ROLE OF GLUTATHIONE IN THE HYPOXIC CELL CYTO-TOXICITY OF MISONIDAZOLE

Abstract

Misonidazole (MIS) is a hypoxic cell radiosensitizer currently undergoing phase III clinical trials in the treatment of cancer by radiation. It is also a cytotoxic agent with specificity toward hypoxic cells, and consequently has a tumoricidal effect in laboratory animals. The tumoricidal effect has not been clinically applicable, in part because the initial resistance to the cytotoxic action of MIS (the nonexponential portion, or shoulder, of the semilogarithmic plot of the surviving fraction of the cell population vs. the time of exposure to MIS, referred to hereafter as the shoulder of the survival curve) for cells treated with MIS under hypoxic conditions is too large to be overcome at clinically tolerable doses of MIS. Pretreatment of Chinese hamster ovary cells in vitro with diethylmaleate to deplete intracellular glutathione results in a substantial decrease in the shoulder of the survival curve for MIS-treated hypoxic cells. Restoration of glutathione results in restoration of the shoulder of the survival curve and a slight extension beyond that seen with control cells. Evidently, glutathione protects against the cytotoxic effect of MIC. Glutathione depletion does not significantly affect the rate of binding of MIS metabolites to cellular macromolecules, indicating that the cytotoxicity of MIS is not simply a reflection of massive binding of MIS metabolites to cellular constituents. The cytotoxicity of MIS toward hypoxic cells may be a result of hydrogen abstraction from target molecules by free radicals formed in the reduction of the nitro group.