The presence of radiation resistant hypoxic cells in tumors adversely affects cancer therapy by the use of x-rays of Gamma-rays. Hypoxic cell radiation sensitizers such as the nitroimidazoles, metronidazole and misonidazole, have been used to overcome this problem due to hypoxic cells. The full potential of clinical benefits has not been achieved because undesireable side effects, due to nerve damage, occur when these drugs are administered in large doses. We plan to study the mechanisms involved in the interactions of these electron affinic nitro compounds with mammalian enzymes such as xanthine oxidase and cytochrome P450 reductase which are known to reduce several nitro compounds. We will apply biochemical and ESR techniques to study the mechanisms of these reactions which may be important in terms of the cytotoxic and neurotoxic action of these drugs. We have found that nitro and nitroso compounds can accelerate autooxidation of catecholamines and ascorbate. We have detected free radical intermediates during the interactions of nitro and nitroso compounds with catecholamines, ascorbate and reduced glutathione. Metronidazole and misonidazole depress the heart rate and body temperature of mice. This may reflect catecholamine depletion in these animals. Therefore, we want to test whether short term and chronic administration of metronidazole and misonidazole lowers the norephinephrine and dopamine content of heart and brain of mice. In view of the tendency of nitro compounds to interact with nitro compounds, we want to test the effect of catecholamines on the radiosensitization, mutagenicity and cytotoxicity of the nitroimidazoles, metronidazole and misonidazole. We plan to use tissue culture cells for these studies. We have developed a hypothesis based on our preliminary studies and the work of others that neurotoxicity of misonidazole may be due to (i) oxidation and depletion of catecholamines, ascorbic acid and sulfhydryl compounds, and (ii) formation of hydroxyl, superoxide and hydronitroxyl free radicals. Our studies will help us to better understand the mechanism of cytotoxic action of these radiosensitizers and may provide answers which may help increase their usefulness in the radiation therapy of cancer.