Ivan Spasojevic

Positions:

Associate Professor in Medicine

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1999

Duke University

Grants:

Biomarker Studies for Novel Anti-Cancer Agents

Administered By
Medicine, Medical Oncology
Awarded By
National Institutes of Health
Role
Research Associate
Start Date
End Date

Development of CaMKK2 inhibitor drug for acute radiation syndrome

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
Columbia University
Role
Investigator
Start Date
End Date

Human EGFRvIII-specific BiTE for the treatment of Glioblastoma

Administered By
Neurosurgery
Awarded By
National Institutes of Health
Role
Investigator
Start Date
End Date

Measurement of oxidative stress biomarkers in human plasma and urine

Administered By
Duke Cancer Institute
Awarded By
University of California - Berkeley
Role
Principal Investigator
Start Date
End Date

Treatment of Neuropathic Pain after SCI with a Catalytic Oxidoreductant

Administered By
Anesthesiology
Awarded By
University of Alabama at Birmingham
Role
Co Investigator
Start Date
End Date

Publications:

Urinary F2-isoprostanes and the risk of hypertension.

PURPOSE: There is strong biological plausibility for a causal role of reactive oxygen species in vascular pathology but no direct epidemiological evidence linking elevated reactive oxygen species levels to hypertension development. We examined cross-sectional and prospective associations between oxidative status (urinary F2-isoprostanes) and hypertension in the Insulin Resistance Atherosclerosis Study cohort (n = 831). METHODS: The cohort included non-Hispanic white, Hispanic, and non-Hispanic black individuals, with 252 (30%) having prevalent hypertension and 579 participants normotensive at baseline, 122 (21%) of whom developed hypertension during the 5-year follow-up. Four urinary F2-isoprostane isomers were quantified in baseline specimens using LC/MS-MS and were summarized as a composite index. Examined outcomes included hypertension status (yes/no), systolic (SBP) and diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP). RESULTS: Prevalent and incident hypertension were associated with greater age, Black race, impaired glucose tolerance, and greater BMI. F2-IsoP levels were lower among men and among non-Hispanic Blacks, were inversely associated with age, and were directly associated with BMI. No cross-sectional association was found between F2-isoprostanes and hypertension status (OR = 0.93, 0.77-0.12). Among the continuous measures of blood pressure only PP was associated with F2-isoprostanes at baseline (beta-coefficient = 0.99, 0.11-1.86). No prospective association was found between F2-isoprostanes and incident hypertension: OR = 0.98, 0.77-1.25. No prospective associations were found for systolic blood pressure and diastolic blood pressure, and pulse pressure. Mean arterial pressure showed an inverse association (beta-coefficient = -0.16, -0.31 to -0.01). CONCLUSIONS: Elevated F2-isoprostane levels do not increase the risk of hypertension.
Authors
Melton, CD; Luo, R; Wong, BJ; Spasojevic, I; Wagenknecht, LE; D'Agostino, RB; Il'yasova, D
MLA Citation
Melton, Charles David, et al. “Urinary F2-isoprostanes and the risk of hypertension.Ann Epidemiol, vol. 27, no. 6, June 2017, pp. 391–96. Pubmed, doi:10.1016/j.annepidem.2017.05.005.
URI
https://scholars.duke.edu/individual/pub1255218
PMID
28558917
Source
pubmed
Published In
Ann Epidemiol
Volume
27
Published Date
Start Page
391
End Page
396
DOI
10.1016/j.annepidem.2017.05.005

A comprehensive evaluation of catalase-like activity of different classes of redox-active therapeutics.

Because of the increased insight into the biological role of hydrogen peroxide (H2O2) under physiological and pathological conditions and the role it presumably plays in the action of natural and synthetic redox-active drugs, there is a need to accurately define the type and magnitude of reactions that may occur with this intriguing and key species of redoxome. Historically, and frequently incorrectly, the impact of catalase-like activity has been assigned to play a major role in the action of many redox-active drugs, mostly SOD mimics and peroxynitrite scavengers, and in particular MnTBAP(3-) and Mn salen derivatives. The advantage of one redox-active compound over another has often been assigned to the differences in catalase-like activity. Our studies provide substantial evidence that Mn(III) N-alkylpyridylporphyrins couple with H2O2 in actions other than catalase-related. Herein we have assessed the catalase-like activities of different classes of compounds: Mn porphyrins (MnPs), Fe porphyrins (FePs), Mn(III) salen (EUK-8), and Mn(II) cyclic polyamines (SOD-active M40403 and SOD-inactive M40404). Nitroxide (tempol), nitrone (NXY-059), ebselen, and MnCl2, which have not been reported as catalase mimics, were used as negative controls, while catalase enzyme was a positive control. The dismutation of H2O2 to O2 and H2O was followed via measuring oxygen evolved with a Clark oxygen electrode at 25°C. The catalase enzyme was found to have kcat(H2O2)=1.5×10(6)M(-1) s(-1). The yield of dismutation, i.e., the maximal amount of O2 evolved, was assessed also. The magnitude of the yield reflects an interplay between the kcat(H2O2) and the stability of compounds toward H2O2-driven oxidative degradation, and is thus an accurate measure of the efficacy of a catalyst. The kcat(H2O2) values for 12 cationic Mn(III) N-substituted (alkyl and alkoxyalkyl) pyridylporphyrin-based SOD mimics and Mn(III) N,N'-dialkylimidazolium porphyrin, MnTDE-2-ImP(5+), ranged from 23 to 88M(-1) s(-1). The analogous Fe(III) N-alkylpyridylporphyrins showed ~10-fold higher activity than the corresponding MnPs, but the values of kcat(H2O2) are still ~4 orders of magnitude lower than that of the enzyme. While the kcat(H2O2) values for Fe ethyl and n-octyl analogs were 803.5 and 368.4M(-1) s(-1), respectively, the FePs are more prone to H2O2-driven oxidative degradation, therefore allowing for similar yields in H2O2 dismutation as analogous MnPs. The kcat(H2O2) values are dependent on the electron deficiency of the metal site as it controls the peroxide binding in the first step of the dismutation process. SOD-like activities depend on electron deficiency of the metal site also, as it controls the first step of O2(●-) dismutation. In turn, the kcat(O2(●-)) parallels the kcat(H2O2). Therefore, the electron-rich anionic non-SOD mimic MnTBAP(3-) has essentially very low catalase-like activity, kcat(H2O2)=5.8M(-1) s(-1). The catalase-like activities of Mn(III) and Fe(III) porphyrins are at most, 0.0004 and 0.05% of the enzyme activity, respectively. The kcat(H2O2) values of 8.2 and 6.5M(-1) s(-1) were determined for electron-rich Mn(II) cyclic polyamine-based compounds, M40403 and M40404, respectively. The EUK-8, with modest SOD-like activity, has only slightly higher kcat(H2O2)=13.5M(-1) s(-1). The biological relevance of kcat(H2O2) of MnTE-2-PyP(5+), MnTDE-2-ImP(5+), MnTBAP(3-), FeTE-2-PyP(5+), M40403, M40404, and Mn salen was evaluated in wild-type and peroxidase/catalase-deficient E. coli.
Authors
Tovmasyan, A; Maia, CGC; Weitner, T; Carballal, S; Sampaio, RS; Lieb, D; Ghazaryan, R; Ivanovic-Burmazovic, I; Ferrer-Sueta, G; Radi, R; Reboucas, JS; Spasojevic, I; Benov, L; Batinic-Haberle, I
MLA Citation
Tovmasyan, Artak, et al. “A comprehensive evaluation of catalase-like activity of different classes of redox-active therapeutics.Free Radic Biol Med, vol. 86, Sept. 2015, pp. 308–21. Pubmed, doi:10.1016/j.freeradbiomed.2015.05.018.
URI
https://scholars.duke.edu/individual/pub1073783
PMID
26026699
Source
pubmed
Published In
Free Radic Biol Med
Volume
86
Published Date
Start Page
308
End Page
321
DOI
10.1016/j.freeradbiomed.2015.05.018

Differential localization and potency of manganese porphyrin superoxide dismutase-mimicking compounds in Saccharomyces cerevisiae.

Cationic Mn(III) porphyrin complexes based on MnTM-2-PyP are among the most promising superoxide dismutase (SOD) mimicking compounds being considered as potential anti-inflammatory drugs. We studied four of these active compounds in the yeast Saccharomyces cerevisiae, MnTM-2-PyP, MnTE-2-PyP, MnTnHex-2-PyP, and MnTnBu-2-PyP, each of which differs only in the length of its alkyl substituents. Each was active in improving the aerobic growth of yeast lacking SOD (sod1∆) in complete medium, and the efficacy of each mimic was correlated with its characteristic catalytic activity. We also studied the partitioning of these compounds between mitochondria and cytosol and found that the more hydrophobic members of the series accumulated in the mitochondria. Moreover, the degree to which a mimic mitigated the sod1Δ auxotrophic phenotype for lysine relative to its auxotrophic phenotype for methionine depended upon its level of lipophilicity-dependent accumulation inside the mitochondria. We conclude that localization within the cell is an important factor in biological efficacy in addition to the degree of catalytic activity, and we discuss possible explanations for this effect.
Authors
Li, AM; Martins, J; Tovmasyan, A; Valentine, JS; Batinic-Haberle, I; Spasojevic, I; Gralla, EB
MLA Citation
Li, Alice Ma, et al. “Differential localization and potency of manganese porphyrin superoxide dismutase-mimicking compounds in Saccharomyces cerevisiae.Redox Biol, vol. 3, 2014, pp. 1–6. Pubmed, doi:10.1016/j.redox.2014.09.003.
URI
https://scholars.duke.edu/individual/pub1050719
PMID
25462059
Source
pubmed
Published In
Redox Biology
Volume
3
Published Date
Start Page
1
End Page
6
DOI
10.1016/j.redox.2014.09.003

The effect of aprepitant and race on the pharmacokinetics of cyclophosphamide in breast cancer patients.

PURPOSE: The prodrug cyclophosphamide is metabolized by cytochrome P450(CYP)2B6 to the active metabolite, 4-hydroxycyclophosphamide (4-OH), and by CYP3A4/5 to toxic chloracetaldehyde and 2-dechloroethylcyclophosphamide (DCE). Since aprepitant is a moderate inhibitor of CYP3A4, the study was designed to determine whether its concurrent use alters the pharmacokinetics (PK) of cyclophosphamide. In addition, we sought to determine the effect of race and pharmacogenomics on cyclophosphamide PK. METHODS: Eighteen patients with localized breast cancer were randomized in this double-blinded cross-over study to receive aprepitant or placebo in addition to cyclophosphamide 600 mg/m(2) and doxorubicin 60 mg/m(2). Blood samples were collected for both PK analysis of cyclophosphamide and metabolites and pharmacogenomic analysis. Single nucleotide polymorphisms genotyped were CYP3A4*1B, CYP3A5*3, and CYP2B6*6. RESULTS: The geometric mean area under concentration-time curve (AUC(0-t) μg/mL h) for cyclophosphamide was 282 following aprepitant and 230 following placebo (ratio 1.23; 90% CI 1.13, 1.33). 4-OH AUC(0-t) (μg/mL h) was 6.80 following aprepitant and 6.96 following placebo (ratio 0.98; 90% CI 0.88, 1.08). DCE AUC(0-t) (μg/mL h) was 6.76 following aprepitant and 9.37 following placebo (ratio 0.72; 90% CI 0.64, 0.81). Genotype analysis was confounded by race. Race was a significant predictor of DCE lnAUC(0-t) (P = 0.0169) as African Americans had approximately a 2-fold higher DCE AUC than Caucasians. CONCLUSIONS: Aprepitant altered the exposure of cyclophosphamide and DCE but not the active 4-OH metabolite, making it unlikely that aprepitant would change the clinical efficacy of cyclophosphamide. African Americans were also found to have altered PK compared with Caucasian patients.
Authors
Walko, CM; Combest, AJ; Spasojevic, I; Yu, AYC; Bhushan, S; Hull, JH; Hoskins, J; Armstrong, D; Carey, L; Collicio, F; Dees, EC
MLA Citation
Walko, Christine M., et al. “The effect of aprepitant and race on the pharmacokinetics of cyclophosphamide in breast cancer patients.Cancer Chemother Pharmacol, vol. 69, no. 5, May 2012, pp. 1189–96. Pubmed, doi:10.1007/s00280-011-1815-5.
URI
https://scholars.duke.edu/individual/pub808359
PMID
22245954
Source
pubmed
Published In
Cancer Chemother Pharmacol
Volume
69
Published Date
Start Page
1189
End Page
1196
DOI
10.1007/s00280-011-1815-5

Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome.

Point mutations of the NADP(+)-dependent isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) occur early in the pathogenesis of gliomas. When mutated, IDH1 and IDH2 gain the ability to produce the metabolite (R)-2-hydroxyglutarate (2HG), but the downstream effects of mutant IDH1 and IDH2 proteins or of 2HG on cellular metabolism are unknown. We profiled >200 metabolites in human oligodendroglioma (HOG) cells to determine the effects of expression of IDH1 and IDH2 mutants. Levels of amino acids, glutathione metabolites, choline derivatives, and tricarboxylic acid (TCA) cycle intermediates were altered in mutant IDH1- and IDH2-expressing cells. These changes were similar to those identified after treatment of the cells with 2HG. Remarkably, N-acetyl-aspartyl-glutamate (NAAG), a common dipeptide in brain, was 50-fold reduced in cells expressing IDH1 mutants and 8.3-fold reduced in cells expressing IDH2 mutants. NAAG also was significantly lower in human glioma tissues containing IDH mutations than in gliomas without such mutations. These metabolic changes provide clues to the pathogenesis of tumors associated with IDH gene mutations.
Authors
Reitman, ZJ; Jin, G; Karoly, ED; Spasojevic, I; Yang, J; Kinzler, KW; He, Y; Bigner, DD; Vogelstein, B; Yan, H
MLA Citation
Reitman, Zachary J., et al. “Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome.Proc Natl Acad Sci U S A, vol. 108, no. 8, Feb. 2011, pp. 3270–75. Pubmed, doi:10.1073/pnas.1019393108.
URI
https://scholars.duke.edu/individual/pub748456
PMID
21289278
Source
pubmed
Published In
Proc Natl Acad Sci U S A
Volume
108
Published Date
Start Page
3270
End Page
3275
DOI
10.1073/pnas.1019393108