Role of glutathione in the hypoxic cell cytotoxicity of misonidazole.

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Misonidazole () is a hypoxic cell radiosensitizer currently undergoing Phase III clinical trials in the treatment of by radiation. It is also a cytotoxic agent with specificity toward hypoxic cells, and consequently has a tumoricidal effect in laboratory . This tumoricidal effect has not been clinically applicable, in part because the initial resistance to the cytotoxic action of (the nonexponential portion, or shoulder, of the semilogarithmic plot of the surviving fraction of the cell population versus the time of exposure to , referred to hereafter as the shoulder of the survival curve) for cells treated with under hypoxic conditions is too large to be overcome at clinically tolerable doses of . We report here that pretreatment of ovary cells in vitro with diethylmaleate to deplete results in a substantial decrease in the shoulder of the survival curve for -treated hypoxic cells. Restoration of results in restoration of the shoulder of the survival curve and a slight extension beyond that seen with control cells. These results demonstrate that protects against the cytotoxic effect of . However, depletion does not significantly affect the rate of of metabolites to cellular macromolecules, indicating that the cytotoxicity of is not simply a reflection of massive of metabolites to cellular constituents. We propose that the cytotoxicity of toward hypoxic cells is a result of hydrogen abstraction from target molecules by free radicals formed in the reduction of the .

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Animals Cricetulus Ovary Cell Line Anoxia Nitroimidazoles Glutathione Transferase Glutathione Antineoplastic Agents Cell Survival