DEVELOPMENT OF SUPEROXIDE DISMUTASE MIMICS

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Our laboratory has shown that nitroxides, which have been used as EPR spin labels exhibit superoxide dismutase (SOD) activity and are quite effective agents in protecting cells against a wide variety of oxidative stresses. Our lead compound, Tempol, a water soluble nitroxide has been shown to protect mammalian cells against superoxide generated from xanthine/xanthine oxidase, and direct hydrogen peroxide cytotoxicity. 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. Further chemical characterization of the SOD mimic activity of nitroxides has revealed the presence of an oxoammonium cation intermediate. This information will be used to identify for maximal protective capacity based on their oxidation potential and charge. Tempol has been shown to protect cells against mutation induction mediated by superoxide, hydrogen peroxide, and radiation. Tempol has also been shown to protect cells exposed to various chemotherapy drugs including mitomycin C and SR-4233. Not only might these agents be useful in protecting against certain chemotherapy agents but should be instructive in determining mechanisms of action. Topically applied, Tempol has been shown to protect against radiation- induced alopecia in guinea pigs. It has also been shown to be a novel class of anti-ulcerogenic compounds. 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 inter-relating the biochemistry and metabolism of nitroxides to endogenously produced endothelial relaxation factor, nitric oxide.