We will continue to explore the importance of oxidative events in the cytotoxicity of anticancer drugs with different cellular targets including lipid-rich membranes. We wish to develop oxidative and membrane strategies to use as adjuncts to enhance traditional chemotherapy and make it more selective for neoplastic cells. The hypothesis to be tested is that oxidatively active mediators, especially the signaling molecule nitric oxide, can be used to therapeutic advantage. Our preliminary evidence shows that nitric oxide amplifies anthracycline chemotherapy. Initial investigations will be done in vitro to confirm the most promising drugs, and the optimal times and concentrations of drugs and nitric oxide to be used subsequently in vivo. We will also study cultured heart cells to ascertain if the strategy has potential selectivity. In related studies, we have found that H2O2 causes apoptosis in human leukemia cells, and it may be mediated by peroxidase. H2O2 derived from intracellular oxidation reactions, and free radicals derived from lipids of neoplastic cell membranes may play a central role in the mechanism of cancer chemotherapy agents with diverse and distinct targets. In our studies membrane-active and DNA-active drugs will be compared. Sensitive/resistant cell line pairs will be used to explore the relationship of peroxidation and cytotoxicity. The kinetic and concentration relationship of each peroxidative event to immediate cytotoxicity and clonogenic survival will be determined. Manipulation of oxidative susceptibility will be done using transfection of antioxidant enzymes, glutathione depletion, and antioxidants. A membrane modification model by which cells can be enriched with polyunsaturated fatty acids of various types, thereby increasing their susceptibility to peroxidative events, will be used in some studies to amplify events not otherwise detectable. An understanding of these modulators or mediators can provide a powerful new strategy for anticancer chemotherapy especially as adjuvants along with traditional cytotoxic cancer chemotherapy. Clinical contexts will be pursued, but not forced. The results could lead to the design of innovative ways to experimentally manipulate free radical events to increase selectivity of agents for neoplastic cells or overcome resistance.
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