NITROXIDES AS PROTECTORS AGAINST OXIDATIVE STRESS

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Nitroxides 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. Preliminary studies using a rodent tumor model have shown that tempol does not protect tumor tissue, The mechanism of this finding may involve differential metabolic reduction properties of normal versus tumor. Additionally, work has begun to identify the most efficient nitroxide for protection purposes. We have recently evaluated approximately 110 nitroxides in a structure activity relationship study. These nitroxides were kindly given to us from Dr. Hideg of Hungary, an international expert on nitroxide synthesis. We have identified 6 nitroxides that afford significantly more radioprotection than tempol (the first nitroxide shown to have radioprotective properties). Interestingly, we have also identified 3 analogs that radiosensitize aerobic cells. Mechanistic studies are underway to explore this finding. We have also demonstrated that nitroxides administered to animals after local irradiation to the kidney offers significant protection. More recently we have been investigating the mechanism by which these agents stimulate catalase like activity in heme proteins which otherwise would in combination produce highly toxic oxidants. Since these agents readily penetrate cell membranes, they may be of use in other areas of medical research such as ischemia/reperfusion injury studies. Furthermore, these studies have opened the possibility of interrelating the biochemistry and metabolism of nitroxides to endogenously produced endothelial relaxation factor, nitric oxide.