Many agents, including anesthetics, cancer chemotherapeutic agents and antibiotics are activated to cytotoxic products under anaerobic or hypoxic conditions. The role of glutathione in protecting cells from cytotoxic agents which are activated under hypoxia is not well known. Furthermore, little information is available on the regulation of glutathione levels during hypoxia. This information may be critical for predicting cellular sensitivities to drugs and chemicals activated under hypoxic conditions by tumor cells. The effects of glutathione depletion on mitomycin C cytotoxicity toward both aerobic and hypoxic tumor cells will be assessed by comparison to dose response curves for the drug in cells that have been treated with diethylmaleate or butathionine sulfoxamine with those for cells treated with mitomycin alone. The addition of exogenous non-protein sulfhydryl compounds to cells will be used in an effort to protect cells from the deleterious effects of mitomycin C. Prostaglandin synthesis inhibitors such as indomethacin and aspirin will be used to assess the role of cyclooxygenase in activating mitomycin C to a cytotoxic agent. In addition, the correlation between alterations in mitomycin C induced cytotoxicity by glutathione depletion or prostaglandin synthetase inhibition and the formation of the putative cell lesion will be investigated. The levels of DNA-DNA crosslinks will be measured by alkaline elution techniques and compared with cytotoxicity of mitomycin C under the conditions which alter the lethality of the drug toward tumor cells. These studies will enhance our understanding of the biochemical responses of tumor cells to cytotoxic chemotherapy and will add to our knowledge on the mechanism of mitomycin C in aerobic and hypoxic tumor cells.
