Mechanism of misonidazole-linked cytotoxicity and altered radiation response: role of cellular thiols

The effectiveness of misonidazole as a hypoxic radiosensitizer of mammalian cells is increased by prolonged exposure of hypoxic cells to the drug. Increased radiosensitization occurs even after the cells are washed free of excess Hall and Biaglow, 1977; Whitmore et al., 1978; Varnes et al., 1981). Hall et al. (1977) suggested and Biaglow et al. 1978) found that drug intermediates, produced during hypoxic incubation of cells with misonidazole, might react with endogenous non-protein thiols (NPSH). These thiols function to protect the cell against deleterious intermediates that could otherwise attack and modify critical macromolecules such as DNA, RNA and protein. This hypothesis is in agreement with the cytotoxic mechanisms proposed earlier for many different nitro compounds (Biaglow, 1981). With respect to the effects of preincubation with misonidazole on the radiation response, alterations in both NPSH and protein thiols (Varnes et al., 1981) would be expected to alter the shoulder of the radiation response curve if hydrogen-donating species such as NPSH are involved in chemical repair of radiation damage (Chapman et al., 1973) or if thiol-containing enzymes are necessary for biochemical repair of damaged macromolecules (Han et al., 1976).