cross-talk using an unbiased microarray approach. In addition to generating a host of novel ERRalpha target genes, this study yielded the surprising result that most ERRalpha-regulated genes are unrelated to estrogen signaling. The relatively small number of genes regulated by both ERalpha and ERRalpha led us to expand our study to the more aggressive and less clinically treatable ERalpha-negative class of breast cancers. In this setting, we found that ERRalpha expression is required for the basal level of expression of many known and novel ERRalpha target genes. Introduction of a small interfering RNA directed to ERRalpha into the highly aggressive breast carcinoma MDA-MB-231 cell line dramatically reduced the migratory potential of these cells. Although stable knockdown of ERRalpha expression in MDA-MB-231 cells had no effect on in vitro cell proliferation, a significant reduction of tumor growth rate was observed when these cells were implanted as xenografts. Our results confirm a role for ERRalpha in breast cancer growth and highlight it as a potential therapeutic target for estrogen receptor-negative breast cancer.

Authors
Stein, RA; Chang, C-Y; Kazmin, DA; Way, J; Schroeder, T; Wergin, M; Dewhirst, MW; McDonnell, DP
MLA Citation
Stein, Rebecca A., et al. “Estrogen-related receptor alpha is critical for the growth of estrogen receptor-negative breast cancer..” Cancer Res, vol. 68, no. 21, Nov. 2008, pp. 8805–12. Pubmed, doi:10.1158/0008-5472.CAN-08-1594.
PMID
18974123
Source
pubmed
Published In
Cancer Res
Volume
68
Issue
21
Publish Date
2008
Start Page
8805
End Page
8812
DOI
10.1158/0008-5472.CAN-08-1594

Radiofrequency ablation: the effect of distance and baseline temperature on thermal dose required for coagulation.

PURPOSE: To determine the effects of applied current, distance from an RF electrode and baseline tissue temperature upon thermal dosimetry requirements to induce coagulation in ex vivo bovine liver and in vivo porcine muscle models. MATERIALS AND METHODS: RF ablation was performed in ex vivo liver at varying baseline temperatures-19-21 degrees C (n = 114), 8-10 degrees C (n = 27), and 27-28 degrees C (n = 27)-using a 3-cm tip electrode and systematically varied current 400-1,300 mA, to achieve defined diameters of coagulation (20, 30 and 40 +/- 2 mm), and in in vivo muscle (n = 18) to achieve 35 mm +/- 2 mm of coagulation. Thermal dose required for coagulation was calculated as the area under the curve and cumulative equivalent minutes at 43 degrees C. RESULTS: Thermal dose correlated with current in a negative exponential fashion for all three diameters of coagulation in ex vivo experiments (p < 0.001). The temperatures at the end of RF heating at the ablation margin were not reproducible, but varied 38 degrees C-74.7 degrees C, for 30 mm coagulation in ex vivo liver, and 59.8 degrees C-68.4 degrees C in the in vivo experiment. CEM(43) correlated with current as a family of positive exponential functions (r(2) = 0.76). However, a very wide range of CEM(43) values (on the order of 10(15)) was noted. Although baseline temperatures in the ex vivo experiment did not change required thermal dose, the relationships between end temperature at the ablation margin and RF current were statistically different (p < 0.001) as analysed at the 400 mA intercept. CONCLUSIONS: In both models, thermal dosimetry required to achieve coagulation was not constant, but current and distance dependent. Hence, other formulas for thermal dose equivalence may be needed to predict conditions for thermal ablation.

Authors
Mertyna, P; Dewhirst, MW; Halpern, E; Goldberg, W; Goldberg, SN
MLA Citation
Mertyna, Pawel, et al. “Radiofrequency ablation: the effect of distance and baseline temperature on thermal dose required for coagulation..” Int J Hyperthermia, vol. 24, no. 7, Nov. 2008, pp. 550–59. Pubmed, doi:10.1080/02656730802035662.
PMID
18608586
Source
pubmed
Published In
Int J Hyperthermia
Volume
24
Issue
7
Publish Date
2008
Start Page
550
End Page
559
DOI
10.1080/02656730802035662

Improving the quantitative accuracy of optical-emission computed tomography by incorporating an attenuation correction: application to HIF1 imaging.

Optical computed tomography (optical-CT) and optical-emission computed tomography (optical-ECT) are new techniques for imaging the 3D structure and function (including gene expression) of whole unsectioned tissue samples. This work presents a method of improving the quantitative accuracy of optical-ECT by correcting for the 'self'-attenuation of photons emitted within the sample. The correction is analogous to a method commonly applied in single-photon-emission computed tomography reconstruction. The performance of the correction method was investigated by application to a transparent cylindrical gelatin phantom, containing a known distribution of attenuation (a central ink-doped gelatine core) and a known distribution of fluorescing fibres. Attenuation corrected and uncorrected optical-ECT images were reconstructed on the phantom to enable an evaluation of the effectiveness of the correction. Significant attenuation artefacts were observed in the uncorrected images where the central fibre appeared approximately 24% less intense due to greater attenuation from the surrounding ink-doped gelatin. This artefact was almost completely removed in the attenuation-corrected image, where the central fibre was within approximately 4% of the others. The successful phantom test enabled application of attenuation correction to optical-ECT images of an unsectioned human breast xenograft tumour grown subcutaneously on the hind leg of a nude mouse. This tumour cell line had been genetically labelled (pre-implantation) with fluorescent reporter genes such that all viable tumour cells expressed constitutive red fluorescent protein and hypoxia-inducible factor 1 transcription-produced green fluorescent protein. In addition to the fluorescent reporter labelling of gene expression, the tumour microvasculature was labelled by a light-absorbing vasculature contrast agent delivered in vivo by tail-vein injection. Optical-CT transmission images yielded high-resolution 3D images of the absorbing contrast agent, and revealed highly inhomogeneous vasculature perfusion within the tumour. Optical-ECT emission images yielded high-resolution 3D images of the fluorescent protein distribution in the tumour. Attenuation-uncorrected optical-ECT images showed clear loss of signal in regions of high attenuation, including regions of high perfusion, where attenuation is increased by increased vascular ink stain. Application of attenuation correction showed significant changes in an apparent expression of fluorescent proteins, confirming the importance of the attenuation correction. In conclusion, this work presents the first development and application of an attenuation correction for optical-ECT imaging. The results suggest that successful attenuation correction for optical-ECT is feasible and is essential for quantitatively accurate optical-ECT imaging.

Authors
Kim, E; Bowsher, J; Thomas, AS; Sakhalkar, H; Dewhirst, M; Oldham, M
MLA Citation
Kim, E., et al. “Improving the quantitative accuracy of optical-emission computed tomography by incorporating an attenuation correction: application to HIF1 imaging..” Phys Med Biol, vol. 53, no. 19, Oct. 2008, pp. 5371–83. Pubmed, doi:10.1088/0031-9155/53/19/007.
PMID
18765891
Source
pubmed
Published In
Physics in Medicine and Biology
Volume
53
Issue
19
Publish Date
2008
Start Page
5371
End Page
5383
DOI
10.1088/0031-9155/53/19/007

Tumor microvascular permeability is a key determinant for antivascular effects of doxorubicin encapsulated in a temperature sensitive liposome.

Previous data have demonstrated that doxorubicin (DOX) released from a lysolecithin-containing thermosensitive liposome (LTSL) can shut down blood flow in a human tumor xenograft (FaDu) in mice when the treatment is combined with hyperthermia (HT), suggesting that LTSL-DOX is a potential antivascular agent. To further understand mechanisms of the treatment, we investigated effects of LTSL-DOX (5 mg/kg body weight) plus HT (42 degrees C, 1 h) on microcirculation in another tumor (a murine mammary carcinoma, 4T07) implanted in mouse dorsal skin-fold chambers and dose responses of tumor (FaDu and 4T07) and endothelial cells to LTSL-DOX or free DOX with or without HT. We observed that LTSL-DOXHT could significantly reduce blood flow and microvascular density in 4T07 tumors. The antivascular efficacy of LTSLDOX- HT could be enhanced through increasing tumor microvascular permeability of liposomes by using platelet activating factor (PAF). We also observed that the dose responses of FaDu and 4T07 to DOX in vitro were similar to each other and could be enhanced by HT. Taken together, these data suggested that tumor microvascular permeability was more critical than the sensitivity of tumor cells to DOX in determining the antivascular efficacy of LTSL-DOX-HT treatment.

Authors
Chen, Q; Krol, A; Wright, A; Needham, D; Dewhirst, MW; Yuan, F
MLA Citation
Chen, Qing, et al. “Tumor microvascular permeability is a key determinant for antivascular effects of doxorubicin encapsulated in a temperature sensitive liposome..” Int J Hyperthermia, vol. 24, no. 6, Sept. 2008, pp. 475–82. Pubmed, doi:10.1080/02656730701854767.
PMID
18608573
Source
pubmed
Published In
Int J Hyperthermia
Volume
24
Issue
6
Publish Date
2008
Start Page
475
End Page
482
DOI
10.1080/02656730701854767

Hyperthermia and nanotechnology - a note from the Editor-in-chief.

Authors
Dewhirst, MW
MLA Citation
Dewhirst, Mark W. “Hyperthermia and nanotechnology - a note from the Editor-in-chief..” Int J Hyperthermia, vol. 24, no. 6, Sept. 2008, pp. 449–50. Pubmed, doi:10.1080/02656730802227236.
PMID
18923988
Source
pubmed
Published In
Int J Hyperthermia
Volume
24
Issue
6
Publish Date
2008
Start Page
449
End Page
450
DOI
10.1080/02656730802227236

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response (Nature Reviews Cancer (2008) 8, (425-437))

Authors
Dewhirst, MW; Cao, Y; Moeller, B
MLA Citation
Dewhirst, M. W., et al. “Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response (Nature Reviews Cancer (2008) 8, (425-437)).” Nature Reviews Cancer, vol. 8, no. 8, Aug. 2008. Scopus, doi:10.1038/nrc2438.
Source
scopus
Published In
Nature Reviews. Cancer
Volume
8
Issue
8
Publish Date
2008
Start Page
654
DOI
10.1038/nrc2438

First international association of hyperthermic oncology Tsudomu Sugahara award.

Authors
Dewhirst, M
MLA Citation
Dewhirst, Mark. “First international association of hyperthermic oncology Tsudomu Sugahara award..” Int J Hyperthermia, vol. 24, no. 5, Aug. 2008, pp. 442–43. Pubmed, doi:10.1080/02656730802195052.
PMID
18716943
Source
pubmed
Published In
Int J Hyperthermia
Volume
24
Issue
5
Publish Date
2008
Start Page
442
End Page
443
DOI
10.1080/02656730802195052

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response (vol 8, pg 425, 2008)

Authors
Dewhirst, MW; Cao, Y; Moeller, B
MLA Citation
Dewhirst, Mark W., et al. “Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response (vol 8, pg 425, 2008).” Nature Reviews Cancer, vol. 8, no. 8, Aug. 2008.
Source
wos-lite
Published In
Nature Reviews. Cancer
Volume
8
Issue
8
Publish Date
2008

The pervasive presence of fluctuating oxygenation in tumors.

Tumor hypoxia is a persistent obstacle for traditional therapies in solid tumors. Strategies for mitigating the effects of hypoxic tumor cells have been developed under the assumption that chronically hypoxic tumor cells were the central cause of treatment resistance. In this study, we show that instabilities in tumor oxygenation are a prevalent characteristic of three tumor lines and previous characterization of tumor hypoxia as being primarily diffusion-limited does not accurately portray the tumor microenvironment. Phosphorescence lifetime imaging was used to measure fluctuations in vascular pO(2) in rat fibrosarcomas, 9L gliomas, and R3230 mammary adenocarcinomas grown in dorsal skin-fold window chambers (n = 6 for each tumor type) and imaged every 2.5 minutes for a duration of 60 to 90 minutes. O(2) delivery to tumors is constantly changing in all tumors, resulting in continuous reoxygenation events throughout the tumor. Vascular pO(2) maps show significant spatial heterogeneity at each time point, as well as between time points. The fluctuations in oxygenation occur with a common periodicity within and between tumors, suggesting a common mechanism, but have tumor type-dependent spatial patterns. The widespread presence of fluctuations in tumor oxygenation has broad ranging implications for tumor progression, stress response, and signal transduction, which are altered by oxygenation/reoxygenation events.

Authors
Cárdenas-Navia, LI; Mace, D; Richardson, RA; Wilson, DF; Shan, S; Dewhirst, MW
MLA Citation
Cárdenas-Navia, Laura I., et al. “The pervasive presence of fluctuating oxygenation in tumors..” Cancer Res, vol. 68, no. 14, July 2008, pp. 5812–19. Pubmed, doi:10.1158/0008-5472.CAN-07-6387.
PMID
18632635
Source
pubmed
Published In
Cancer Res
Volume
68
Issue
14
Publish Date
2008
Start Page
5812
End Page
5819
DOI
10.1158/0008-5472.CAN-07-6387

Induction of the human heat shock promoter HSP70B by nutritional stress: implications for cancer gene therapy.

BACKGROUND: We designed and tested, in vitro, an adenoviral construct containing the feline interleukin-12 (IL-12) gene under control of the heat-inducible promoter HSP70B. This construct, AdhspfIL12, was used in a phase I trial in feline soft tissue sarcomas. During the course of our experiments, we noted that IL-12 was being produced in the transfected Crandell Feline Kidney (CrFK) cells under certain conditions even in the absence of hyperthermia. This observation was further explored to identify the cause of this unintended HSP70B induction. MATERIALS AND METHODS: We used real-time PCR as a sensitive method to quantitatively detect the presence of even small amounts of IL-12 mRNA. This served as a surrogate indicator of HSP70B induction. Various conditions were tested to induce the heat shock promoter, including nutritional deprivation, radiation and changes in pH. RESULTS: Nutritional stresses, specifically the absence of glucose and glutamine, could induce the heat shock promoter, thus, resulting in production of the downstream gene product. Other factors known to trigger the heat shock response, pH change, and reactive oxygen species production were also studied but were not found to contribute to heat shock promoter induction in our setting. CONCLUSIONS: The human heat shock promoter (HSP70B) is reported to be an efficient and tightly regulated promoter. We discovered, using sensitive real-time PCR techniques, that it can also be induced in response to cellular nutrient stresses. The pros and cons of this phenomenon and its implications for cancer gene therapy are discussed.

Authors
Siddiqui, F; Avery, PR; Li, C-Y; Zhang, X; LaRue, SM; Dewhirst, MW; Ullrich, RL
MLA Citation
Siddiqui, Farzan, et al. “Induction of the human heat shock promoter HSP70B by nutritional stress: implications for cancer gene therapy..” Cancer Invest, vol. 26, no. 6, July 2008, pp. 553–61. Pubmed, doi:10.1080/07357900701788015.
PMID
18584345
Source
pubmed
Published In
Cancer Invest
Volume
26
Issue
6
Publish Date
2008
Start Page
553
End Page
561
DOI
10.1080/07357900701788015

Low-intensity alternating electric fields: a potentially safe and effective treatment of cancer?

Authors
Schroeder, T; Viglianti, BL; Dewhirst, MW
MLA Citation
Schroeder, Thies, et al. “Low-intensity alternating electric fields: a potentially safe and effective treatment of cancer?.” Onkologie, vol. 31, no. 7, July 2008, pp. 357–58. Pubmed, doi:10.1159/000140601.
PMID
18596380
Source
pubmed
Published In
Onkologie
Volume
31
Issue
7
Publish Date
2008
Start Page
357
End Page
358
DOI
10.1159/000140601

Bromelain treatment decreases neutrophil migration to sites of inflammation.

Bromelain, a mixture of proteases derived from pineapple stem, has been reported to have therapeutic benefits in a variety of inflammatory diseases, including murine inflammatory bowel disease. The purpose of this work was to understand potential mechanisms for this anti-inflammatory activity. Exposure to bromelain in vitro has been shown to remove a number of cell surface molecules that are vital to leukocyte trafficking, including CD128a/CXCR1 and CD128b/CXCR2 that serve as receptors for the neutrophil chemoattractant IL-8 and its murine homologues. We hypothesized that specific proteolytic removal of CD128 molecules by bromelain would inhibit neutrophil migration to IL-8 and thus decrease acute responses to inflammatory stimuli. Using an in vitro chemotaxis assay, we demonstrated a 40% reduction in migration of bromelain- vs. sham-treated human neutrophils in response to rhIL-8. Migration to the bacterial peptide analog fMLP was unaffected, indicating that bromelain does not induce a global defect in leukocyte migration. In vivo bromelain treatment generated a 50-85% reduction in neutrophil migration in 3 different murine models of leukocyte migration into the inflamed peritoneal cavity. Intravital microscopy demonstrated that although in vivo bromelain treatment transiently decreased leukocyte rolling, its primary long-term effect was abrogation of firm adhesion of leukocytes to blood vessels at the site of inflammation. These changes in adhesion were correlated with rapid re-expression of the bromelain-sensitive CD62L/L-selectin molecules that mediate rolling following in vivo bromelain treatment and minimal re-expression of CD128 over the time period studied. Taken together, these studies demonstrate that bromelain can effectively decrease neutrophil migration to sites of acute inflammation and support the specific removal of the CD128 chemokine receptor as a potential mechanism of action.

Authors
Fitzhugh, DJ; Shan, S; Dewhirst, MW; Hale, LP
MLA Citation
Fitzhugh, David J., et al. “Bromelain treatment decreases neutrophil migration to sites of inflammation..” Clin Immunol, vol. 128, no. 1, July 2008, pp. 66–74. Pubmed, doi:10.1016/j.clim.2008.02.015.
PMID
18482869
Source
pubmed
Published In
Clin Immunol
Volume
128
Issue
1
Publish Date
2008
Start Page
66
End Page
74
DOI
10.1016/j.clim.2008.02.015

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response.

Hypoxia and free radicals, such as reactive oxygen and nitrogen species, can alter the function and/or activity of the transcription factor hypoxia-inducible factor 1 (HIF1). Interplay between free radicals, hypoxia and HIF1 activity is complex and can influence the earliest stages of tumour development. The hypoxic environment of tumours is heterogeneous, both spatially and temporally, and can change in response to cytotoxic therapy. Free radicals created by hypoxia, hypoxia-reoxygenation cycling and immune cell infiltration after cytotoxic therapy strongly influence HIF1 activity. HIF1 can then promote endothelial and tumour cell survival. As discussed here, a constant theme emerges: inhibition of HIF1 activity will have therapeutic benefit.

Authors
Dewhirst, MW; Cao, Y; Moeller, B
MLA Citation
Dewhirst, Mark W., et al. “Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response..” Nat Rev Cancer, vol. 8, no. 6, June 2008, pp. 425–37. Pubmed, doi:10.1038/nrc2397.
PMID
18500244
Source
pubmed
Published In
Nat Rev Cancer
Volume
8
Issue
6
Publish Date
2008
Start Page
425
End Page
437
DOI
10.1038/nrc2397

Comparison of three physiologically-based pharmacokinetic models for the prediction of contrast agent distribution measured by dynamic MR imaging.

PURPOSE: To compare the performance of three physiologically-based pharmacokinetic (PBPK) models for predicting gadolinium contrast agent concentration-time curves (Gd-CTCs) obtained in superior sagittal sinus (SSS), cerebral cortex, and psoas muscle. MATERIALS AND METHODS: Three published whole-body PBPK models were modified to predict Gd-CTCs in normal-appearing tissue. The models differed in the number of organs modeled and total number of compartments, and were designated as the "well-mixed," "delay," and "dispersion" models. The suitability of the three models to predict Gd-CTC was studied using data from dynamic contrast-enhanced MR perfusion imaging obtained at 1.5T from 10 patients with glioblastoma multiforme and at 3.0T from five patients with liver metastases. RESULTS: The dispersion model produced better fits than the delay model in the SSS (P < 0.0001) and cerebral cortex (P < 0.0001), and better fits than the well-mixed model in psoas muscle (P < 0.005). No model produced better fits than the dispersion model at any of the three locations. CONCLUSION: In this evaluation, the dispersion model was most robust for prediction of Gd-CTCs derived from dynamic contrast-enhanced (DCE)-MRI. This represents a preliminary step in the development of a PBPK model useful for predicting Gd-CTCs at a time resolution appropriate for dynamic MRI applications.

Authors
Barboriak, DP; MacFall, JR; Viglianti, BL; Dewhirst Dvm, MW
MLA Citation
Barboriak, Daniel P., et al. “Comparison of three physiologically-based pharmacokinetic models for the prediction of contrast agent distribution measured by dynamic MR imaging..” J Magn Reson Imaging, vol. 27, no. 6, June 2008, pp. 1388–98. Pubmed, doi:10.1002/jmri.21344.
PMID
18504759
Source
pubmed
Published In
Journal of Magnetic Resonance Imaging : Jmri
Volume
27
Issue
6
Publish Date
2008
Start Page
1388
End Page
1398
DOI
10.1002/jmri.21344

Inhibition of in vivo tumor angiogenesis and growth via systemic delivery of an angiopoietin 2-specific RNA aptamer.

BACKGROUND: Cellular events mediated by the Tie2 receptor are important to tumor neovascularization. Despite the complex interplay of the best-characterized Tie2 ligands, angiopoietins 1 and 2, Ang2 is purportedly "proangiogenic" in the presence of vascular endothelial growth factor. We examined whether in vivo administration of an RNA aptamer that specifically blocks Ang 2 would inhibit tumor angiogenesis and growth. METHODS: Ang2-mediated Tie2 receptor phosphorylation was assessed in vitro in the absence and presence of aptamer coupled to polyethylene glycol. IN VIVO ANGIOGENESIS ASSAY: CT26 murine colon carcinoma cells expressing green fluorescent protein were delivered into mouse dorsal skinfold window chambers. Animals received daily intraperitoneal injections of phosphate-buffered saline, low-dose (Ang2 aptamer-LD; 1 mg/kg/d), or high-dose aptamer (Ang2 aptamer-HD; 10 mg/kg/d). Vascular length density was measured under fluorescence microscopy. PRIMARY TUMOR GROWTH: CT26 cells expressing luciferase were injected into flanks of BALB/c mice to allow tumor growth monitoring by bioluminescence imaging. Animals received continuous phosphate-buffered saline or aptamer (1 mg/kg/d) via ALZET pumps. Tumors were assessed for CD31/PECAM-1 immunostaining and Hoechst dye uptake. RESULTS: Pegylated aptamer inhibited Tie2 phosphorylation. Systemic aptamer administration reduced vascular length density (P < or = 0.03) and decreased bioluminescence emission (P < 0.04), corresponding to 50% decrease in tumor volume (P = 0.04). Control tumors displayed abundant vascular marker staining, in contrast to tumors from aptamer-treated animals. CONCLUSIONS: in vivo administration of a clinically relevant, pegylated RNA aptamer specifically designed against Ang2 inhibited tumor angiogenesis and growth. These findings support targeted Ang2 inhibition as a relevant anti-angiogenic, anti-neoplastic strategy.

Authors
Sarraf-Yazdi, S; Mi, J; Moeller, BJ; Niu, X; White, RR; Kontos, CD; Sullenger, BA; Dewhirst, MW; Clary, BM
MLA Citation
Sarraf-Yazdi, Shiva, et al. “Inhibition of in vivo tumor angiogenesis and growth via systemic delivery of an angiopoietin 2-specific RNA aptamer..” J Surg Res, vol. 146, no. 1, May 2008, pp. 16–23. Pubmed, doi:10.1016/j.jss.2007.04.028.
PMID
17950331
Source
pubmed
Published In
Journal of Surgical Research
Volume
146
Issue
1
Publish Date
2008
Start Page
16
End Page
23
DOI
10.1016/j.jss.2007.04.028

One-stop-shop tumor imaging: buy hypoxia, get lactate free.

The ability to noninvasively assess physiological changes in solid tumors is desired for its diagnostic and therapeutic potential. In this issue of JCI, Matsumoto and colleagues reveal their development and use of a novel imaging approach, combining pulsed electron paramagnetic resonance imaging (EPRI) with conventional MRI to image squamous cell carcinoma tumor-bearing mice (See the related article beginning on page 1965). This method provides coregistered images of oxygenation and blood volume/flow with the underlying anatomy and concentrations of metabolites such as lactate and choline. This technique, combining functional and anatomic imaging, shows immediate preclinical applicability in monitoring factors that control tumor hypoxia and metabolism and may have future clinical potential for monitoring tumor response to treatment.

Authors
Manzoor, AA; Schroeder, T; Dewhirst, MW
MLA Citation
Manzoor, Ashley A., et al. “One-stop-shop tumor imaging: buy hypoxia, get lactate free..” J Clin Invest, vol. 118, no. 5, May 2008, pp. 1616–19. Pubmed, doi:10.1172/JCI35543.
PMID
18431517
Source
pubmed
Published In
The Journal of Clinical Investigation
Volume
118
Issue
5
Publish Date
2008
Start Page
1616
End Page
1619
DOI
10.1172/JCI35543

Changed microvascular adaptation characteristics may explain heterogeneity and hypoxia of tumor perfusion

Authors
Pries, AR; Cornelissen, AJM; Sloot, AA; Dreher, M; Hinkeldey, M; Hoepfner, M; Dewhirst, MW; Secomb, TW
MLA Citation
Pries, Axel R., et al. “Changed microvascular adaptation characteristics may explain heterogeneity and hypoxia of tumor perfusion.” Faseb Journal, vol. 22, FEDERATION AMER SOC EXP BIOL, Apr. 2008.
Source
wos
Published In
Faseb Journal
Volume
22
Publish Date
2008

Use of bioluminescence imaging to detect enhanced hepatic and systemic tumor growth following partial hepatectomy in mice.

BACKGROUND: The impact of partial hepatectomy on intra-hepatic and distant tumor growth is a matter of controversy. Utilizing a highly sensitive tumor imaging strategy, we sought to demonstrate whether this growth-acceleration occurs, and to develop an animal model with which to investigate potential therapeutic strategies. METHODS: Mice bearing constitutively-active luciferase-expressing tumor cells were subjected to either 70% partial hepatectomy (PH; n=10) or a sham operation (n=11). Mice were sacrificed 14 days later and remnant livers (or anatomic equivalents in the control group) and lungs harvested for bioluminescence detection. RESULTS: Remnant liver weights were significantly increased in PH compared to equivalent lobes in sham-operated animals (t-test; p=0.005). Tumor burden as measured by bioluminescence was significantly higher in both liver and lung specimens in the PH group (Wilcoxon's Rank Sum test; p=0.01 and 0.004, respectively). CONCLUSIONS: Following PH, enhanced metastatic growth was depicted regionally and systemically with bioluminescence imaging providing an objective measure of tumor burden. This preclinical model can help to identify adjuvant therapies that can influence both tumor growth and liver regeneration.

Authors
Sarraf-Yazdi, S; Mi, J; Dewhirst, MW; Clary, BM
MLA Citation
Sarraf-Yazdi, S., et al. “Use of bioluminescence imaging to detect enhanced hepatic and systemic tumor growth following partial hepatectomy in mice..” Eur J Surg Oncol, vol. 34, no. 4, Apr. 2008, pp. 476–81. Pubmed, doi:10.1016/j.ejso.2007.06.001.
PMID
17698312
Source
pubmed
Published In
Eur J Surg Oncol
Volume
34
Issue
4
Publish Date
2008
Start Page
476
End Page
481
DOI
10.1016/j.ejso.2007.06.001

Fast temperature optimization of multi-source hyperthermia applicators with reduced-order modeling of 'virtual sources'.

The goal of this work is to build the foundation for facilitating real-time magnetic resonance image guided patient treatment for heating systems with a large number of physical sources (e.g. antennas). Achieving this goal requires knowledge of how the temperature distribution will be affected by changing each source individually, which requires time expenditure on the order of the square of the number of sources. To reduce computation time, we propose a model reduction approach that combines a smaller number of predefined source configurations (fewer than the number of actual sources) that are most likely to heat tumor. The source configurations consist of magnitude and phase source excitation values for each actual source and may be computed from a CT scan based plan or a simplified generic model of the corresponding patient anatomy. Each pre-calculated source configuration is considered a 'virtual source'. We assume that the actual best source settings can be represented effectively as weighted combinations of the virtual sources. In the context of optimization, each source configuration is treated equivalently to one physical source. This model reduction approach is tested on a patient upper-leg tumor model (with and without temperature-dependent perfusion), heated using a 140 MHz ten-antenna cylindrical mini-annular phased array. Numerical simulations demonstrate that using only a few pre-defined source configurations can achieve temperature distributions that are comparable to those from full optimizations using all physical sources. The method yields close to optimal temperature distributions when using source configurations determined from a simplified model of the tumor, even when tumor position is erroneously assumed to be approximately 2.0 cm away from the actual position as often happens in practical clinical application of pre-treatment planning. The method also appears to be robust under conditions of changing, nonlinear, temperature-dependent perfusion. The proposed approach of using virtual sources reduces the number of variables that must be optimized to achieve a tumor-focused temperature distribution, thereby reducing the calculation time required in real-time control applications to about 1/3 to 1/4 of that required for full optimization.

Authors
Cheng, K-S; Stakhursky, V; Craciunescu, OI; Stauffer, P; Dewhirst, M; Das, SK
MLA Citation
Cheng, Kung-Shan, et al. “Fast temperature optimization of multi-source hyperthermia applicators with reduced-order modeling of 'virtual sources'..” Phys Med Biol, vol. 53, no. 6, Mar. 2008, pp. 1619–35. Pubmed, doi:10.1088/0031-9155/53/6/008.
PMID
18367792
Source
pubmed
Published In
Physics in Medicine and Biology
Volume
53
Issue
6
Publish Date
2008
Start Page
1619
End Page
1635
DOI
10.1088/0031-9155/53/6/008

Optical clearing of unsectioned specimens for three-dimensional imaging via optical transmission and emission tomography.

Optical computed tomography (optical-CT) and optical emission computed tomography (optical-ECT) are new techniques that enable unprecedented high-resolution 3-D multimodal imaging of tissue structure and function. Applications include imaging macroscopic gene expression and microvasculature structure in unsectioned biological specimens up to 8 cm(3). A key requisite for these imaging techniques is effective sample preparation including optical clearing, which enables light transport through the sample while preserving the signal (either light absorbing stain or fluorescent proteins) in representative form. We review recent developments in optical-CT and optical-ECT, and compatible "fluorescence-friendly" optical clearing protocols.

Authors
Oldham, M; Sakhalkar, H; Oliver, T; Allan Johnson, G; Dewhirst, M
MLA Citation
Oldham, Mark, et al. “Optical clearing of unsectioned specimens for three-dimensional imaging via optical transmission and emission tomography..” J Biomed Opt, vol. 13, no. 2, Mar. 2008. Pubmed, doi:10.1117/1.2907968.
PMID
18465962
Source
pubmed
Published In
Journal of Biomedical Optics
Volume
13
Issue
2
Publish Date
2008
Start Page
021113
DOI
10.1117/1.2907968

Analytic solution to steady-state radial diffusion of a substrate with first-order reaction kinetics in the tissue of a Krogh's cylinder.

It is often useful to calculate the concentration profile for a substrate undergoing reaction in the tissue surrounding a capillary. In this paper, we consider a model geometry consisting of a long straight cylinder of tissue surrounding a capillary. Substrate diffuses radially out of the capillary through the tissue, with consumption of substrate in the tissue directly proportional to substrate concentration (i.e., first-order reaction kinetics). The model is extended to include the case where a cylinder of necrotic tissue surrounds a metabolically active inner tissue cylinder. A simple analytic solution is derived, and concentration profiles are generated for various combinations of parameters. Compared to the case where substrate consumption is independent of concentration, this model predicts much more rapid depletion of substrate near the capillary interface. This can have significant implications for the calculation of the hypoxic fraction (e.g., tissue with pO(2)<0.5-5 mmHg) when tumor oxygenation is modeled. The model also permits calculation of the limiting substrate concentration for cell viability when the reaction rate constant is known and vice versa.

Authors
Kirkpatrick, JP; Dewhirst, MW
MLA Citation
Kirkpatrick, John P., and Mark W. Dewhirst. “Analytic solution to steady-state radial diffusion of a substrate with first-order reaction kinetics in the tissue of a Krogh's cylinder..” Radiat Res, vol. 169, no. 3, Mar. 2008, pp. 350–54. Pubmed, doi:10.1667/RR1166.1.
PMID
18302491
Source
pubmed
Published In
Radiation Research
Volume
169
Issue
3
Publish Date
2008
Start Page
350
End Page
354
DOI
10.1667/RR1166.1

Elevated CAIX Expression is Associated with an Increased Risk of Distant Failure in Early-Stage Cervical Cancer.

Tumor hypoxia is associated with adverse outcome in many malignancies. The goal of this study was to determine if elevated expression of carbonic anhydrase IX (CAIX), a biomarker of hypoxia, predicts for recurrence in early-stage cervical cancer. The charts of all patients with early-stage cervical cancer, primarily FIGO IB, treated by radical hysterectomy at our institution from 1988-2001 were reviewed. Adequate pathologic specimens from patients who recurred or who had at least three years follow-up and remained disease-free were stained for CAIX. An immunohistochemical score (IHC) was generated from the extent/intensity of staining. Outcome, as measured by freedom from recurrence (FFR), distant metastases (FFDM) and local recurrence (FFLR), was analyzed as a function of age, IHC, lymph node status (LN) and histology. Forty-two relapsing patients and 76 non-relapsing patients were evaluated. In univariate analysis, +LN, though not IHC or histology, was a significant predictor of any recurrence. Both +LN and higher IHC were associated with decreased FFDM but not FFLR. Patients with both +LN and elevated IHC more frequently exhibited distant metastases as first site of failure (5-year FFDM 50%) than patients with only +LN, elevated IHC or neither feature (70, 85 and 95%, respectively, p = 0.0004). In multivariable analysis, only +LN was significantly associated with poorer FFDM (hazard ratio 4.6, p = 0.0015) though there was a strong trend with elevated CAIX expression (p = 0.069). Elevated CAIX expression is associated with more frequent distant metastases in early-stage cervical cancer, suggesting that patients with this characteristic may benefit from more aggressive treatment.

Authors
Kirkpatrick, JP; Rabbani, ZN; Bentley, RC; Hardee, ME; Karol, S; Meyer, J; Oosterwijk, E; Havrilesky, L; Secord, AA; Vujaskovic, Z; Dewhirst, MW; Jones, EL
MLA Citation
Kirkpatrick, John P., et al. “Elevated CAIX Expression is Associated with an Increased Risk of Distant Failure in Early-Stage Cervical Cancer..” Biomark Insights, vol. 3, Feb. 2008, pp. 45–55.
PMID
19578493
Source
pubmed
Published In
Biomarker Insights
Volume
3
Publish Date
2008
Start Page
45
End Page
55

Rationale for and measurement of liposomal drug delivery with hyperthermia using non-invasive imaging techniques.

The purpose of this review is to present an overview of the state-of-the-art imaging modalities used to track drug delivery from liposomal formulations into tumors during or after hyperthermia treatment. Liposomes are a drug delivery system comprised of a phospholipid bilayer surrounding an aqueous core and have been shown to accumulate following hyperthermia therapy. Use of contrast-containing liposomes in conjunction with hyperthermia therapy holds great promise to be able to directly measure drug dose concentrations as well as to non-invasively describe patterns of drug distribution with MR and PET/SPECT imaging modalities. We will review the rationale for using this approach and the potential advantages of having such information available during and after treatment.

Authors
Tashjian, JA; Dewhirst, MW; Needham, D; Viglianti, BL
MLA Citation
Tashjian, Jessica A., et al. “Rationale for and measurement of liposomal drug delivery with hyperthermia using non-invasive imaging techniques..” Int J Hyperthermia, vol. 24, no. 1, Feb. 2008, pp. 79–90. Pubmed, doi:10.1080/02656730701840147.
PMID
18214771
Source
pubmed
Published In
International Journal of Hyperthermia : the Official Journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group
Volume
24
Issue
1
Publish Date
2008
Start Page
79
End Page
90
DOI
10.1080/02656730701840147

PET of hypoxia and perfusion with 62Cu-ATSM and 62Cu-PTSM using a 62Zn/62Cu generator.

OBJECTIVE: Copper-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) and copper-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (Cu-PTSM) are being studied as potential markers of hypoxia and perfusion, respectively. The use of short-lived radionuclides (e.g., 62Cu) has advantages for clinical PET, including a lower radiation dose than long-lived radionuclides and serial imaging capability. A 62Zn/62Cu microgenerator and rapid synthesis kits now provide a practical means of producing 62Cu-PTSM and 62Cu-ATSM on-site. Tumors can be characterized with 62Cu-PTSM, 62Cu-ATSM, and 18F-FDG PET scans during one session. We present the initial clinical data in two patients with lung neoplasms. CONCLUSION: Hypoxia and perfusion are important parameters in tumor physiology and can have major implications in diagnosis, prognosis, treatment planning, and response to therapy. We have shown the feasibility of performing 62Cu-ATSM and 62Cu-PTSM PET together with FDG PET/CT during a single imaging session to provide information on both perfusion and hypoxia and tumor anatomy and metabolism.

Authors
Wong, TZ; Lacy, JL; Petry, NA; Hawk, TC; Sporn, TA; Dewhirst, MW; Vlahovic, G
MLA Citation
Wong, Terence Z., et al. “PET of hypoxia and perfusion with 62Cu-ATSM and 62Cu-PTSM using a 62Zn/62Cu generator..” Ajr Am J Roentgenol, vol. 190, no. 2, Feb. 2008, pp. 427–32. Pubmed, doi:10.2214/AJR.07.2876.
PMID
18212229
Source
pubmed
Published In
Ajr. American Journal of Roentgenology
Volume
190
Issue
2
Publish Date
2008
Start Page
427
End Page
432
DOI
10.2214/AJR.07.2876

Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan.

PURPOSE: The combination of a vascular endothelial growth factor (VEGF) -neutralizing antibody, bevacizumab, and irinotecan is associated with high radiographic response rates and improved survival outcomes in patients with recurrent malignant gliomas. The aim of these retrospective studies was to evaluate tumor vascularity and expression of components of the VEGF pathway and hypoxic responses as predictive markers for radiographic response and survival benefit from the bevacizumab and irinotecan therapy. PATIENTS AND METHODS: In a phase II trial, 60 patients with recurrent malignant astrocytomas were treated with bevacizumab and irinotecan. Tumor specimens collected at the time of diagnosis were available for further pathologic studies in 45 patients (75%). VEGF, VEGF receptor-2, CD31, hypoxia-inducible carbonic anhydrase 9 (CA9), and hypoxia-inducible factor-2alpha were semiquantitatively assessed by immunohistochemistry. Radiographic response and survival outcomes were correlated with these angiogenic and hypoxic markers. RESULTS: Of 45 patients, 27 patients had glioblastoma multiforme, and 18 patients had anaplastic astrocytoma. Twenty-six patients (58%) had at least partial radiographic response. High VEGF expression was associated with increased likelihood of radiographic response (P = .024) but not survival benefit. Survival analysis revealed that high CA9 expression was associated with poor survival outcome (P = .016). CONCLUSION: In this patient cohort, tumor expression levels of VEGF, the molecular target of bevacizumab, were associated with radiographic response, and the upstream promoter of angiogenesis, hypoxia, determined survival outcome, as measured from treatment initiation. Validation in a larger clinical trial is warranted.

Authors
Sathornsumetee, S; Cao, Y; Marcello, JE; Herndon, JE; McLendon, RE; Desjardins, A; Friedman, HS; Dewhirst, MW; Vredenburgh, JJ; Rich, JN
MLA Citation
Sathornsumetee, Sith, et al. “Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan..” J Clin Oncol, vol. 26, no. 2, Jan. 2008, pp. 271–78. Pubmed, doi:10.1200/JCO.2007.13.3652.
PMID
18182667
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
2
Publish Date
2008
Start Page
271
End Page
278
DOI
10.1200/JCO.2007.13.3652

TU‐FF‐A4‐03: Improving the Accuracy of Optical‐Emission‐CT Imaging Through Application of a Non‐Uniform Attenuation Correction

Purpose: Optical computed tomography (optical‐CT) and emission tomography (optical‐ECT) are new techniques with demonstrated potential for imaging structure and function (including gene expression) in unsectioned tissue samples. This work presents the first attempts to improve the accuracy of optical‐ECT by incorporating an attenuation correction analogous to that applied in SPECT. Method and Materials: Optical‐ECT can be described as a linear system Ax=b, where x is the fluorescing distribution, b is the expected value of measured projections, and A describes the mapping from x to b. An in‐house code (Spect‐Map) originally developed for SPECT reconstruction was adapted for application to optical‐ECT. Verification of the method was performed by imaging a phantom containing a known distribution of fluorescing wires. Optical‐CT/ECT projections were taken consecutively to ensure accurate co‐registration. Attenuation‐uncorrected and ‐corrected optical‐ECT images were reconstructed by calculating A assuming zero attenuation and the optical‐CT‐measured non‐uniform attenuation, respectively. Successful preliminary verification led to the application of attenuation correction to optical‐ECT images of unsectioned human breast xenograft tumors which had transcribed fluorescing proteins labeling viable tumor burden (RFP) and HIF1 distribution (GFP). Results: Significant attenuation artifacts were observed in the uncorrected optical‐ECT image of the phantom. The middle wire appeared artificially less intense due to greater attenuation from the surrounding ink‐doped gel. This artifact was successfully removed in the attenuation‐corrected image, demonstrating basic performance of the method. Fluorescence intensities of the wires varied by as much as 29% in the uncorrected image versus 3% in the corrected image. Application of the attenuation correction to xenograft tumor images shows significant changes in apparent expression of fluorescing proteins. Interpretation and results will be presented. Conclusion: These results suggest that Spect‐Map has been successfully adapted to perform attenuation correction for optical‐ECT imaging. Preliminary xenograft tumor reconstructions indicate that attenuation correction is vital for accurate optical‐ECT imaging. © 2008, American Association of Physicists in Medicine. All rights reserved.

Authors
Kim, E; Bowsher, J; Sakhalkar, H; Dewhirst, M; Oldham, M
MLA Citation
Kim, E., et al. “TU‐FF‐A4‐03: Improving the Accuracy of Optical‐Emission‐CT Imaging Through Application of a Non‐Uniform Attenuation Correction.” Medical Physics, vol. 35, no. 6, 2008. Scopus, doi:10.1118/1.2962658.
Source
scopus
Published In
Medical Physics
Volume
35
Issue
6
Publish Date
2008
Start Page
2923
DOI
10.1118/1.2962658

SU‐GG‐T‐367: Fast Hyperthermia Temperature Optimization for Pelvic Carcinoma Patient Treated in Sigma‐Eye Applicator

Purpose: Though hyperthermia shows promising features being used with radiation and chemotherapy, it requires accurate spatial power focusing, which leads a workload proportional to square of number of antennas in an applicator. This motivates this investigation of model reduction method for pelvic‐carcinoma patient treated in Sigma‐Eye applicator. Method and Materials: A patient placed in the middle ring of this 100 MHz 3‐ring 12‐antenna applicator was used to validate our approach. A ‘similar’ patient with different thermal property values, perfusion values and was placed between the middle and low ring was used to determined virtual source (VS) basis vectors. A VS vector is a weighted combination of magnitudes and phases of 12 antennas and was determined to maximize averaged tumor temperature. Physical variables were projected to a reduced VS subspace spanned by a few VS vectors. Temperature response functions of tumor and normal tissues were determined in this reduced subspace and then used in temperature optimization iteration process. Results: By comparing the optimized temperature elevation distributions, we found it is indeed feasible to use a few chosen (best) VS basis vectors to optimally treat a pelvic carcinoma patient in Sigma‐Eye applicator; even when we determined those virtual source basis vectors from an existing “similar” patient. Conclusion: This success suggests a faster and easier pre‐treatment temperature optimization approach that relives workloads of physicians. © 2008, American Association of Physicists in Medicine. All rights reserved.

Authors
Cheng, K; Stakhursky, V; Craciunescu, O; Stauffer, P; Dewhirst, M; Das, S
MLA Citation
Cheng, K., et al. “SU‐GG‐T‐367: Fast Hyperthermia Temperature Optimization for Pelvic Carcinoma Patient Treated in Sigma‐Eye Applicator.” Medical Physics, vol. 35, no. 6, 2008, pp. 2809–10. Scopus, doi:10.1118/1.2962119.
Source
scopus
Published In
Medical Physics
Volume
35
Issue
6
Publish Date
2008
Start Page
2809
End Page
2810
DOI
10.1118/1.2962119

SU‐GG‐T‐366: Hyperthermia Treatment for a Patient with Two Shank Sarcomas Treated by a Fast Pre‐Treatment Optimization Method

Purpose: Cancerous cells are infiltrative and can invade neighborhood and/or distant body. While hyperthermia shows promising synergistic effects being used with radiation and/or chemotherapy, current microwave/radiofrequency power focusing techniques only focus one target at a time. Therefore, patients with multi‐sarcoma need to perform multi‐treatment in different days since a hyperthermia treatment requires maintaining tumor temperature >= 43°C for 60 minutes. Thus we investigate the feasibility of determining an optimal antenna setting that simultaneously elevates temperatures at two near‐by shank sarcomas so that patient comfort is enhanced and treatment times and costs are reduced. Method and Materials: A patient with two sarcomas was chosen to numerically validate our approach. Patient shank was surrounded by a 10‐antenna mini‐annual‐phased‐array (MAPA) operating at 138 MHz. A water bolus was placed between patient and MAPA to provide electric coupling and thermal cooling. A set of antenna settings were determined with a goal of maximizing averaged tumor temperature and were determined from the patient. The first few best antenna settings were chosen as virtual source (VS) basis vectors to span the reduced subspace. Magnitudes and phases of all 10 antennas were projected into this reduced subspace and then a set of temperature response functions for tumor and normal tissues were determined in this subspace. Numerical optimization was conducted to determine the optimal antenna setting that simultaneously elevates tumor temperatures and maintains safe normal tissue temperatures. Results: Results showed that we can use the 10‐antenna MAPA to simultaneously heat two sarcomas, and leave normal tissue undamaged. Furthermore, by comparing optimized temperatures when all 10 antennas were activated with that when only 4 VSs were used, we found these optimized temperatures are very comparable. Conclusion: Therefore, we presented an algorithm that allows physicians to treat patients with multi‐sarcoma and it also improves treatment planning efficiently. © 2008, American Association of Physicists in Medicine. All rights reserved.

Authors
Cheng, K; Li, Z; Stauffer, P; Joines, W; Dewhirst, M; Das, S
MLA Citation
Cheng, K., et al. “SU‐GG‐T‐366: Hyperthermia Treatment for a Patient with Two Shank Sarcomas Treated by a Fast Pre‐Treatment Optimization Method.” Medical Physics, vol. 35, no. 6, 2008. Scopus, doi:10.1118/1.2962118.
Source
scopus
Published In
Medical Physics
Volume
35
Issue
6
Publish Date
2008
Start Page
2809
DOI
10.1118/1.2962118

In vivo monitoring of a fluorescently labeled antibody in mice with breast cancer xenografts

Following the uptake kinetics of a monoclonal antibody cancer therapy in vivo is addressed in this study via the use of a surface probe to assay a fluorescent label attached to the antibody. Female NCr-nu athymic mice were implanted with cells from a human breast cancer MCF7HER2 line that over expresses clinically relevant levels of the HER2/neu protein. Herceptin (trastuzumab) and a negative control antibody for mouse IgG Ab-1 were labeled with Alexa Fluor 647 fluorescent dye and the mice received a single bolus injection (tail vein) of one of the two antibodies. The relative signal in the tumor region was compared with that from normal tissue and a ratio of the signal levels was recorded as a function of time. As expected, Herceptin was found to concentrate in the HER2+ tumors (high tumor-to-normal ratio), whereas the tumor-to-normal ratio for the negative control antibody was flat in time and close to unity. It is suggested that fluorescence assays of this type might be possible in vivo in humans using a telemetric, implantable version of the probe used in this study. © 2007 IEEE.

Authors
Black, RD; Bolick, NG; Richardson, RA; Dewhirst, MW
MLA Citation
Black, R. D., et al. “In vivo monitoring of a fluorescently labeled antibody in mice with breast cancer xenografts.” Ieee Sensors Journal, vol. 8, no. 1, Jan. 2008, pp. 81–88. Scopus, doi:10.1109/JSEN.2007.912911.
Source
scopus
Published In
Ieee Sensors Journal
Volume
8
Issue
1
Publish Date
2008
Start Page
81
End Page
88
DOI
10.1109/JSEN.2007.912911

Response to comments by Dr. Luijik and Dr. Schippers

Authors
Zhou, SM; Hoppenworth, EJ; Das, SK; Wang, ZH; Sun, XJ; Yin, FF; Dewhirst, MW
MLA Citation
Zhou, S. M., et al. “Response to comments by Dr. Luijik and Dr. Schippers.” Medical Physics, vol. 35, no. 6, Jan. 2008. Scopus, doi:10.1118/1.2912367.
Source
scopus
Published In
Medical Physics
Volume
35
Issue
6
Publish Date
2008
Start Page
2560
DOI
10.1118/1.2912367

Spectral imaging facilitates visualization and measurements of unstable and abnormal microvascular oxygen transport in tumors.

Abnormal microvasculature contributes to the pathophysiologic microenvironment of tumors. Understanding microvascular tumor oxygen transport is necessary to comprehend the factors that influence tumor biology, physiology, and therapy. Previously, we described an in vivo spectral imaging microscopy system for measurements of microvessel hemoglobin saturation (HbSat). We measure temporal fluctuations and spatial gradients in tumor microvessel oxygenation and identify instances of anastomoses between vessels with significantly different oxygenations. Slow periodic fluctuations in HbSat <0.2 cycles per minute were observed. These measurements are consistent with microelectrode measurements of fluctuating tumor oxygenation. Gradients in HbSat along individual tumor microvessels were measured that were larger in magnitude than normal tissue microvessels. Images were captured of anastomoses of tumor microvessels with diameters 20%). Shunting of inspired oxygen, presumably due to arteriovenous anastomoses, from tumor feeding arterioles to adjacent venules was imaged. This effect was confined to a region around the tumor and was not observed in nearby normal microvessels. Imaging measurements of tumor microvessel oxygen transport may offer insight to current questions regarding oxygen-related tumor biology and treatment responses, and spectral imaging may be a useful research tool in this regard.

Authors
Sorg, BS; Hardee, ME; Agarwal, N; Moeller, BJ; Dewhirst, MW
MLA Citation
Sorg, Brian S., et al. “Spectral imaging facilitates visualization and measurements of unstable and abnormal microvascular oxygen transport in tumors..” J Biomed Opt, vol. 13, no. 1, Jan. 2008. Pubmed, doi:10.1117/1.2837439.
PMID
18315384
Source
pubmed
Published In
Journal of Biomedical Optics
Volume
13
Issue
1
Publish Date
2008
Start Page
014026
DOI
10.1117/1.2837439

RNA aptamer-targeted inhibition of NF-kappa B suppresses non-small cell lung cancer resistance to doxorubicin.

Due to the prevalence of tumor chemoresistance, the clinical response of advanced non-small cell lung cancer (NSCLC) to chemotherapy is poor. We suppressed tumor resistance to doxorubicin (Dox) in A549 cells, a human NSCLC cell line, both in vitro and in vivo in a lung tumor xenograft model, using a novel adenoviral expression system to deliver an RNA aptamer (A-p50) that specifically inhibits nuclear factor-kappaB (NF-kappaB) activation. By achieving selective, targeted, and early inhibition of NF-kappaB activity, we demonstrate that NF-kappaB plays a critical role in Dox-induced chemoresistance by regulating genes involved in proliferation (Ki-67), response to DNA damage (GADD153), antiapoptosis (Bcl-XL), and pH regulation (CA9). This Dox-induced NF-kappaB activation and subsequent chemoresistance is dependent on expression of p53. We also demonstrate that NF-kappaB promotes angiogenesis in the presence of Dox via the hypoxia-inducible factor-1alpha/vascular endothelial growth factor (HIF-1alpha/VEGF) pathway, revealing a previously unknown mechanism of NSCLC resistance to Dox. These studies provide important insights into the mechanisms of Dox-induced chemoresistance, and they demonstrate a novel, effective, and clinically practical strategy for interfering with these processes.

Authors
Mi, J; Zhang, X; Rabbani, ZN; Liu, Y; Reddy, SK; Su, Z; Salahuddin, FK; Viles, K; Giangrande, PH; Dewhirst, MW; Sullenger, BA; Kontos, CD; Clary, BM
MLA Citation
Mi, Jing, et al. “RNA aptamer-targeted inhibition of NF-kappa B suppresses non-small cell lung cancer resistance to doxorubicin..” Mol Ther, vol. 16, no. 1, Jan. 2008, pp. 66–73. Pubmed, doi:10.1038/sj.mt.6300320.
PMID
17912235
Source
pubmed
Published In
Molecular Therapy : the Journal of the American Society of Gene Therapy
Volume
16
Issue
1
Publish Date
2008
Start Page
66
End Page
73
DOI
10.1038/sj.mt.6300320

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Authors
DEWHIRST, M
MLA Citation
DEWHIRST, M. W. “Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response.” Nat Rev Cancer, vol. 8, 2008, pp. 425–37.
Source
cinii-english
Published In
Nat Rev Cancer
Volume
8
Publish Date
2008
Start Page
425
End Page
437

State of the journal, 2007

Authors
Dewhirst, MW
MLA Citation
Dewhirst, M. W. “State of the journal, 2007.” International Journal of Hyperthermia, vol. 23, no. 8, Dec. 2007, pp. 607–08. Scopus, doi:10.1080/02656730701836962.
Source
scopus
Published In
International Journal of Hyperthermia : the Official Journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group
Volume
23
Issue
8
Publish Date
2007
Start Page
607
End Page
608
DOI
10.1080/02656730701836962

Low molecular weight catalytic metalloporphyrin antioxidant AEOL 10150 protects lungs from fractionated radiation.

The objective of this study was to determine whether administration of a catalytic antioxidant, Mn(III) tetrakis(N,N'-diethylimidazolium-2-yl) porphyrin, AEOL10150, reduces the severity of long-term lung injury induced by fractionated radiation (RT). Fisher 344 rats were randomized into five groups: RT+AEOL10150 (2.5 mg/kg BID), AEOL10150 (2.5 mg/kg BID) alone, RT+ AEOL10150 (5 mg/kg BID), AEOL10150 (5 mg/kg BID) alone and RT alone. Animals received five 8 Gy fractions of RT to the right hemithorax. AEOL10150 was administered 15 min before RT and 8 h later during the period of RT treatment (5 days), followed by subcutaneous injections for 30 days, twice daily. Lung histology at 26 weeks revealed a significant decrease in lung structural damage and collagen deposition in RT+AEOL10150 (5 mg/kg BID) group, in comparison to RT alone. Immunohistochemistry studies revealed a significant reduction in tissue hypoxia (HIF1alpha, CAIX), angiogenic response (VEGF, CD-31), inflammation (ED-1), oxidative stress (8-OHdG, 3-nitrotyrosine) and fibrosis pathway (TGFbeta1, Smad3, p-Smad2/3), in animals receiving RT+ AEOL10150 (5 mg/kg BID). Administration of AEOL10150 at 5 mg/kg BID during and after RT results in a significant protective effect from long-term RT-induced lung injury. Low dose (2.5 mg/kg BID) delivery of AEOL10150 has no beneficial radioprotective effects.

Authors
Rabbani, ZN; Salahuddin, FK; Yarmolenko, P; Batinic-Haberle, I; Thrasher, BA; Gauter-Fleckenstein, B; Dewhirst, MW; Anscher, MS; Vujaskovic, Z
MLA Citation
Rabbani, Zahid N., et al. “Low molecular weight catalytic metalloporphyrin antioxidant AEOL 10150 protects lungs from fractionated radiation..” Free Radic Res, vol. 41, no. 11, Nov. 2007, pp. 1273–82. Pubmed, doi:10.1080/10715760701689550.
PMID
17957541
Source
pubmed
Published In
Free Radical Research
Volume
41
Issue
11
Publish Date
2007
Start Page
1273
End Page
1282
DOI
10.1080/10715760701689550

Online feedback focusing algorithm for hyperthermia cancer treatment.

PURPOSE: Magnetic resonance (MR) imaging is increasingly being utilized to visualize the 3D temperature distribution in patients during treatment with hyperthermia or thermal ablation therapy. The goal of this work is to lay the foundation for improving the localization of heat in tumors with an online focusing algorithm that uses MR images as feedback to iteratively steer and focus heat into the target. METHODS: The algorithm iteratively updates the model that quantifies the relationship between the source (antenna) settings and resulting tissue temperature distribution. At each step in the iterative process, optimal settings of power and relative phase of each antenna are computed to maximize averaged tumor temperature in the model. The MR-measured thermal distribution is then used to update/correct the model. This iterative procedure is repeated until convergence, i.e. until the model prediction and MR thermal image are in agreement. A human thigh tumor model heated in a 140 MHz four-antenna cylindrical mini-annular phased array is used for numerical validation of the proposed algorithm. Numerically simulated temperatures are used during the iterative process as surrogates for MR thermal images. Gaussian white noise with a standard deviation of 0.3 degrees C and zero mean is added to simulate MRI measurement uncertainty. The algorithm is validated for cases where the source settings for the first iteration are based on erroneous models: (1) tissue property variability, (2) patient position mismatch, (3) a simple idealized patient model built from CT-based actual geometry, and (4) antenna excitation uncertainty due to load dependent impedance mismatch and antenna cross-coupling. Choices of starting heating vector are also validated. RESULTS: The algorithm successfully steers and focuses a tumor when there is no antenna excitation uncertainty. Temperature is raised to > or = 43 degrees C for more than about 90% of tumor volume, accompanied by less than about 20% of normal tissue volume being raised to a temperature > or = 41 degrees C. However, when there is antenna excitation uncertainty, about 40% to 80% of normal tissue volume is raised to a temperature > or = 41 degrees C. No significant tumor heating improvement is observed in all simulations after about 25 iteration steps. CONCLUSIONS: A feedback control algorithm is presented and shown to be successful in iteratively improving the focus of tissue heating within a four-antenna cylindrical phased array hyperthermia applicator. This algorithm appears to be robust in the presence of errors in assumed tissue properties, including realistic deviations of tissue properties and patient position in applicator. Only moderate robustness was achieved in the presence of misaligned applicator/tumor positioning and antenna excitation errors resulting from load mismatch or antenna cross coupling.

Authors
Cheng, K-S; Stakhursky, V; Stauffer, P; Dewhirst, M; Das, SK
MLA Citation
Cheng, Kung-Shan, et al. “Online feedback focusing algorithm for hyperthermia cancer treatment..” Int J Hyperthermia, vol. 23, no. 7, Nov. 2007, pp. 539–54. Pubmed, doi:10.1080/02656730701678877.
PMID
17943551
Source
pubmed
Published In
International Journal of Hyperthermia : the Official Journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group
Volume
23
Issue
7
Publish Date
2007
Start Page
539
End Page
554
DOI
10.1080/02656730701678877

International Phase III Trial of Chemoradiotherapy ± Hyperthermia for Locally Advanced Cervix Cancer: Interim Update on Toxicities

Authors
Jones, EL; Vujaskovic, Z; Craciunescu, O; Prosnitz, LR; Havrilesky, L; Secord, A; Stauffer, P; Dewhirst, MW
MLA Citation
Jones, E. L., et al. “International Phase III Trial of Chemoradiotherapy ± Hyperthermia for Locally Advanced Cervix Cancer: Interim Update on Toxicities.” International Journal of Radiation Oncology*Biology*Physics, vol. 69, no. 3, Elsevier BV, 2007, pp. S392–93. Crossref, doi:10.1016/j.ijrobp.2007.07.1513.
Source
crossref
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
69
Issue
3
Publish Date
2007
Start Page
S392
End Page
S393
DOI
10.1016/j.ijrobp.2007.07.1513

A 400 MHz hyperthermia system using rotating spiral antennas for uniform treatment of large superficial and sub-surface tumors

Numerous studies have shown that hyperthermia can significantly increase the tumor-killing effects of radiation therapy and/or chemotherapy. Superficial tumors are usually treated with waveguide-based systems operating at 915 MHz which do not heat evenly or deeply enough for typical disease that spreads below and across the skin surface. A 400MHz system that has been shown capable of treating somewhat larger and deeper volumes in previous animal and human clinical trials is investigated in this effort with the intent to further improve the technology. Real-time temperature, oxygen, and power reflection coefficient measurements are added for accurate control and deposition of the prescribed thermal dose while also assessing physiological response of the treated area. The hearing performance of three spiral antenna applicators is evaluated in two ways. First the power deposition pattern is simulated with Ansoft HFSS for a single stationary microstrip spiral applicator radiating into muscle tissue. Next the power deposition averaged over one cycle of rotation is simulated with Ansoft HFSS for a single asymmetrically rotated spiral, and for larger heating patterns an asymmetrically rotated two antenna spiral array. To verify the simulations, the power deposition pattern of the largest dual spiral scanning applicator was evaluated in a muscle equivalent tissue phantom using infrared imaging of a 'splitphantom' load and the results compared to the HFSS simulated patterns. The data show that these spiral antennas heat uniformly above 50% of the maximum heating rate just beyond the perimeter of the scanning or fixed spiral structure, producing for the largest dual spiral a 17cm diameter region at a depth of 3cm. The results of a previous human clinical trial using these spiral applicators is presented along with our plans to optimize the applicator in terms of real time control and extent of hearing based on new HFSS modeling and thermal analysis tools. © 2007 IEEE.

Authors
Arabe, OA; Maccarini, PF; Jones, EL; Hanna, G; Samulski, TV; Dewhirst, MW; Thrall, DE; Stauffer, PR
MLA Citation
Arabe, O. A., et al. “A 400 MHz hyperthermia system using rotating spiral antennas for uniform treatment of large superficial and sub-surface tumors.” Ieee Mtt S International Microwave Symposium Digest, Oct. 2007, pp. 1333–36. Scopus, doi:10.1109/MWSYM.2007.380458.
Source
scopus
Published In
2017 Ieee Mtt S International Microwave Symposium (Ims)
Publish Date
2007
Start Page
1333
End Page
1336
DOI
10.1109/MWSYM.2007.380458

Epinephrine-induced activation of LW-mediated sickle cell adhesion and vaso-occlusion in vivo.

Sickle red cell (SS RBC) adhesion is believed to contribute to the process of vaso-occlusion in sickle cell disease (SCD). We previously found that the LW RBC adhesion receptor can be activated by epinephrine to mediate SS RBC adhesion to endothelial alphavbeta3 integrin. To determine the contribution of LW activation to vaso-occlusive events in vivo, we investigated whether in vitro treatment of SS RBCs by epinephrine resulted in vaso-occlusion in intact microvasculature after RBC infusion into nude mice. Epinephrine enhanced human SS but not normal RBC adhesion to murine endothelial cells in vitro and to endothelium in vivo, promoting vaso-occlusion and RBC organ sequestration. Murine sickle RBCs also responded to epinephrine with increased adhesion to postcapillary endothelium in nude mice. Epinephrine-induced SS RBC adhesion, vaso-occlusion, and RBC organ trapping could be prevented by the beta-adrenergic receptor (beta-AR) antagonist, propranolol. Infusion of soluble recombinant LW also significantly reduced adhesion and vaso-occlusion. In addition, epinephrine-treated SS RBCs induced activation of murine leukocyte adhesion to endothelium as well. We conclude that LW activation by epinephrine via beta-AR stimulation can promote both SS RBC and leukocyte adhesion as well as vaso-occlusion, suggesting that both epinephrine and LW play potentially pathophysiological roles in SCD.

Authors
Zennadi, R; Moeller, BJ; Whalen, EJ; Batchvarova, M; Xu, K; Shan, S; Delahunty, M; Dewhirst, MW; Telen, MJ
MLA Citation
Zennadi, Rahima, et al. “Epinephrine-induced activation of LW-mediated sickle cell adhesion and vaso-occlusion in vivo..” Blood, vol. 110, no. 7, Oct. 2007, pp. 2708–17. Pubmed, doi:10.1182/blood-2006-11-056101.
PMID
17609430
Source
pubmed
Published In
Blood
Volume
110
Issue
7
Publish Date
2007
Start Page
2708
End Page
2717
DOI
10.1182/blood-2006-11-056101

Monitoring changes in the microenvironment during targeted therapies

Both antiangiogenic and vascular-targeted therapies hold great promise. The approval of some antiangiogenic agents in combination with other therapies bode well for the future clinical use of these agents. Similarly, the increased interest in vascular-targeting approaches shows potential, particularly when combined with radiotherapy and/or chemotherapy. In both of these approaches, however, it is imperative that suitable biomarkers be employed to monitor treatment effects and ensure optimal use. To achieve the highest efficacy of these treatment modalities, it may be mandatory to determine the response of antiangiogenic and antivascular compounds to ascertain an appropriate treatment schedule on an individualized basis (see Figure 1).

Authors
Wergin, M; Willett, CG; Dewhirst, MW
MLA Citation
Wergin, M., et al. “Monitoring changes in the microenvironment during targeted therapies.” Oncology, vol. 21, no. 11, Oct. 2007, pp. 1354–70.
Source
scopus
Published In
Oncology (Williston Park, N.Y.)
Volume
21
Issue
11
Publish Date
2007
Start Page
1354
End Page
1370

Corneal Angiogenesis Assay

New vessel growth in the avascular and transparent cornea occurs under a variety of pathological conditions and is readily distinguishable. Therefore, the corneal neovascularization (CNV) assay has become a widely used in vivo model for angiogenesis research. Many techniques, including chemical cauterization and mechanical manipulations have been developed. This chapter describes the background, physiology, induction techniques and image analysis of CNV with emphasis on the most frequently applied micropocket assay. In this assay, angiogenesis is induced by placing a polymer pellet containing an angiogenic factor, such as bFGF, into a surgically created stromal pocket and allowing for its sustained release. A putative anti- or pro-angiogenic substance is incorporated into the pellet, or given locally or systemically. The degree of suppression or enhancement of angiogenesis is quantified by image analysis. CNV assay offers a quantitable and precise means of screening for angiogenesis inhibitors, but also has limitations. It is desirable to combine CNV with other in vivo assays to investigate angiogenesis. © 2006 John Wiley & Sons, Ltd.

Authors
Shan, S; Dewhirst, MW
MLA Citation
Shan, S., and M. W. Dewhirst. Corneal Angiogenesis Assay. Sept. 2007, pp. 203–28. Scopus, doi:10.1002/9780470029350.ch11.
Source
scopus
Publish Date
2007
Start Page
203
End Page
228
DOI
10.1002/9780470029350.ch11

Treatment with imatinib improves drug delivery and efficacy in NSCLC xenografts.

Imatinib, an inhibitor of PDGF-Rbeta and other tyrosine kinase receptors, has been shown to decrease microvessel density and interstitial fluid pressure in solid tumours, thereby improving subsequent delivery of small molecules. The purpose of this study was to test whether pretreatment with imatinib increases the efficacy of traditional chemotherapy in mice bearing non-small cell lung carcinoma xenografts, and to investigate the effects of imatinib on liposomal drug delivery. Efficacy treatment groups included (n=9-10): saline control, imatinib alone (oral gavage, 100 mg kg(-1) x 7 days), docetaxel alone (10 mg kg(-1) i.p. 2 x /week until killing), and imatinib plus docetaxel (started on day 7 of imatinib). Tumours were monitored until they reached four times the initial treatment volume (4 x V) or 28 days. A separate experiment compared tumour doxorubicin concentrations (using high performance liquid chromatography) 24 h after treatment with liposomal doxorubicin alone (6 mg kg(-1) i.v., n=9) or imatinib plus liposomal doxorubicin (n=16). Imatinib plus docetaxel resulted in significantly improved antitumour efficacy (0/10 animals reached 4 x V by 28 days) when compared to docetaxel alone (3/9 reached 4 x V, P=0.014) or imatinib alone (9/10 reached 4 x V, P=0.025). Pretreatment with imatinib also significantly increased tumour concentrations of liposomal doxorubicin. Overall, these preclinical studies emphasise the potential of imatinib as an adjunct to small molecule or liposomal chemotherapy.

Authors
Vlahovic, G; Ponce, AM; Rabbani, Z; Salahuddin, FK; Zgonjanin, L; Spasojevic, I; Vujaskovic, Z; Dewhirst, MW
MLA Citation
Vlahovic, G., et al. “Treatment with imatinib improves drug delivery and efficacy in NSCLC xenografts..” Br J Cancer, vol. 97, no. 6, Sept. 2007, pp. 735–40. Pubmed, doi:10.1038/sj.bjc.6603941.
PMID
17712313
Source
pubmed
Published In
British Journal of Cancer
Volume
97
Issue
6
Publish Date
2007
Start Page
735
End Page
740
DOI
10.1038/sj.bjc.6603941

Radiation and a metalloporphyrin radioprotectant in a mouse prostate tumor model

Background: Antioxidants have the potential to protect normal tissues against radiation-induced damage, but must not protect tumor cells during radiotherapy. The major objectives were to determine whether a metalloporphyrin antioxidant affects prostate tumor response to radiation and identify possible mechanisms of interaction. Materials and Methods: C57BL/6 mice with RM-9 tumor were treated with manganese (III) meso-tetrakis(1,3-diethylimidazolium-2-yl) porphyrin (MnTDE-2-ImP) and 10 gray (Gy) radiation. Tumor volume was quantified and a subset/group was evaluated for hypoxia-inducible factor-1α (HIF-1α), bone marrow-derived cell populations and cytokines. Results: The addition of MnTDE-2-ImP transiently increased tumor response compared to radiation alone. The group receiving drug plus radiation had reduced intratumoral HIF-1α and decreased capacity to secrete TNF-α, whereas production of IL-4 was increased. There were no toxicities associated with combination treatment. Conclusion: The results demonstrate that MnTDE-2-ImP did not protect the RM-9 prostate tumor against radiation; instead, radiation effectiveness was modestly increased. Possible mechanisms include reduction of radiation-induced HIF-1α and an altered cytokine profile.

Authors
Gridley, DS; Makinde, AY; Luo, X; Rizvi, A; Crapo, JD; Dewhirst, MW; Moeller, BJ; Pearlstein, RD; Slater, JM
MLA Citation
Gridley, D. S., et al. “Radiation and a metalloporphyrin radioprotectant in a mouse prostate tumor model.” Anticancer Research, vol. 27, no. 5 A, Sept. 2007, pp. 3101–09.
Source
scopus
Published In
Anticancer Research
Volume
27
Issue
5 A
Publish Date
2007
Start Page
3101
End Page
3109

Radiation and a metalloporphyrin radioprotectant in a mouse prostate tumor model.

BACKGROUND: Antioxidants have the potential to protect normal tissues against radiation-induced damage, but must not protect tumor cells during radiotherapy. The major objectives were to determine whether a metalloporphyrin antioxidant affects prostate tumor response to radiation and identify possible mechanisms of interaction. MATERIALS AND METHODS: C57BL/6 mice with RM-9 tumor were treated with manganese (III) meso-tetrakis (1,3-diethylimidazolium-2-yl) porphyrin (MnTDE-2-ImP) and 10 gray (Gy) radiation. Tumor volume was quantified and a subset/group was evaluated for hypoxia-inducible factor-1alpha (HIF-1alpha), bone marrow-derived cell populations and cytokines. RESULTS: The addition of MnTDE-2-ImP transiently increased tumor response compared to radiation alone. The group receiving drug plus radiation had reduced intratumoral HIF-1alpha and decreased capacity to secrete TNF-alpha, whereas production of IL-4 was increased. There were no toxicities associated with combination treatment. CONCLUSION: The results demonstrate that MnTDE-2-ImP did not protect the RM-9 prostate tumor against radiation; instead, radiation effectiveness was modestly increased. Possible mechanisms include reduction of radiation-induced HIF-1alpha and an altered cytokine profile.

Authors
Gridley, DS; Makinde, AY; Luo, X; Rizvi, A; Crapo, JD; Dewhirst, MW; Moeller, BJ; Pearlstein, RD; Slater, JM
MLA Citation
Gridley, Daila S., et al. “Radiation and a metalloporphyrin radioprotectant in a mouse prostate tumor model..” Anticancer Res, vol. 27, no. 5A, Sept. 2007, pp. 3101–09.
PMID
17970050
Source
pubmed
Published In
Anticancer Research
Volume
27
Issue
5A
Publish Date
2007
Start Page
3101
End Page
3109

The potential role of intrinsic hypoxia markers as prognostic variables in cancer.

Tumor hypoxia is related to tumor progression and therapy resistance, which leads to poor patient outcome. It has been suggested that measuring the hypoxic status of a tumor helps to predict patient outcome and to select more targeted treatment. However, current methods using needle electrodes or exogenous markers have limitations due to their invasiveness or necessity for preinjection. Recent studies showed that hypoxia-regulated genes could be alternatively used as endogenous hypoxia markers. This is a review of 15 hypoxia-regulated genes, including hypoxia-inducible factor-1 and its targets, and their correlation with tumor hypoxia and patient outcome from 213 studies. Though most of the studies showed significance of these genes in predicting prognosis, there was no definitive prognostic and hypoxia marker. In conclusion, this review suggests the need for further studies with standardized methods to examine gene expression, as well as the use of multiple gene expressions.

Authors
Moon, EJ; Brizel, DM; Chi, J-TA; Dewhirst, MW
MLA Citation
Moon, Eui Jung, et al. “The potential role of intrinsic hypoxia markers as prognostic variables in cancer..” Antioxid Redox Signal, vol. 9, no. 8, Aug. 2007, pp. 1237–94. Pubmed, doi:10.1089/ars.2007.1623.
PMID
17571959
Source
pubmed
Published In
Antioxidants & Redox Signaling
Volume
9
Issue
8
Publish Date
2007
Start Page
1237
End Page
1294
DOI
10.1089/ars.2007.1623

An in vitro system to evaluate the effects of ischemia on survival of cells used for cell therapy.

Maintaining cell viability is a major challenge associated with transplanting cells into ischemic myocardium to restore function. A likely contributor to significant cell death during cardiac cell therapy is hypoxia/anoxia. We developed a system that enabled quantification and association of cell survival with oxygen and nutrient values within in vitro constructs. Myoblasts were suspended in 2% collagen gels in 1 cm diameter x 1 cm deep constructs. At 48 +/- 3 h post-seeding, oxygen levels were measured using microelectrodes and gels were snap-frozen. Bioluminescence metabolite imaging and TUNEL staining were performed on cryosections. Oxygen and glucose consumption and lactate production rates were calculated by fitting data to Fick's second law of diffusion with Michaelis-Menten kinetics. Oxygen levels dropped to 0 mmHg and glucose levels dropped from 4.28 to 3.18 mM within the first 2000 mum of construct depth. Cell viability dropped to approximately 40% over that same distance and continued to drop further into the construct. We believe this system provides a reproducible and controllable test bed to compare survival, proliferation, and phenotype of various cell inputs (e.g., myoblasts, mesenchymal stem cells, and cardiac stem cells) and the impact of different treatment regimens on the likelihood of survival of transplanted cells.

Authors
Davis, BH; Schroeder, T; Yarmolenko, PS; Guilak, F; Dewhirst, MW; Taylor, DA
MLA Citation
Davis, Bryce H., et al. “An in vitro system to evaluate the effects of ischemia on survival of cells used for cell therapy..” Ann Biomed Eng, vol. 35, no. 8, Aug. 2007, pp. 1414–24. Pubmed, doi:10.1007/s10439-007-9301-2.
PMID
17417737
Source
pubmed
Published In
Annals of Biomedical Engineering
Volume
35
Issue
8
Publish Date
2007
Start Page
1414
End Page
1424
DOI
10.1007/s10439-007-9301-2

Predicting lung radiotherapy-induced pneumonitis using a model combining parametric Lyman probit with nonparametric decision trees.

PURPOSE: To develop and test a model to predict for lung radiation-induced Grade 2+ pneumonitis. METHODS AND MATERIALS: The model was built from a database of 234 lung cancer patients treated with radiotherapy (RT), of whom 43 were diagnosed with pneumonitis. The model augmented the predictive capability of the parametric dose-based Lyman normal tissue complication probability (LNTCP) metric by combining it with weighted nonparametric decision trees that use dose and nondose inputs. The decision trees were sequentially added to the model using a "boosting" process that enhances the accuracy of prediction. The model's predictive capability was estimated by 10-fold cross-validation. To facilitate dissemination, the cross-validation result was used to extract a simplified approximation to the complicated model architecture created by boosting. Application of the simplified model is demonstrated in two example cases. RESULTS: The area under the model receiver operating characteristics curve for cross-validation was 0.72, a significant improvement over the LNTCP area of 0.63 (p = 0.005). The simplified model used the following variables to output a measure of injury: LNTCP, gender, histologic type, chemotherapy schedule, and treatment schedule. For a given patient RT plan, injury prediction was highest for the combination of pre-RT chemotherapy, once-daily treatment, female gender and lowest for the combination of no pre-RT chemotherapy and nonsquamous cell histologic type. Application of the simplified model to the example cases revealed that injury prediction for a given treatment plan can range from very low to very high, depending on the settings of the nondose variables. CONCLUSIONS: Radiation pneumonitis prediction was significantly enhanced by decision trees that added the influence of nondose factors to the LNTCP formulation.

Authors
Das, SK; Zhou, S; Zhang, J; Yin, F-F; Dewhirst, MW; Marks, LB
MLA Citation
Das, Shiva K., et al. “Predicting lung radiotherapy-induced pneumonitis using a model combining parametric Lyman probit with nonparametric decision trees..” Int J Radiat Oncol Biol Phys, vol. 68, no. 4, July 2007, pp. 1212–21. Pubmed, doi:10.1016/j.ijrobp.2007.03.064.
PMID
17637394
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
68
Issue
4
Publish Date
2007
Start Page
1212
End Page
1221
DOI
10.1016/j.ijrobp.2007.03.064

Self-consistent tumor control probability and normal tissue complication probability models based on generalized EUD.

Traditional methods to compute the tumor control probability (TCP) or normal tissue complication probability (NTCP) typically require a heterogeneous radiation dose distribution to be converted into a simple uniform dose distribution with an equivalent biological effect. Several power-law type dose-volume-histogram reduction schemes, particularly Niemierko's generalized equivalent uniform dose model [Med. Phys. 26, 1000 (1999)], have been proposed to achieve this goal. In this study, we carefully examine the mathematical outcome of these schemes. We demonstrate that (1) for tumors, with each tumor cell independently responding to local radiation dose, a closed-form analytical solution for tumor survival fraction and TCP can be obtained; (2) for serial structured normal tissues, an exponential power-law form relating survival to functional sub-unit (FSU) radiation is required, and a closed-form analytical solution for the related NTCP is provided; (3) in the case of a parallel structured normal tissue, when NTCP is determined solely by the number of the surviving FSUs, a mathematical solution is available only when there is a non-zero threshold dose and/or a finite critical dose defining the radiotherapy response. Some discussion is offered for the partial irradiation effect on normal tissues in this category; (4) for normal tissues with alternative architectures, where the radiation response of FSU is inhomogeneous, there is no exact global mathematical solution for SF or NTCP within the available schemes. Finally, numerical fits of our models to some experimental data are also presented.

Authors
Zhou, S-M; Das, SK; Wang, Z; Sun, X; Dewhirst, M; Yin, F-F; Marks, LB
MLA Citation
Zhou, Su-Min, et al. “Self-consistent tumor control probability and normal tissue complication probability models based on generalized EUD..” Med Phys, vol. 34, no. 7, July 2007, pp. 2807–15. Pubmed, doi:10.1118/1.2740010.
PMID
17821988
Source
pubmed
Published In
Medical Physics
Volume
34
Issue
7
Publish Date
2007
Start Page
2807
End Page
2815
DOI
10.1118/1.2740010

A note from the Editor-in-Chief

Authors
Dewhirst, MW
MLA Citation
Dewhirst, M. W. “A note from the Editor-in-Chief.” International Journal of Hyperthermia, vol. 23, no. 1, June 2007, pp. 1–2. Scopus, doi:10.1080/02656730601161651.
Source
scopus
Published In
International Journal of Hyperthermia : the Official Journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group
Volume
23
Issue
1
Publish Date
2007
Start Page
1
End Page
2
DOI
10.1080/02656730601161651

Erythropoietin blockade inhibits the induction of tumor angiogenesis and progression.

BACKGROUND: The induction of tumor angiogenesis, a pathologic process critical for tumor progression, is mediated by multiple regulatory factors released by tumor and host cells. We investigated the role of the hematopoietic cytokine erythropoietin as an angiogenic factor that modulates tumor progression. METHODOLOGY/PRINCIPAL FINDINGS: Fluorescently-labeled rodent mammary carcinoma cells were injected into dorsal skin-fold window chambers in mice, an angiogenesis model that allows direct, non-invasive, serial visualization and real-time assessment of tumor cells and neovascularization simultaneously using intravital microscopy and computerized image analysis during the initial stages of tumorigenesis. Erythropoietin or its antagonist proteins were co-injected with tumor cells into window chambers. In vivo growth of cells engineered to stably express a constitutively active erythropoietin receptor EPOR-R129C or the erythropoietin antagonist R103A-EPO were analyzed in window chambers and in the mammary fat pads of athymic nude mice. Co-injection of erythropoietin with tumor cells or expression of EPOR-R129C in tumor cells significantly stimulated tumor neovascularization and growth in window chambers. Co-injection of erythropoietin antagonist proteins (soluble EPOR or anti-EPO antibody) with tumor cells or stable expression of antagonist R103A-EPO protein secreted from tumor cells inhibited angiogenesis and impaired tumor growth. In orthotopic tumor xenograft studies, EPOR-R129C expression significantly promoted tumor growth associated with increased expression of Ki67 proliferation antigen, enhanced microvessel density, decreased tumor hypoxia, and increased phosphorylation of extracellular-regulated kinases ERK1/2. R103A-EPO antagonist expression in mammary carcinoma cells was associated with near-complete disruption of primary tumor formation in the mammary fat pad. CONCLUSIONS/SIGNIFICANCE: These data indicate that erythropoietin is an important angiogenic factor that regulates the induction of tumor cell-induced neovascularization and growth during the initial stages of tumorigenesis. The suppression of tumor angiogenesis and progression by erythropoietin blockade suggests that erythropoietin may constitute a potential target for the therapeutic modulation of angiogenesis in cancer.

Authors
Hardee, ME; Cao, Y; Fu, P; Jiang, X; Zhao, Y; Rabbani, ZN; Vujaskovic, Z; Dewhirst, MW; Arcasoy, MO
MLA Citation
Hardee, Matthew E., et al. “Erythropoietin blockade inhibits the induction of tumor angiogenesis and progression..” Plos One, vol. 2, no. 6, June 2007. Pubmed, doi:10.1371/journal.pone.0000549.
PMID
17579721
Source
pubmed
Published In
Plos One
Volume
2
Issue
6
Publish Date
2007
Start Page
e549
DOI
10.1371/journal.pone.0000549

Requirements for T lymphocyte migration in explanted lymph nodes.

Although the requirements for T lymphocyte homing to lymph nodes (LNs) are well studied, much less is known about the requirements for T lymphocyte locomotion within LNs. Imaging of murine T lymphocyte migration in explanted LNs using two-photon laser-scanning fluorescence microscopy provides an opportunity to systematically study these requirements. We have developed a closed system for imaging an intact LN with controlled temperature, oxygenation, and perfusion rate. Naive T lymphocyte locomotion in the deep paracortex of the LN required a perfusion rate of >13 microm/s and a partial pressure of O(2) (pO(2)) of >7.4%. Naive T lymphocyte locomotion in the subcapsular region was 38% slower and had higher turning angles and arrest coefficients than naive T lymphocytes in the deep paracortex. T lymphocyte activation decreased the requirement for pO(2), but also decreased the speed of locomotion in the deep paracortex. Although CCR7(-/-) naive T cells displayed a small reduction in locomotion, systemic treatment with pertussis toxin reduced naive T lymphocyte speed by 59%, indicating a contribution of Galpha(i)-mediated signaling, but involvement of other G protein-coupled receptors besides CCR7. Receptor knockouts or pharmacological inhibition in the adenosine, PG/lipoxygenase, lysophosphatidylcholine, and sphingosine-1-phosphate pathways did not individually alter naive T cell migration. These data implicate pO(2), tissue architecture, and G-protein coupled receptor signaling in regulation of naive T lymphocyte migration in explanted LNs.

Authors
Huang, JH; Cárdenas-Navia, LI; Caldwell, CC; Plumb, TJ; Radu, CG; Rocha, PN; Wilder, T; Bromberg, JS; Cronstein, BN; Sitkovsky, M; Dewhirst, MW; Dustin, ML
MLA Citation
Huang, Julie H., et al. “Requirements for T lymphocyte migration in explanted lymph nodes..” J Immunol, vol. 178, no. 12, June 2007, pp. 7747–55. Pubmed, doi:10.4049/jimmunol.178.12.7747.
PMID
17548612
Source
pubmed
Published In
The Journal of Immunology
Volume
178
Issue
12
Publish Date
2007
Start Page
7747
End Page
7755
DOI
10.4049/jimmunol.178.12.7747

Hyperthermia in the treatment of gynecologic cancer: A review of the cervix cancer experience

Authors
Jones, EL; Vujaskovic, Z; Dewhirst, MW
MLA Citation
Jones, E. L., et al. “Hyperthermia in the treatment of gynecologic cancer: A review of the cervix cancer experience.” Strahlentherapie Und Onkologie, vol. 183, URBAN & VOGEL, 2007, pp. 152–152.
Source
wos
Published In
Strahlentherapie Und Onkologie
Volume
183
Publish Date
2007
Start Page
152
End Page
152

Hypoxia and radiotherapy: opportunities for improved outcomes in cancer treatment.

A large body of clinical evidence exists to suggest that tumor hypoxia negatively impacts radiotherapy. As a result, there has been longstanding active research into novel methods of improving tumor oxygenation, targeting hypoxic tumor cells, and otherwise modulating the effect hypoxia has on how tumors respond to radiation. Over time, as more has been learned about the many ways hypoxia affects tumors, our understanding of the mechanisms connecting hypoxia to radiosensitivity has become increasingly broad and complicated. This has opened up new potential avenues for interrupting hypoxia's negative effects on tumor radiosensitivity. Here, we will review what is currently known about the spectrum of influence hypoxia has over the way tumors respond to radiation. Particular focus will be placed on recent discoveries suggesting that hypoxia-inducible factor-1 (HIF-1), a transcription factor that upregulates its target genes under hypoxic conditions, plays a major role in determining tumor radiosensitivity. HIF-1 and/or its target genes may represent therapeutic targets which could be manipulated to influence hypoxia's impact on tumor radiosensitivity.

Authors
Moeller, BJ; Richardson, RA; Dewhirst, MW
MLA Citation
Moeller, Benjamin J., et al. “Hypoxia and radiotherapy: opportunities for improved outcomes in cancer treatment..” Cancer Metastasis Rev, vol. 26, no. 2, June 2007, pp. 241–48. Pubmed, doi:10.1007/s10555-007-9056-0.
PMID
17440683
Source
pubmed
Published In
Cancer Metastasis Reviews
Volume
26
Issue
2
Publish Date
2007
Start Page
241
End Page
248
DOI
10.1007/s10555-007-9056-0

In memoriam: Edward L Gillette (1932-2006).

Authors
Dewhirst, MW
MLA Citation
Dewhirst, Mark W. “In memoriam: Edward L Gillette (1932-2006)..” Radiat Res, vol. 167, no. 6, June 2007, pp. 745–47. Pubmed, doi:10.1667/RRXX01.1.
PMID
17523854
Source
pubmed
Published In
Radiation Research
Volume
167
Issue
6
Publish Date
2007
Start Page
745
End Page
747
DOI
10.1667/RRXX01.1

Exploring the role of HIF-1 in early angiogenesis and response to radiotherapy.

The objective of this review is to examine the role that HIF-1 plays in the initiation of angiogenesis and in radiotherapy response. Although these two phenomena may at first seem unrelated, there are parallelisms to be drawn associated with the importance of reactive oxygen species in controlling the transcriptional activity of HIF-1, independently of its main driving force, hypoxia. Knowledge of the mechanisms underlying the control of HIF-1 leads to rationale for its inhibition in a range of clinical scenarios.

Authors
Dewhirst, MW; Cao, Y; Li, CY; Moeller, B
MLA Citation
Dewhirst, Mark W., et al. “Exploring the role of HIF-1 in early angiogenesis and response to radiotherapy..” Radiother Oncol, vol. 83, no. 3, June 2007, pp. 249–55. Pubmed, doi:10.1016/j.radonc.2007.05.016.
PMID
17560674
Source
pubmed
Published In
Radiotherapy and Oncology
Volume
83
Issue
3
Publish Date
2007
Start Page
249
End Page
255
DOI
10.1016/j.radonc.2007.05.016

Angiostatin-like activity of a monoclonal antibody to the catalytic subunit of F1F0 ATP synthase.

The antiangiogenic protein angiostatin inhibits ATP synthase on the endothelial cell surface, blocking cellular proliferation. To examine the specificity of this interaction, we generated monoclonal antibodies (mAb) directed against ATP synthase. mAb directed against the beta-catalytic subunit of ATP synthase (MAb3D5AB1) inhibits the activity of the F(1) domain of ATP synthase and recognizes the catalytic beta-subunit of ATP synthase. We located the antibody recognition site of MAb3D5AB1 in domains containing the active site of the beta-subunit. MAb3D5AB1 also binds to purified Escherichia coli F(1) with an affinity 25-fold higher than the affinity of angiostatin for this protein. MAb3D5AB1 inhibits the hydrolytic activity of F(1) ATP synthase at lower concentrations than angiostatin. Like angiostatin, MAb3D5AB1 inhibits ATP generation by ATP synthase on the endothelial cell surface in acidic conditions, the typical tumor microenvironment where cell surface ATP synthase exhibits greater activity. MAb3D5AB1 disrupts tube formation and decreases intracellular pH in endothelial cells exposed to low extracellular pH. Neither angiostatin nor MAb3D5AB1 showed an antiangiogenic effect in the corneal neovascularization assay; however, both were effective in the low-pH environment of the chicken chorioallantoic membrane assay. Thus, MAb3D5AB1 shows angiostatin-like properties superior to angiostatin and may be exploited in cancer chemotherapy.

Authors
Chi, SL; Wahl, ML; Mowery, YM; Shan, S; Mukhopadhyay, S; Hilderbrand, SC; Kenan, DJ; Lipes, BD; Johnson, CE; Marusich, MF; Capaldi, RA; Dewhirst, MW; Pizzo, SV
MLA Citation
Chi, Sulene L., et al. “Angiostatin-like activity of a monoclonal antibody to the catalytic subunit of F1F0 ATP synthase..” Cancer Res, vol. 67, no. 10, May 2007, pp. 4716–24. Pubmed, doi:10.1158/0008-5472.CAN-06-1094.
PMID
17510399
Source
pubmed
Published In
Cancer Research
Volume
67
Issue
10
Publish Date
2007
Start Page
4716
End Page
4724
DOI
10.1158/0008-5472.CAN-06-1094

Thermal cycling enhances the accumulation of a temperature-sensitive biopolymer in solid tumors.

The delivery of anticancer therapeutics to solid tumors remains a critical problem in the treatment of cancer. This study reports a new methodology to target a temperature-responsive macromolecular drug carrier, an elastin-like polypeptide (ELP) to solid tumors. Using a dorsal skin fold window chamber model and intravital laser scanning confocal microscopy, we show that the ELP forms micron-sized aggregates that adhere to the tumor vasculature only when tumors are heated to 41.5 degrees C. Upon return to normothermia, the vascular particles dissolve into the plasma, increasing the vascular concentration, which drives more ELPs across the tumor blood vessel and significantly increases its extravascular accumulation. These observations suggested that thermal cycling of tumors would increase the exposure of tumor cells to ELP drug carriers. We investigated this hypothesis in this study by thermally cycling an implanted tumor in nude mice from body temperature to 41.5 degrees C thrice within 1.5 h, and showed the repeated formation of adherent microparticles of ELP in the heated tumor vasculature in each thermal cycle. These results suggest that thermal cycling of tumors can be repeated multiple times to further increase the accumulation of a thermally responsive polymeric drug carrier in solid tumors over a single heat-cool cycle. More broadly, this study shows a new approach--tumor thermal cycling--to exploit stimuli-responsive polymers in vivo to target the tumor vasculature or extravascular compartment with high specificity.

Authors
Dreher, MR; Liu, W; Michelich, CR; Dewhirst, MW; Chilkoti, A
MLA Citation
Dreher, Matthew R., et al. “Thermal cycling enhances the accumulation of a temperature-sensitive biopolymer in solid tumors..” Cancer Res, vol. 67, no. 9, May 2007, pp. 4418–24. Pubmed, doi:10.1158/0008-5472.CAN-06-4444.
PMID
17483356
Source
pubmed
Published In
Cancer Research
Volume
67
Issue
9
Publish Date
2007
Start Page
4418
End Page
4424
DOI
10.1158/0008-5472.CAN-06-4444

Targeting the molecular effects of a hypoxic tumor microenvironment.

Tumor hypoxia is a serious and enduring problem for traditional solid tumor therapies. Many scientists continue to explore methods to improve or exploit tumor oxygenation; more recently, scientists have also focused on altering the molecular effects of hypoxia. These cellular responses to hypoxia and the resulting physiological effects, with a focus on angiogenesis, invasion/metastases, apoptosis, and metabolism, are examined. Recent efforts to mitigate or exploit these molecular pathways alone and in conjunction with traditional therapies are also explored. Current experimental results suggest that targeting multiple downstream molecular pathways of hypoxia will be more effective than targeting a single molecular pathway of hypoxia, and careful planning is necessary in scheduling these new therapies to optimize their effects in combination with traditional therapies.

Authors
Cardenas-Navia, LI; Richardson, RA; Dewhirst, MW
MLA Citation
Cardenas-Navia, L. Isabel, et al. “Targeting the molecular effects of a hypoxic tumor microenvironment..” Front Biosci, vol. 12, May 2007, pp. 4061–78.
PMID
17485359
Source
pubmed
Published In
Frontiers in Bioscience : a Journal and Virtual Library
Volume
12
Publish Date
2007
Start Page
4061
End Page
4078

Functional imaging in bulk tissue specimens using optical emission tomography: fluorescence preservation during optical clearing.

Optical emission computed tomography (optical-ECT) is a technique for imaging the three-dimensional (3D) distribution of fluorescent probes in biological tissue specimens with high contrast and spatial resolution. In optical-ECT, functional information can be imaged by (i) systemic application of functional labels (e.g. fluorophore labelled proteins) and/or (ii) endogenous expression of fluorescent reporter proteins (e.g. red fluorescent protein (RFP), green fluorescent protein (GFP)) in vivo. An essential prerequisite for optical-ECT is optical clearing, a procedure where tissue specimens are made transparent to light by sequential perfusion with fixing, dehydrating and clearing agents. In this study, we investigate clearing protocols involving a selection of common fixing (4% buffered paraformaldehyde (PFA), methanol and ethanol), dehydrating (methanol and ethanol) and clearing agents (methyl salicylate and benzyl-alcohol-benzyl-benzoate (BABB)) in order to determine a 'fluorescence friendly' clearing procedure. Cell culture experiments were employed to optimize the sequence of chemical treatments that best preserve fluorescence. Texas red (TxRed), fluorescein isothiocyanate (FITC), RFP and GFP were tested as fluorophores and fluorescent reporter proteins of interest. Fluorescent and control cells were imaged on a microscope using a DSred2 and FITC filter set. The most promising clearing protocols of cell culture experiments were applied to whole xenograft tumour specimens, to test their effectiveness in large unsectioned samples. Fluorescence of TxRed/FITC fluorophores was not found to be significantly affected by any of the test clearing protocols. RFP and GFP fluorescence, however, was found to be significantly greater when cell fixation was in ethanol. Fixation in either PFA or methanol resulted in diminished fluorescence. After ethanol fixation, the RFP and GFP fluorescence proved remarkably robust to subsequent exposure to either methyl salicylate or BABB. The optimized optical clearing procedure of ethanol fixation followed by methyl salicylate clearing preserved the fluorescence of constitutive RFP in whole xenograft tumour specimens, about 1 cc in dimension, indicating successful extension from cell plating experiments to whole tissue samples. Finally, the feasibility of imaging the 3D distribution of viable tumour cells (as indicated by the RFP emission) is demonstrated by optical-ECT imaging of cleared xenograft tumours using an in-house system.

Authors
Sakhalkar, HS; Dewhirst, M; Oliver, T; Cao, Y; Oldham, M
MLA Citation
Sakhalkar, H. S., et al. “Functional imaging in bulk tissue specimens using optical emission tomography: fluorescence preservation during optical clearing..” Phys Med Biol, vol. 52, no. 8, Apr. 2007, pp. 2035–54. Pubmed, doi:10.1088/0031-9155/52/8/001.
PMID
17404454
Source
pubmed
Published In
Physics in Medicine and Biology
Volume
52
Issue
8
Publish Date
2007
Start Page
2035
End Page
2054
DOI
10.1088/0031-9155/52/8/001

Systemic overexpression of angiopoietin-2 promotes tumor microvessel regression and inhibits angiogenesis and tumor growth.

Angiopoietin-2 (Ang-2) is a conditional antagonist and agonist for the endothelium-specific Tie-2 receptor. Although endogenous Ang-2 cooperates with vascular endothelial growth factor (VEGF) to protect tumor endothelial cells, the effect on tumor vasculature of high levels of exogenous Ang-2 with different levels of VEGF has not been studied in detail. Here, we report that systemic overexpression of Ang-2 leads to unexpected massive tumor vessel regression within 24 h, even without concomitant inhibition of VEGF. By impairing pericyte coverage of the tumor vasculature, Ang-2 destabilizes the tumor vascular bed while improving perfusion in surviving tumor vessels. Ang-2 overexpression transiently exacerbates tumor hypoxia without affecting ATP levels. Although sustained systemic Ang-2 overexpression does not affect tumor hypoxia and proliferation, it significantly inhibits tumor angiogenesis, promotes tumor apoptosis, and suppresses tumor growth. The similar antitumoral, antiangiogenic efficacy of systemic overexpression of Ang-2, soluble VEGF receptor-1, and the combination of both suggests that concomitant VEGF inhibition is not required for Ang-2-induced tumor vessel regression and growth delay. This study shows the important roles of Ang-2-induced pericyte dropout during tumor vessel regression. It also reveals that elevated Ang-2 levels have profound pleiotropic effects on tumor vessel structure, perfusion, oxygenation, and apoptosis.

Authors
Cao, Y; Sonveaux, P; Liu, S; Zhao, Y; Mi, J; Clary, BM; Li, C-Y; Kontos, CD; Dewhirst, MW
MLA Citation
Cao, Yiting, et al. “Systemic overexpression of angiopoietin-2 promotes tumor microvessel regression and inhibits angiogenesis and tumor growth..” Cancer Res, vol. 67, no. 8, Apr. 2007, pp. 3835–44. Pubmed, doi:10.1158/0008-5472.CAN-06-4056.
PMID
17440098
Source
pubmed
Published In
Cancer Research
Volume
67
Issue
8
Publish Date
2007
Start Page
3835
End Page
3844
DOI
10.1158/0008-5472.CAN-06-4056

Regulation of HIF-1alpha stability through S-nitrosylation.

Hypoxia-inducible factor 1 (HIF-1) is a master transcriptional factor. Under normal oxygen tension, HIF-1 activity is usually suppressed due to the rapid, oxygen-dependent degradation of one of its two subunits, HIF-1alpha. Here we report that normoxic HIF-1 activity can be upregulated through NO-mediated S-nitrosylation and stabilization of HIF-1alpha. In murine tumors, exposure to ionizing radiation stimulated the generation of NO in tumor-associated macrophages. As a result, the HIF-1alpha protein is S-nitrosylated at Cys533 (through "biotin switch" assay) in the oxygen-dependent degradation domain, which prevents its destruction. Importantly, this mechanism appears to be independent of the prolylhydroxylase-based pathway that is involved in oxygen-dependent regulation of HIF-1alpha. Selective disruption of this S-nitrosylation significantly attenuated both radiation-induced and macrophage-induced activation of HIF-1alpha. This interaction between NO and HIF-1 sheds new light on their involvement in tumor response to treatment as well as mammalian inflammation process in general.

Authors
Li, F; Sonveaux, P; Rabbani, ZN; Liu, S; Yan, B; Huang, Q; Vujaskovic, Z; Dewhirst, MW; Li, C-Y
MLA Citation
Li, Fang, et al. “Regulation of HIF-1alpha stability through S-nitrosylation..” Mol Cell, vol. 26, no. 1, Apr. 2007, pp. 63–74. Pubmed, doi:10.1016/j.molcel.2007.02.024.
PMID
17434127
Source
pubmed
Published In
Molecular Cell
Volume
26
Issue
1
Publish Date
2007
Start Page
63
End Page
74
DOI
10.1016/j.molcel.2007.02.024

Effects of fluctuating oxygenation on tirapazamine efficacy: Theoretical predictions.

PURPOSE: To examine the effects of fluctuating oxygen levels on the hypoxic cytotoxin tirapazamine (TPZ) using theoretical predictions. METHODS AND MATERIALS: Tirapazamine's pharmacokinetic and pharmacodynamic oxygen dependence has previously been characterized in vitro. Here, a one-dimensional theoretical model was used to examine the effects of fluctuating hypoxia on metabolized TPZ concentration, assuming sinusoidally fluctuating oxygen levels. TPZ concentration is changing according to published experimental data. Simulations of experimentally observed time-courses of perivascular pO2 were also conducted. RESULTS: The predicted pharmacodynamic effect of TPZ was increased with fluctuating (vs. constant) hypoxia at all frequencies (1-30 min period) and all amplitudes (1-15 mm Hg). Additionally, fluctuating oxygen resulted in more metabolized TPZ near the oxygen source as compared with the steady-state condition of the same overall average pO2. CONCLUSIONS: Fluctuating pO2 reduced the concentration of metabolized TPZ at distances farther from the source, thereby limiting its ability to reach and kill the most hypoxic cells. These results suggest that the kinetics of fluctuating oxygenation should be taken into account when considering drug designs that involve oxygen-sensitive agents.

Authors
Cárdenas-Navia, LI; Secomb, TW; Dewhirst, MW
MLA Citation
Cárdenas-Navia, L. Isabel, et al. “Effects of fluctuating oxygenation on tirapazamine efficacy: Theoretical predictions..” Int J Radiat Oncol Biol Phys, vol. 67, no. 2, Feb. 2007, pp. 581–86. Pubmed, doi:10.1016/j.ijrobp.2006.10.002.
PMID
17236974
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
67
Issue
2
Publish Date
2007
Start Page
581
End Page
586
DOI
10.1016/j.ijrobp.2006.10.002

Intermittent hypoxia furthers the rationale for hypoxia-inducible factor-1 targeting.

Hypoxia-inducible factor-1 (HIF-1) stabilization is a pivotal event in the response to hypoxic stress. A study in the December 15, 2006 issue of Cancer Research shows that HIF-1 stabilization occurs more robustly as a result of intermittent hypoxia compared with chronic hypoxia. The findings of this study suggest that intermittent hypoxia might influence the efficacy of radiotherapy by more strongly affecting the growth and survival of vascular endothelial cells. This finding offers additional encouragement to efforts to target HIF-1 for cancer therapy.

Authors
Dewhirst, MW
MLA Citation
Dewhirst, Mark W. “Intermittent hypoxia furthers the rationale for hypoxia-inducible factor-1 targeting..” Cancer Res, vol. 67, no. 3, Feb. 2007, pp. 854–55. Pubmed, doi:10.1158/0008-5472.CAN-06-4744.
PMID
17283112
Source
pubmed
Published In
Cancer Research
Volume
67
Issue
3
Publish Date
2007
Start Page
854
End Page
855
DOI
10.1158/0008-5472.CAN-06-4744

Long-term administration of a small molecular weight catalytic metalloporphyrin antioxidant, AEOL 10150, protects lungs from radiation-induced injury.

PURPOSE: To determine whether administration of a catalytic antioxidant, Mn(III) tetrakis(N,N'-diethylimidazolium-2-yl) porphyrin, AEOL 10150, with superoxide dismutase (SOD) mimetic properties, reduces the severity of radiation-induced injury to the lung from single-dose irradiation (RT) of 28 Gy. METHODS AND MATERIALS: Rats were randomly divided into four different dose groups (0, 1, 10, and 30 mg/kg/day of AEOL 10150), receiving either short-term (1 week) or long-term (10 weeks) drug administration via osmotic pumps. Rats received single-dose irradiation (RT) of 28 Gy to the right hemithorax. Breathing rates, body weights, blood samples, histopathology, and immunohistochemistry were used to assess lung damage. RESULTS: There was no significant difference in any of the study endpoints between the irradiated controls and the three groups receiving RT and short-term administration of AEOL 10150. For the long-term administration, functional determinants of lung damage 20 weeks postradiation were significantly worse for RT + phosphate-buffered saline (PBS) and RT + 1 mg/kg/day of AEOL 10150 as compared with the irradiated groups treated with higher doses of AEOL 10150 (10 or 30 mg/kg/day). Lung histology at 20 weeks revealed a significant decrease in structural damage and collagen deposition in rats receiving 10 or 30 mg/kg/day after radiation in comparison to the RT + PBS and 1 mg/kg/day groups. Immunohistochemistry demonstrated a significant reduction in macrophage accumulation, oxidative stress, and hypoxia in rats receiving AEOL 10150 (10 or 30 mg/kg/day) after lung irradiation compared with the RT + PBS and 1 mg/kg/day groups. CONCLUSIONS: The chronic administration of a novel catalytic antioxidant, AEOL 10150, demonstrates a significant protective effect from radiation-induced lung injury. AEOL 10150 has its primary impact on the cascade of events after irradiation, and adding the drug before irradiation and its short-term administration have no significant additional benefits.

Authors
Rabbani, ZN; Batinic-Haberle, I; Anscher, MS; Huang, J; Day, BJ; Alexander, E; Dewhirst, MW; Vujaskovic, Z
MLA Citation
Rabbani, Zahid N., et al. “Long-term administration of a small molecular weight catalytic metalloporphyrin antioxidant, AEOL 10150, protects lungs from radiation-induced injury..” Int J Radiat Oncol Biol Phys, vol. 67, no. 2, Feb. 2007, pp. 573–80. Pubmed, doi:10.1016/j.ijrobp.2006.09.053.
PMID
17236973
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
67
Issue
2
Publish Date
2007
Start Page
573
End Page
580
DOI
10.1016/j.ijrobp.2006.09.053

Multiple etiologies of tumor hypoxia require multifaceted solutions.

Authors
Dewhirst, MW; Navia, IC; Brizel, DM; Willett, C; Secomb, TW
MLA Citation
Dewhirst, Mark W., et al. “Multiple etiologies of tumor hypoxia require multifaceted solutions..” Clin Cancer Res, vol. 13, no. 2 Pt 1, Jan. 2007, pp. 375–77. Pubmed, doi:10.1158/1078-0432.CCR-06-2629.
PMID
17255256
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
13
Issue
2 Pt 1
Publish Date
2007
Start Page
375
End Page
377
DOI
10.1158/1078-0432.CCR-06-2629

Magnetic resonance imaging of temperature-sensitive liposome release: drug dose painting and antitumor effects.

BACKGROUND: In preclinical studies, lysolipid-based temperature-sensitive liposomes (LTSLs) containing chemotherapy drugs administered in combination with local hyperthermia have been found to increase tumor drug concentrations and improve antitumor efficacy of the drugs. We used a novel magnetic resonance imaging (MRI) method to measure the temporal and spatial patterns of drug delivery in a rat fibrosarcoma model during treatment with LTSLs containing doxorubicin and an MRI contrast agent (manganese) (Dox/Mn-LTSLs) administered at different times with respect to hyperthermia. METHODS: Rats bearing 10- to 12-mm fibrosarcomas (n = 6-7 per group) were treated with Dox/Mn-LTSLs (at a dose of 5 mg doxorubicin/kg body weight) before and/or during 60 minutes of local tumor hyperthermia administered via a catheter inserted at the center of the tumor. Drug distribution was monitored continuously via MRI. Magnetic resonance changes were used to calculate intratumoral doxorubicin concentrations throughout treatment. Tumors were monitored until they reached five times their volume on the day of treatment or 60 days. Doxorubicin concentrations and times for tumors to reach five times their volume on the day of treatment were analyzed using the Kruskal-Wallis test and the Kaplan-Meier product-limit method, respectively. All statistical tests were two-sided. RESULTS: Administration of Dox/Mn-LTSLs before, during, and both before and during hyperthermia yielded central, peripheral, and uniform drug distributions, respectively. Doxorubicin accumulated more quickly and reached higher concentrations in the tumor when Dox/Mn-LTSLs were administered during hyperthermia than when administered before hyperthermia (rate: 9.8 versus 1.8 microg/min, difference = 8.0 microg/min, 95% confidence interval [CI] = 6.8 to 12.8 microg/min, P = .003; concentration: 15.1 versus 8.0 ng/mg, difference = 7.1 ng/mg, 95% CI = 3.6 to 10.6 ng/mg, P = .028). LTSL administered during hyperthermia also yielded the greatest antitumor effect, with a median time for tumors to reach five times their volume on the day of treatment of 34 days (95% CI = 30 days to infinity) compared with 18.5 days (95% CI = 16 to 23 days) for LTSL before hyperthermia and 22.5 days (95% CI = 15 to 25 days) for LTSL before and during hyperthermia. CONCLUSIONS: In this rat fibrosarcoma model, LTSLs were most effective when delivered during hyperthermia, which resulted in a peripheral drug distribution.

Authors
Ponce, AM; Viglianti, BL; Yu, D; Yarmolenko, PS; Michelich, CR; Woo, J; Bally, MB; Dewhirst, MW
MLA Citation
Ponce, Ana M., et al. “Magnetic resonance imaging of temperature-sensitive liposome release: drug dose painting and antitumor effects..” J Natl Cancer Inst, vol. 99, no. 1, Jan. 2007, pp. 53–63. Pubmed, doi:10.1093/jnci/djk005.
PMID
17202113
Source
pubmed
Published In
J Natl Cancer Inst
Volume
99
Issue
1
Publish Date
2007
Start Page
53
End Page
63
DOI
10.1093/jnci/djk005

A 400 MHz hyperthermia system using rotating spiral antennas for uniform treatment of large superficial and sub-surface tumors

Authors
Arabe, OA; Maccarini, PF; Jones, EL; Hanna, G; Samulski, TV; Dewhirst, MW; Thrall, DE; Stauffer, PR
MLA Citation
Arabe, Omar A., et al. “A 400 MHz hyperthermia system using rotating spiral antennas for uniform treatment of large superficial and sub-surface tumors.” 2007 Ieee/Mtt S International Microwave Symposium Digest, Vols 1 6, IEEE, 2007, pp. 1329-+.
Source
wos
Published In
2017 Ieee Mtt S International Microwave Symposium (Ims)
Publish Date
2007
Start Page
1329
End Page
+

TH‐E‐M100E‐03: Optimizing the Methodology for Incorporating SPECT‐Guidance to Reduce Intensity Modulated Radiation Therapy (IMRT) Dose to Functioning Lung

Purpose: Single photon emission computed tomography (SPECT) provides a spatial distribution map of lung perfusion. Previously, an algorithmic methodology was developed using IMRT and SPECT guidance to deliberately divert dose away from higher functioning (perfused) lung, thereby potentially reducing lung toxicity. This work aims to refine this methodology by determining the optimal number and segmentation method for incorporating different levels of functionality. Method and Materials: The lowest 15% of SPECT numbers were discarded as background noise. The remaining values were then divided equally so that each segment had the same range. IMRT treatment plans incorporating functional information were generated with the lung subdivided into varying numbers of SPECT segments. The segments ranged from 2 to the number beyond which there was no improvement in the Dose Functional Histogram (DFH) or function‐weighted lung volume above 20/30 Gy (F20/ F30). The thresholds of 20/30 Gy were chosen for their significance in predicting radiation‐induced pneumonitis. The plans generated using SPECT guidance were compared against “conventional” plans, generated with the assumption that lung function was spatially homogeneous. Results: Of all the SPECT plans generated, those created with four segments produced the most favorable results overall. The results were variable, with the four segment SPECT‐guided plans showing marginal to large improvement over conventional plans. One patient had a 42.9% and 61.7% reduction in F20and F30values, respectively, when compared to the conventional plan. For all patients, on average, the F20and F30values were reduced by 16.5% ± 18.3% and 21.1% ± 26.0%, respectively. Conclusion: A standardized intensity‐based segmentation procedure is crucial for routine use of SPECT‐guidance in IMRT lung treatment planning. The simple procedure outlined here is valid for a range of patients. Segmenting lung SPECT into four intensity regions appears to provide the greatest benefit in reducing radiotherapy‐induced functional lung damage. © 2007, American Association of Physicists in Medicine. All rights reserved.

Authors
Mcguire, S; Zhou, S; Marks, L; Dewhirst, M; Yin, F; Das, S
MLA Citation
Mcguire, S., et al. “TH‐E‐M100E‐03: Optimizing the Methodology for Incorporating SPECT‐Guidance to Reduce Intensity Modulated Radiation Therapy (IMRT) Dose to Functioning Lung.” Medical Physics, vol. 34, no. 6, 2007. Scopus, doi:10.1118/1.2761773.
Source
scopus
Published In
Medical Physics
Volume
34
Issue
6
Publish Date
2007
Start Page
2654
DOI
10.1118/1.2761773

A phase I trial of hyperthermia-induced interleukin-12 gene therapy in spontaneously arising feline soft tissue sarcomas.

Interleukin-12 (IL-12), a proinflammatory cytokine, shows anticancer properties. Systemically administered IL-12 causes dose-dependent toxicity. To achieve localized intratumoral gene expression, an adenoviral gene therapy vector with IL-12 controlled by a heat-inducible promoter (heat shock promoter 70B) was developed and tested in a phase I clinical trial in cats with spontaneously arising soft tissue sarcoma. A feasibility study was done in 16 cats with soft tissue sarcoma using murine IL-12 and/or enhanced green fluorescent protein adenoviral vectors under cytomegalovirus or heat shock promoter 70 control. Subsequently, we conducted a phase I clinical trial using an adenoviral feline IL-12 construct in 13 cats with soft tissue sarcoma. The soft tissue sarcomas were irradiated (48 Gy/16 fractions) followed by intratumoral injection of adenovirus. Twenty-four hours postinjection, tumors were heated (41 degrees C, 60 min). Tumor expression of feline IL-12 and IFN-gamma was determined. Cats were monitored for systemic toxicity. For the murine IL-12 construct, an association was noted between viral dose and murine IL-12 levels within tumor, whereas serum levels were minimal. Mild toxicity was noted at 10(11) plaque-forming units (pfu). With the feline IL-12 construct, high levels of feline IL-12 mRNA were detected in tumor biopsies with low or absent IFN-gamma mRNA following gene therapy. Hematologic and hepatic toxicities were noted at the highest viral doses and were associated with detection of IFN-gamma mRNA in tumor. It is possible to localize gene expression and limit systemic toxicity of IL-12 using the hyperthermia-induced gene therapy approach. The maximum tolerated dose of the feline IL-12 adenoviral vector was 10(10) pfu/tumor as dose-limiting toxicities were noted at the 4 x 10(10) pfu dose.

Authors
Siddiqui, F; Li, C-Y; Larue, SM; Poulson, JM; Avery, PR; Pruitt, AF; Zhang, X; Ullrich, RL; Thrall, DE; Dewhirst, MW; Hauck, ML
MLA Citation
Siddiqui, Farzan, et al. “A phase I trial of hyperthermia-induced interleukin-12 gene therapy in spontaneously arising feline soft tissue sarcomas..” Mol Cancer Ther, vol. 6, no. 1, Jan. 2007, pp. 380–89. Pubmed, doi:10.1158/1535-7163.MCT-06-0342.
PMID
17237297
Source
pubmed
Published In
Molecular Cancer Therapeutics
Volume
6
Issue
1
Publish Date
2007
Start Page
380
End Page
389
DOI
10.1158/1535-7163.MCT-06-0342

Three-dimensional imaging of whole rodent organs using optical computed and emission tomography.

We explore the potential of optical computed tomography (optical-CT) and optical emission computed tomography (optical-ECT) in a new area-whole organ imaging. The techniques are implemented on an in-house prototype benchtop system with improved image quality and the capacity to image larger samples (up to 3 cm) than previous systems based on stereo microscopes. Imaging performance tests confirm high geometrical accuracy, accurate relative measurement of linear attenuation coefficients, and the ability to image features at the 50-microm level. Optical labeling of organ microvasculature was achieved using two stains deposited via natural in vivo circulatory processes: a passive absorbing ink-based stain and an active fluorescin FITC-lectin conjugate. The lectin protein binds to the endothelial lining, and FITC fluorescense enables optical-ECT imaging. Three-dimensional (3-D) optical-CT images have been acquired of a normal rat heart and left lung and a mouse right lung showing exquisite detail of the functional vasculature and relative perfusion distribution. Coregistered optical-ECT images were also acquired of the mouse lung and kidney. Histological sections confirmed effective labeling of microvasculature throughout the organs. The advantages of optical-CT and optical-ECT include the potential for a unique combination of high resolution and high contrast and compatibility with a wide variety of optical probes, including gene expression labeling fluorescent reporter proteins.

Authors
Oldham, M; Sakhalkar, H; Wang, YM; Guo, P; Oliver, T; Bentley, R; Vujaskovic, Z; Dewhirst, M
MLA Citation
Oldham, Mark, et al. “Three-dimensional imaging of whole rodent organs using optical computed and emission tomography..” J Biomed Opt, vol. 12, no. 1, Jan. 2007. Pubmed, doi:10.1117/1.2709858.
PMID
17343484
Source
pubmed
Published In
Journal of Biomedical Optics
Volume
12
Issue
1
Publish Date
2007
Start Page
014009
DOI
10.1117/1.2709858

C34. Oxygen regulation of tumor perfusion unravels the central pressor activity of cell-free human S-nitrosohemoglobin

Authors
Sonveaux, P; Feron, O; McMahon, TJ; Stamler, JS; Dewhirst, MW
MLA Citation
Sonveaux, P., et al. “C34. Oxygen regulation of tumor perfusion unravels the central pressor activity of cell-free human S-nitrosohemoglobin.” Nitric Oxide, vol. 17, Elsevier BV, 2007, pp. 28–28. Crossref, doi:10.1016/j.niox.2007.09.079.
Source
crossref
Published In
Nitric Oxide
Volume
17
Publish Date
2007
Start Page
28
End Page
28
DOI
10.1016/j.niox.2007.09.079

Tumor necrosis factor-alpha is a potent endogenous mutagen that promotes cellular transformation.

Tumor necrosis factor-alpha (TNF-alpha) is an important inflammation cytokine without known direct effect on DNA. In this study, we found that TNF-alpha can cause DNA damages through reactive oxygen species. The mutagenic effect of TNF-alpha is comparable with that of ionizing radiation. TNF-alpha treatment in cultured cells resulted in increased gene mutations, gene amplification, micronuclei formation, and chromosomal instability. Antioxidants significantly reduced TNF-alpha-induced genetic damage. TNF-alpha also induced oxidative stress and nucleotide damages in mouse tissues in vivo. Moreover, TNF-alpha treatment alone led to increased malignant transformation of mouse embryo fibroblasts, which could be partially suppressed by antioxidants. As TNF-alpha is involved in chronic inflammatory diseases, such as chronic hepatitis, ulcerative colitis, and chronic skin ulcers, and these diseases predispose the patients to cancer development, our results suggest a novel pathway through which TNF-alpha promotes cancer development through induction of gene mutations, in addition to the previously reported mechanisms, in which nuclear factor-kappaB activation was implicated.

Authors
Yan, B; Wang, H; Rabbani, ZN; Zhao, Y; Li, W; Yuan, Y; Li, F; Dewhirst, MW; Li, C-Y
MLA Citation
Yan, Bin, et al. “Tumor necrosis factor-alpha is a potent endogenous mutagen that promotes cellular transformation..” Cancer Res, vol. 66, no. 24, Dec. 2006, pp. 11565–70. Pubmed, doi:10.1158/0008-5472.CAN-06-2540.
PMID
17178846
Source
pubmed
Published In
Cancer Research
Volume
66
Issue
24
Publish Date
2006
Start Page
11565
End Page
11570
DOI
10.1158/0008-5472.CAN-06-2540

Glioma stem cells promote radioresistance by preferential activation of the DNA damage response.

Ionizing radiation represents the most effective therapy for glioblastoma (World Health Organization grade IV glioma), one of the most lethal human malignancies, but radiotherapy remains only palliative because of radioresistance. The mechanisms underlying tumour radioresistance have remained elusive. Here we show that cancer stem cells contribute to glioma radioresistance through preferential activation of the DNA damage checkpoint response and an increase in DNA repair capacity. The fraction of tumour cells expressing CD133 (Prominin-1), a marker for both neural stem cells and brain cancer stem cells, is enriched after radiation in gliomas. In both cell culture and the brains of immunocompromised mice, CD133-expressing glioma cells survive ionizing radiation in increased proportions relative to most tumour cells, which lack CD133. CD133-expressing tumour cells isolated from both human glioma xenografts and primary patient glioblastoma specimens preferentially activate the DNA damage checkpoint in response to radiation, and repair radiation-induced DNA damage more effectively than CD133-negative tumour cells. In addition, the radioresistance of CD133-positive glioma stem cells can be reversed with a specific inhibitor of the Chk1 and Chk2 checkpoint kinases. Our results suggest that CD133-positive tumour cells represent the cellular population that confers glioma radioresistance and could be the source of tumour recurrence after radiation. Targeting DNA damage checkpoint response in cancer stem cells may overcome this radioresistance and provide a therapeutic model for malignant brain cancers.

Authors
Bao, S; Wu, Q; McLendon, RE; Hao, Y; Shi, Q; Hjelmeland, AB; Dewhirst, MW; Bigner, DD; Rich, JN
MLA Citation
Bao, Shideng, et al. “Glioma stem cells promote radioresistance by preferential activation of the DNA damage response..” Nature, vol. 444, no. 7120, Dec. 2006, pp. 756–60. Pubmed, doi:10.1038/nature05236.
PMID
17051156
Source
pubmed
Published In
Nature
Volume
444
Issue
7120
Publish Date
2006
Start Page
756
End Page
760
DOI
10.1038/nature05236

A methodology for using SPECT to reduce intensity-modulated radiation therapy (IMRT) dose to functioning lung.

PURPOSE: Single photon emission computed tomography (SPECT) provides a map of the spatial distribution of lung perfusion. Thus, SPECT guidance can be used to divert dose away from higher-functioning lung, potentially reducing lung toxicity. We present a methodology for achieving this aim and test it in intensity-modulated radiotherapy (IMRT) treatment-planning. METHODS AND MATERIALS: IMRT treatment plans were generated with and without SPECT guidance and compared for 5 patients. Healthy lung was segmented into four regions on the basis of SPECT intensity in the SPECT plan. Dose was sequentially allowed to the target via regions of increasing SPECT intensity. This process results in reduction of dose to functional lung, reflected in the dose-function histogram (DFH). The plans were compared using DFHs and F(20)/F(30) values (F(x) is the functional lung receiving dose above x Gy). RESULTS: In all cases, the SPECT-guided plan produced a more favorable DFH compared with the non-SPECT-guided plan. Additionally, the F(20) and F(30) values were reduced for all patients by an average of 13.6% +/- 5.2% and 10.5% +/- 5.8%, respectively. In all patients, DFHs of the two highest-functioning SPECT regions were reduced, whereas DFHs of the two lower-functioning regions were increased, illustrating the dose "give-take" between SPECT regions during redistribution. CONCLUSIONS: SPECT-guided IMRT shows potential for reducing the dose delivered to highly functional lung regions. This dose reduction could reduce the number of high-grade pneumonitis cases that develop after radiation treatment and improve patient quality of life.

Authors
McGuire, SM; Zhou, S; Marks, LB; Dewhirst, M; Yin, F-F; Das, SK
MLA Citation
McGuire, Sarah M., et al. “A methodology for using SPECT to reduce intensity-modulated radiation therapy (IMRT) dose to functioning lung..” Int J Radiat Oncol Biol Phys, vol. 66, no. 5, Dec. 2006, pp. 1543–52. Pubmed, doi:10.1016/j.ijrobp.2006.07.1377.
PMID
17126212
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
66
Issue
5
Publish Date
2006
Start Page
1543
End Page
1552
DOI
10.1016/j.ijrobp.2006.07.1377

Role of erythropoietin as an angiogenic factor and target in cancer.

Authors
Arcasoy, MO; Hardee, ME; Jiang, X; Dewhirst, MW
MLA Citation
Arcasoy, Murat O., et al. “Role of erythropoietin as an angiogenic factor and target in cancer..” Blood, vol. 108, no. 11, AMER SOC HEMATOLOGY, 2006, pp. 127A-127A.
Source
wos
Published In
Blood
Volume
108
Issue
11
Publish Date
2006
Start Page
127A
End Page
127A

A tracer dose of technetium-99m-labeled liposomes can estimate the effect of hyperthermia on intratumoral doxil extravasation.

PURPOSE: A noninvasive method to monitor intratumoral Doxil delivery in individual patients during targeted tumor therapy is important to predict treatment response. The purpose of this study was to determine if a small tracer dose of technetium-99m (99mTc)-labeled liposomes could be used to quantify the effect of local hyperthermia on intratumoral Doxil extravasation. EXPERIMENTAL DESIGN: Experiments were carried out in a rat fibrosarcoma model with transplanted thigh tumors. Liposomes of approximately same size and composition as Doxil were radiolabeled using [technetium-99m (99mTc)]exametazime. Eight treatment groups received either Doxil, a tracer dose or a large dose of 99mTc-labeled liposomes, or a combination of tracer and Doxil, with or without hyperthermia. This design was chosen to assure that coadministration of both liposomal formulations did not influence their intratumoral distribution. Hyperthermia was done for 45 minutes. Scintigraphic images were obtained at 5 and 18 hours. At 18 hours, tumors were removed and gamma counts as well as doxorubicin concentrations were measured. RESULTS: Intratumoral extravasation of the 99mTc-labeled tracer could be imaged scintigraphically under normothermic and hyperthermic conditions. The thermal enhancement ratio was slightly higher for radiolabeled liposomes than for doxorubicin concentration. However, there was a significant positive correlation of intratumoral doxorubicin concentration and intratumoral uptake of the radiolabeled tracer (expressed as percentage of the injected dose per gram of tissue). Coadministration of radiolabeled liposomes did not negatively influence the amount of drug delivered with Doxil. CONCLUSIONS: The use of a radiolabeled tracer has potential value to monitor drug delivery and estimate the effect of an intervention aimed to increase liposomal accumulation, such as local hyperthermia.

Authors
Kleiter, MM; Yu, D; Mohammadian, LA; Niehaus, N; Spasojevic, I; Sanders, L; Viglianti, BL; Yarmolenko, PS; Hauck, M; Petry, NA; Wong, TZ; Dewhirst, MW; Thrall, DE
MLA Citation
Kleiter, Miriam M., et al. “A tracer dose of technetium-99m-labeled liposomes can estimate the effect of hyperthermia on intratumoral doxil extravasation..” Clin Cancer Res, vol. 12, no. 22, Nov. 2006, pp. 6800–07. Pubmed, doi:10.1158/1078-0432.CCR-06-0839.
PMID
17121901
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
12
Issue
22
Publish Date
2006
Start Page
6800
End Page
6807
DOI
10.1158/1078-0432.CCR-06-0839

Anti-angiogenic effects of interleukin-12 delivered by a novel hyperthermia induced gene construct.

PURPOSE: Interleukin-12 (IL-12) is a pro-inflammatory cytokine possessing anti-cancer and anti-angiogenic properties. This study quantitatively assessed the anti-angiogenic effect of IL-12 delivered using an adenoviral vector with murine IL-12 placed under control of a heat shock promoter. This approach limits systemic toxicity by restricting IL-12 delivery locally to the tumour. The kinetics of the downstream cytokines interferon-gamma (IFN-gamma) and interferon inducible protein-10 (IP-10) and other molecules affecting angiogenesis, vascular endothelial growth factor (VEGF) and plasminogen activator inhibitor-1 (PAI-1) were also studied. MATERIALS AND METHODS: 4T1 tumours were grown in Balb/C mice and the AdhspmIL-12 construct was injected intra-tumourally. The tumours were heated after 24 h using a water bath. At various time points post-heating the tumours were collected and quantitatively assessed for cytokine production and vascularity. RESULTS: A significant reduction was seen in the tumour vasculature of the treated group vs. the control group mice. Systemic effects of IL-12 were limited to generalized immunostimulation. No hepatoxicity was noted. CONCLUSIONS: This study suggests that IL-12 can be effectively delivered using a gene-based approach with a heat shock promoter. This results in quantitatively measurable anti-angiogenesis and general immunostimulation. The complex inter-play of other pro- and anti-angiogenic factors (IFN-gamma, IP-10, VEGF and PAI-1) was also studied.

Authors
Siddiqui, F; Ehrhart, EJ; Charles, B; Chubb, L; Li, C-Y; Zhang, X; Larue, SM; Avery, PR; Dewhirst, MW; Ullrich, RL
MLA Citation
Siddiqui, Farzan, et al. “Anti-angiogenic effects of interleukin-12 delivered by a novel hyperthermia induced gene construct..” Int J Hyperthermia, vol. 22, no. 7, Nov. 2006, pp. 587–606. Pubmed, doi:10.1080/02656730600983063.
PMID
17079216
Source
pubmed
Published In
International Journal of Hyperthermia : the Official Journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group
Volume
22
Issue
7
Publish Date
2006
Start Page
587
End Page
606
DOI
10.1080/02656730600983063

Chemodosimetry of in vivo tumor liposomal drug concentration using MRI.

Effective cancer chemotherapy depends on the delivery of therapeutic drugs to cancer cells at cytotoxic concentrations. However, physiologic barriers, such as variable vessel permeability, high interstitial fluid pressure, and heterogeneous perfusion, make it difficult to achieve that goal. Efforts to improve drug delivery have been limited by the lack of noninvasive tools to evaluate intratumoral drug concentration and distribution. Here we demonstrate that tumor drug concentration can be measured in vivo using T(1)-weighted MRI, following systemic administration of liposomes containing both drug (doxorubicin (DOX)) and contrast agent (manganese (Mn)). Mn and DOX concentrations were calculated using T(1) relaxation times and Mn:DOX loading ratios, as previously described. Two independent validations by high-performance liquid chromatography (HPLC) and histologic fluorescence in a rat fibrosarcoma (FSA) model indicate a concordant linear relationship between DOX concentrations determined using T(1) and those measured invasively. This method of imaging exhibits potential for real-time evaluation of chemotherapeutic protocols and prediction of tumor response on an individual patient basis.

Authors
Viglianti, BL; Ponce, AM; Michelich, CR; Yu, D; Abraham, SA; Sanders, L; Yarmolenko, PS; Schroeder, T; MacFall, JR; Barboriak, DP; Colvin, OM; Bally, MB; Dewhirst, MW
MLA Citation
Viglianti, Benjamin L., et al. “Chemodosimetry of in vivo tumor liposomal drug concentration using MRI..” Magn Reson Med, vol. 56, no. 5, Nov. 2006, pp. 1011–18. Pubmed, doi:10.1002/mrm.21032.
PMID
17029236
Source
pubmed
Published In
Magnetic Resonance in Medicine
Volume
56
Issue
5
Publish Date
2006
Start Page
1011
End Page
1018
DOI
10.1002/mrm.21032

2026

Authors
Yoo, DS; Vujaskovic, Z; Prosnitz, LR; Marks, LB; Blackwell, KL; Dewhirst, MW; Jones, EL
MLA Citation
Yoo, D. S., et al. “2026.” International Journal of Radiation Oncology*Biology*Physics, vol. 66, no. 3, Elsevier BV, 2006, pp. S223–24. Crossref, doi:10.1016/j.ijrobp.2006.07.428.
Source
crossref
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
66
Issue
3
Publish Date
2006
Start Page
S223
End Page
S224
DOI
10.1016/j.ijrobp.2006.07.428

Treatment with Imatinib in NSCLC is associated with decrease of phosphorylated PDGFR-beta and VEGF expression, decrease in interstitial fluid pressure and improvement of oxygenation.

Elevated intratumoral interstitial fluid pressure (IFP) and tumour hypoxia are independent predictive factors for poor survival and poor treatment response in cancer patients. However, the relationship between IFP and tumour hypoxia has not yet been clearly established. Preclinical studies have shown that lowering IFP improves treatment response to cytotoxic therapy. Interstitial fluid pressure can be reduced by inhibition of phosphorylated platelet-derived growth factor receptor-beta (p-PDGFR-beta), a tyrosine kinase receptor frequently overexpressed in cancer stroma, and/or by inhibition of VEGF, a growth factor commonly overexpressed in tumours overexpressing p-PDGFR-beta. We hypothesised that Imatinib, a specific PDGFR-beta inhibitor will, in addition to p-PDGFR-beta inhibition, downregulate VEGF, decrease IFP and improve tumour oxygenation. A549 human lung adenocarcinoma xenografts overexpressing PDGFR-beta were grown in nude mice. Tumour-bearing animals were randomised to control and treatment groups (Imatinib 50 mg kg(-1) via gavage for 4 days). Interstitial fluid pressure was measured in both groups before and after treatment. EF5, a hypoxia marker, was administered 3 h before being killed. Tumours were sectioned and stained for p-PDGFR-beta, VEGF and EF5 binding. Stained sections were viewed with a fluorescence microscope and image analysis was performed. Imatinib treatment resulted in significant reduction of p-PDGFR-beta, VEGF and IFP. Tumour oxygenation was also significantly improved. This study shows that p-PDGFR-beta-overexpressing tumours can be effectively treated with Imatinib to decrease tumour IFP. Importantly, this is the first study demonstrating that Imatinib treatment improves tumour oxygenation and downregulates tumour VEGF expression.

Authors
Vlahovic, G; Rabbani, ZN; Herndon, JE; Dewhirst, MW; Vujaskovic, Z
MLA Citation
Vlahovic, G., et al. “Treatment with Imatinib in NSCLC is associated with decrease of phosphorylated PDGFR-beta and VEGF expression, decrease in interstitial fluid pressure and improvement of oxygenation..” Br J Cancer, vol. 95, no. 8, Oct. 2006, pp. 1013–19. Pubmed, doi:10.1038/sj.bjc.6603366.
Website
http://hdl.handle.net/10161/16114
PMID
17003785
Source
pubmed
Published In
British Journal of Cancer
Volume
95
Issue
8
Publish Date
2006
Start Page
1013
End Page
1019
DOI
10.1038/sj.bjc.6603366

Assessing the ability of the antiangiogenic and anticytokine agent thalidomide to modulate radiation-induced lung injury.

PURPOSE: Thalidomide has broad anticytokine properties, which might protect normal tissues in patients undergoing chemoradiotherapy. The purpose of this study was to determine the maximal tolerated dose of thalidomide when used in combination with vinorelbine plus thoracic radiotherapy. METHODS AND MATERIALS: Eligible patients had inoperable Stage III non-small-cell lung cancer, a Karnofsky Performance Status>or=70, and life expectancy>or=6 months. Patients underwent pretreatment evaluation of lung function. Radiotherapy consisted of 66 Gy in 6.5 weeks. Vinorelbine was administered i.v. (5 mg/m2) 3 times per week just before radiotherapy. Thalidomide was begun at 50 mg, p.o., on day 1 of chemoradiotherapy and continued once daily for 6 months. Side effects were scored using National Cancer Institute Common Toxicity Criteria. RESULTS: Ten patients were enrolled. Of the first 6 patients, 2 developed major thrombotic events that were believed to be possibly related to thalidomide. The study was suspended and modified to require prophylactic anticoagulation. Of the last 4 patients, 2 developed dose-limiting toxicity attributable to thalidomide; both patients required a dose reduction of thalidomide to <50 mg/day. Because the drug is not available in an oral product providing <50 mg/day, the study was closed. CONCLUSIONS: The combination of thalidomide concurrently with thoracic radiotherapy and vinorelbine resulted in excessive toxicity.

Authors
Anscher, MS; Garst, J; Marks, LB; Larrier, N; Dunphy, F; Herndon, JE; Clough, R; Marino, C; Vujaskovic, Z; Zhou, S; Dewhirst, MW; Shafman, TD; Crawford, J
MLA Citation
Anscher, Mitchell S., et al. “Assessing the ability of the antiangiogenic and anticytokine agent thalidomide to modulate radiation-induced lung injury..” Int J Radiat Oncol Biol Phys, vol. 66, no. 2, Oct. 2006, pp. 477–82. Pubmed, doi:10.1016/j.ijrobp.2006.05.031.
PMID
16904841
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
66
Issue
2
Publish Date
2006
Start Page
477
End Page
482
DOI
10.1016/j.ijrobp.2006.05.031

Extracellular pH and P-31 magnetic resonance spectroscopic variables are related to outcome in canine soft tissue sarcomas treated with thermoradiotherapy.

PURPOSE: The objective was to test whether tumor pH and (31)P magnetic resonance spectroscopic end points were related to treatment outcome in pet canine patients with spontaneous soft tissue sarcomas treated with thermoradiotherapy. EXPERIMENTAL DESIGN: Forty-two dogs with evaluable (31)P magnetic resonance spectroscopic end points and pH data were included in this study. Tumor variables (grade and volume), extracellular pH (pHe), T(2) relaxation times, intracellular pH, and selected phosphometabolite ratios were examined for correlation with clinical outcome. RESULTS: From 39 dogs, pHe was a predictor of metastasis-free survival (MFS), with hazard ratio (HR, 0.29; P = 0.005) and overall survival (OS) with (HR, 0.36; P = 0.013). Tumor volume (>19 cm(3)) was related to MFS (HR, 2.14; P = 0.04), time to local failure (HR, 3.4; P = 0.025), and OS (HR, 2.27; P = 0.03). There was no association between T(2) or intracellular pH and clinical outcome. Tumor grade (high versus low/intermediate) and phosphodiester/betaATP ratio were identified as significant predictors for MFS, with (HR, 2.66; P = 0.009) and (HR, 0.75; P = 0.027), respectively, and as predictors of OS with (HR, 2.66; P = 0.009) and (HR, 0.76; P = 0.03), respectively. The phosphodiester/phosphocreatinine ratio predicted time to local failure (HR, 1.24; P = 0.017). CONCLUSIONS: pHe was predictive of metastasis and OS in canine spontaneous sarcomas. To our knowledge, this is the first time that pHe has been shown to be predictive of clinical outcome. The results suggest that additional studies should be considered evaluating the prognostic significance of this variable. Phospholipid resonances, related to membrane metabolism, were related to clinical outcome, confirming recent results reported in human patients with soft tissue sarcomas treated with thermoradiotherapy.

Authors
Lora-Michiels, M; Yu, D; Sanders, L; Poulson, JM; Azuma, C; Case, B; Vujaskovic, Z; Thrall, DE; Charles, HC; Dewhirst, MW
MLA Citation
Lora-Michiels, Michaël, et al. “Extracellular pH and P-31 magnetic resonance spectroscopic variables are related to outcome in canine soft tissue sarcomas treated with thermoradiotherapy..” Clin Cancer Res, vol. 12, no. 19, Oct. 2006, pp. 5733–40. Pubmed, doi:10.1158/1078-0432.CCR-05-2669.
PMID
17020978
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
12
Issue
19
Publish Date
2006
Start Page
5733
End Page
5740
DOI
10.1158/1078-0432.CCR-05-2669

Alternative inclusion of fibroblast growth factor receptor 2 exon IIIc in Dunning prostate tumors reveals unexpected epithelial mesenchymal plasticity.

In epithelial cells, alternative splicing of fibroblast growth factor receptor 2 (FGFR2) transcripts leads to the expression of the FGFR2(IIIb) isoform, whereas in mesenchymal cells, the same process results in the synthesis of FGFR2(IIIc). Expression of the FGFR2(IIIc) isoform during prostate tumor progression suggests a disruption of the epithelial character of these tumors. To visualize the use of FGFR2 exon IIIc in prostate AT3 tumors in syngeneic rats, we constructed minigene constructs that report on alternative splicing. Imaging these alternative splicing decisions revealed unexpected mesenchymal-epithelial transitions in these primary tumors. These transitions were observed more frequently where tumor cells were in contact with stroma. Indeed, these transitions were frequently observed among lung micrometastases in the organ parenchyma and immediately adjacent to blood vessels. Our data suggest an unforeseen relationship between epithelial mesenchymal plasticity and malignant fitness.

Authors
Oltean, S; Sorg, BS; Albrecht, T; Bonano, VI; Brazas, RM; Dewhirst, MW; Garcia-Blanco, MA
MLA Citation
Oltean, Sebastian, et al. “Alternative inclusion of fibroblast growth factor receptor 2 exon IIIc in Dunning prostate tumors reveals unexpected epithelial mesenchymal plasticity..” Proc Natl Acad Sci U S A, vol. 103, no. 38, Sept. 2006, pp. 14116–21. Pubmed, doi:10.1073/pnas.0603090103.
PMID
16963563
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
103
Issue
38
Publish Date
2006
Start Page
14116
End Page
14121
DOI
10.1073/pnas.0603090103

Three-dimensional imaging of xenograft tumors using optical computed and emission tomography.

The physical basis and preliminary applications of optical computed tomography (optical-CT) and optical emission computed tomography (optical-ECT) are introduced, as new techniques with potential to provide unique 3D information on a variety of aspects of tumor structure and function. A particular focus here is imaging tumor micro-vasculature, and the spatial distribution of viable tumor cells, although the techniques have the potential for much wider application. The principle attractiveness of optical-CT and optical-ECT are that high resolution (<20 microm) and high contrast co-registered 3D images of structure and function can be acquired for relatively large intact samples. The unique combination of high contrast and resolution offers advantages over micro-CT and micro-MRI, and the lack of requirement for sectioning offers advantages over confocal microscopy, conventional microscopy, and histological sectioning techniques. Optical-CT/ECT are implemented using in-house custom apparatus and a commercial dissecting microscope capable of both transmission and fluorescence imaging. Basic studies to characterize imaging performance are presented. Negligible geometrical distortion and accurate reconstruction of relative attenuation coefficients was observed. Optical-CT and optical-ECT are investigated here by application to high resolution imaging of HCT116 xenograft tumors, about 1 cc in dimension, which were transfected with constitutive red fluorescent protein (RFP). Tumor microvasculature was stained in vivo by tail vein injection of either passive absorbing dyes or active fluorescent markers (FITC conjugated lectin). Prior to imaging, the tumors were removed (ex vivo) and optically cleared in a key process to make the samples amenable to light transmission. The cleared tumors were imaged in three modes (i) optical-CT to image the 3D distribution of microvasculature as indicated by absorbing dye, (ii) optical-ECT using the FITC excitation and emission filter set, to determine microvasculature as indicated by lectin-endothelial binding, and (iii) optical-ECT using the DSRed2 filter set to determine the 3D distribution of viable tumor as indicated by RFP emission. A clear correlation was observed between the independent vasculature imaging modes (i) and (ii) and postimaging histological sections, providing substantial validation of the optical-CT and optical-ECT techniques. Strong correlation was also observed between the RFP imaging of mode iii, and modes i and ii, supporting the intuitive conclusion that well-perfused regions contain significant viable tumor. In summary, optical-CT and optical-ECT, when combined with new optical clearing techniques, represent powerful new imaging modalities with potential for providing unique information on the structure and function of tumors.

Authors
Oldham, M; Sakhalkar, H; Oliver, T; Wang, YM; Kirpatrick, J; Cao, Y; Badea, C; Johnson, GA; Dewhirst, M
MLA Citation
Oldham, Mark, et al. “Three-dimensional imaging of xenograft tumors using optical computed and emission tomography..” Med Phys, vol. 33, no. 9, Sept. 2006, pp. 3193–202. Pubmed, doi:10.1118/1.2217109.
PMID
17022212
Source
pubmed
Published In
Medical Physics
Volume
33
Issue
9
Publish Date
2006
Start Page
3193
End Page
3202
DOI
10.1118/1.2217109

Apoptotic DNA fragmentation factor maintains chromosome stability in a P53-independent manner.

DNA fragmentation factor (DFF)/caspase-activated DNase (CAD) is responsible for DNA fragmentation, a hallmark event during apoptosis. Although DNA fragmentation is an evolutionarily conserved process across species, its biological function is not clearly understood. In this study, we constructed cell lines expressing a mutant ICAD (inhibitor of CAD) protein that is resistant to caspase cleavage and therefore constantly binds to DFF/CAD and inhibits DNA fragmentation. We found that irradiation of these cells led to increased chromosome aberrations and aneuploidy when compared with their parental controls. The increased chromosome instability is observed irrespective of cellular P53 status, suggesting that the effect of DFF/CAD is independent of P53. Inhibition of apoptotic DNA fragmentation resulted in increased clonogenic survival of irradiated cells and a delay in removal of cells with DNA damages induced by radiation, an effect similar to that in cells with p53 mutations. Consistent with DFF/CAD's effect on clonogenic survival, tumors established from cells deficient in DNA fragmentation showed enhanced growth in nude mice. Therefore, our results suggest that DFF/CAD plays an important and P53-independent role in maintaining chromosome stability and suppressing tumor development.

Authors
Yan, B; Wang, H; Zhuo, D; Li, F; Kon, T; Dewhirst, M; Li, C-Y
MLA Citation
Yan, B., et al. “Apoptotic DNA fragmentation factor maintains chromosome stability in a P53-independent manner..” Oncogene, vol. 25, no. 39, Aug. 2006, pp. 5370–76. Pubmed, doi:10.1038/sj.onc.1209535.
PMID
16619042
Source
pubmed
Published In
Oncogene
Volume
25
Issue
39
Publish Date
2006
Start Page
5370
End Page
5376
DOI
10.1038/sj.onc.1209535

Use of three-dimensional tissue cultures to model extravascular transport and predict in vivo activity of hypoxia-targeted anticancer drugs.

BACKGROUND: Because of the inefficient vasculature of solid tumors, anticancer drugs must penetrate relatively long distances through the extravascular compartment. The requirement for such diffusion may limit their activity, especially that of hypoxia-targeted drugs. We tested whether a three-dimensional pharmacokinetic/pharmacodynamic (PK/PD) model based on a representative mapped tumor microvascular network could predict the therapeutic activity of anticancer drugs in mouse xenograft tumors. METHODS: Diffusion coefficients of the hypoxia-activated anticancer drug tirapazamine (TPZ) and of 15 TPZ analogs were estimated by measuring their transport through HT29 colon cancer multicellular layers (MCLs). Anoxic cytotoxic potency (by clonogenic assay) and metabolism of the TPZ analogs were measured in HT29 cell suspensions, and their plasma pharmacokinetics was measured in CD-1 nude mice. This information was used to create a spatially resolved PK/PD model for the tumor microvascular network. Model predictions were compared with actual hypoxic cell kill as measured by clonogenic assays on HT29 xenograft tumors 18 hours after treatment with each TPZ analog. RESULTS: Modeling TPZ transport in the tumor microvascular network showed substantial drug depletion in the most hypoxic regions, with predicted maximum cell kill of only 3 logs, compared with more than 10 logs if there were no transport impediment. A large range of tissue diffusion coefficients (0.027 x 10(-6)-1.87 x 10(-6) cm2/s) was observed for the TPZ analogs. There was a strong correlation between model-predicted and measured hypoxic cell kill (R2 = 0.89) but a poor correlation when the model did not include extravascular transport (