Nitroxides (such as tempol) which have been used as EPR spin labels have been shown to exhibit superoxide dismutase (SOD) activity and are quite effective agents in protecting cells against a wide variety of oxidative stresses including hydrogen peroxide, superoxide, organic hydroperoxides, redox-cycling chemotherapy drugs, and ionizing radiation. We have demonstrated that Tempol protects both cells in vitro and mice against ionizing radiation. Thus, the nitroxides represent a new class of radiation protectors that may have widespread use in protecting humans against radiation. Importantly, we have shown that tempol does not protect rodent tumor tissue; the mechanism of which we believe involves differential metabolic reduction properties of normal versus tumor tissue. In vivo electron paramagnetic resonance imaging studies in a tumor-bearing animal model has shown more rapid reduction of nitroxides in tumor compared to normal tissue. Recent studies have shown that cells deficient in glucose 6 phosphate dehydrogenase (G6PD) reduce the nitroxide to the hydroxylamine much slower than control cells suggesting a role for this important biochemical pathway in nitroxide reduction. We are presently studying G6PD status in tumor versus normal tissue. Using nitroxide spin probes, the functional EPR imaging system will also enable us to map out oxygen levels in tissue as well as study various redox parameters of tissue.We continue to study the mechanism(s) of nitroxide-mediated radioprotection. Recent studies have shown that only the oxidized form of the nitroxide (as opposed to the reduced form) provides radioprotection. Interestingly, when amino groups are substituted at various positions on the nitroxide ring, radioprotection increases, suggesting the importance perhaps of binding to intracellular targets such as DNA as a necessary component of radioprotection. Studies continue toward evaluating the radioprotective properties of tempol and other nitroxides applied topically to the rectum of rats. Since the rectum is a major normal tissue damaged during radiotherapy for patients with prostate and/or cervix cancer, we will consider using tempol clinically to protect the rectum should our pre-clinical studies prove positive. Our present studies are directed on nitroxide delivery methods to rectal tissue to optimize nitroxide concentration. We are also investigating in in vivo models, the activity of nitroxides alone or appended to macromolecules such as albumin. Since these agents readily penetrate cell membranes, they may be of use in other areas of medical research such as ischemia/reperfusion injury studies, prevention of cataracts, inflammatory processes and aging. We have recently shown that tempol administration after induced ischemia of rat brain markedly reduced the infarct volume associated with ischemia/reperfusion. Preliminary studies have indicated that long term administration of tempol (in the food or drinking water) to p53 knockout mice extends their life span. p53 knockout mice die several months after birth due to rapid tumor induction. Tempol administration extended the life span of these animals ~35-70%. The mechanism of this effect is unknown and is presently a major focus. Likewise, we have shown that long-term administration of tempol to mice results in weight reduction, which we believe impacts leptin and perhaps uncoupling proteins levels. Since nitroxides readily penetrate cell membranes and are potent antioxidants, they may be of use in other areas of medical research such as ischemia/reperfusion injury studies, prevention of cataracts, inflammatory processes, and aging. Lastly, to better understand the effects of tempol treatment at the molecular level we have initiated gene expression studies using cDNA microarrays.

National Institute of Health (NIH)
Division of Clinical Sciences - NCI (NCI)
Intramural Research (Z01)
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Clinical Sciences
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Simone, Nicole L; Soule, Benjamin P; Ly, David et al. (2009) Ionizing radiation-induced oxidative stress alters miRNA expression. PLoS One 4:e6377
Ghosh, Manik C; Tong, Wing-Hang; Zhang, Deliang et al. (2008) Tempol-mediated activation of latent iron regulatory protein activity prevents symptoms of neurodegenerative disease in IRP2 knockout mice. Proc Natl Acad Sci U S A 105:12028-33
Soule, Benjamin P; Hyodo, Fuminori; Matsumoto, Ken-Ichiro et al. (2007) The chemistry and biology of nitroxide compounds. Free Radic Biol Med 42:1632-50
Soule, Benjamin P; Hyodo, Fuminori; Matsumoto, Ken-Ichiro et al. (2007) Therapeutic and clinical applications of nitroxide compounds. Antioxid Redox Signal 9:1731-43
Tsai, Mong-Hsun; Cook, John A; Chandramouli, Gadisetti V R et al. (2007) Gene expression profiling of breast, prostate, and glioma cells following single versus fractionated doses of radiation. Cancer Res 67:3845-52
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Matsumoto, Ken-Ichiro; Hyodo, Fuminori; Matsumoto, Atsuko et al. (2006) High-resolution mapping of tumor redox status by magnetic resonance imaging using nitroxides as redox-sensitive contrast agents. Clin Cancer Res 12:2455-62
Van Waes, Carter; Chang, Angela A; Lebowitz, Peter F et al. (2005) Inhibition of nuclear factor-kappaB and target genes during combined therapy with proteasome inhibitor bortezomib and reirradiation in patients with recurrent head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 63:1400-12

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