NITROXIDES AS PROTECTORS AGAINST OXIDATIVE STRESS

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"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. We have completed an in vitro study to identify the most efficient nitroxide for protection purposes. Over 110 nitroxides were evaluated in a structure activity relationship study. We have identified 6 nitroxides that afford significantly more radioprotection than tempol (the first nitroxide shown to have radioprotective properties) and have also identified 3 analogs that radiosensitize aerobic cells. These agents will be evaluated and compared with tempol in vivo. Large quantities of several of the six protective nitroxides are being synthesized for further study of these newly discovered protectors. We have recently shown that heme proteins exposed to oxidants form highly toxic ferryl moieties and that nitroxides detoxify these toxic species and confer enhanced catalase-like activity to heme species. Reasoning in an analogous fashion we are investigating the affects of nitroxides as modulators of nitric oxide synthase because intermediates within the enzyme which depend on heme redox chemistry may be altered in the presence of nitroxides. We are also investigating in in vivo models, the activity of nitroxides 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.