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Delayed Radioprotection by Thiols

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The goal of this investigation is the characterization of the delayed radioprotective effect induced following exposure of cells to non-protein thiols (NPT). The underlying hypothesis is that NPT exposure of cells results in activation of the redox sensitive nuclear transcription factor kappaB (NFkappaB) and enhancement in manganese superoxide dismutase (MnSOD) gene expression followed by elevated intracellular levels of active MnSOD protein. MnSOD is an anti-oxidant protein that can confer protection against oxidative radical species induced by ionizing radiation. The ability of NPT to induce at a later time elevated MnSOD levels results in a delayed radioprotective effect that will have implications in radioprotection in general, and tumor protection in particular. This study focuses on four clinically approved NPT, amifostine, mesna, Nacetylcysteine (NAC), and captopril. These NPT are currently in clinical use, and the potential for their induction of a delayed radioprotective effect in tumors of patients undergoing cancer treatment is a here-tofore unrecognized problem. Four specific aims are proposed. Aim 1 seeks to test the hypothesis that NPT over a range of doses will enhance MnSOD gene expression, leading to elevated intracellular levels of active MnSOD protein accompanied by increased catalase and glutathione peroxidase (GPx) activities in cultured tumor and non-tumor cells. Aim 2 will test the hypothesis that elevated MnSOD activity will result in enhanced radioprotection, especially at 2 Gy. Aim 3 is focused on testing the hypothesis that either single or multiple exposures of animals to NPT will result in elevated MnSOD gene expression and protein activity in both normal and tumor tissues, the latter grown as pulmonary tumor nodules or solid tumors in the hind legs of animals. Aim 4 will test the hypothesis that elevated MnSOD activity will result in delayed radioprotection to selected normal and tumor tissues as determined by quantitative survival assays, i.e., spleen colony assay, intestinal microcolony assay, lung colony assay, and the TCD50 assay. Two alternative hypotheses will also be tested. One elevated MnSOD activity can result in anti-oxidant imbalance relating to catalase and GPx activities, resulting in hydrogen peroxide buildup and radiation sensitization. Two, elevation in MnSOD level without a concomitant increase in enzymatic activity can result from nitration of MnSOD by peroxynitrite (ONOO-).

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