The successful treatment of malignant solid tumors by chemotherapeutic regimens requires the eradication of both the aerobic and hypoxic cells comprising the tumor. Agents such as Adriamycin and mitomycin c have been shown to be preferentially cytotoxic to the more difficultly eradicated hypoxic tumor cells versus their aerobic counterparts. These agents, however, are toxic to aerobic cells and severe side effects, possibly due to the generation of toxic oxygen radicals by these agents, greatly limit their therapeutic efficacy. Evidence suggests that the cytotoxic mechanism of action of these agents to hypoxic cells may be different from their cytotoxic mechanism of action to aerobic cells. Attenuation of their aerobic toxicity relative to their hypoxic toxicity could greatly enhance their therapeutic efficacy. This proposal is designed to test the effectiveness of antioxidant (i.e., alpha-tocopherol, beta-carotene and sulfhydryl containing compounds) pretreatment regimens which would decrease aerobic cell cytotoxicity relative to hypoxic cell cytotoxicity. EMT6 mouse mammary tumor cells will serve as the model system. Successful in vitro regimens will be further tested in vivo using the mouse mammary EMT6 solid tumor model. In vivo tests will measure antioxidant host protection from drug toxicity as well as the antioxidant effect on tumor response to drug treatment and x- irradiation. It is envisioned that this pretreatment therapy will enhance the preferential cytotoxicity of these agents to hypoxic cells by decreasing potential side effects and thereby increasing the therapeutic efficacy of these chemotherapeutic agents. (Antioxidant treatment regimens, which increase the preferential cytoxicity of the chemotherpeutic agents tested to hypoxic cells, will be combined with x-irradiation to formulate a therapeutic regimen of increased efficacy against solid tumors).
