Radiosensitizing and cytotoxic properties of ortho-substituted 4- and 5-nitroimidazoles: Role of NPSH reactivity

Abstract

Chinese hamster (V79) cells were used to investigate the radiosensitizing efficiency and chemical reactivity with non-protein sulfhydryl (NPSH) compounds such as glutathione, for a series of a-substituted 4 and 5 nitroimidazoles. When added to cells 5 minutes prior to irradiation, MJL-1–191-VII (1-methyl-5-sulfonamide-4-nitroimidazole) sensitizes hypoxic cells commensurate with its electron affinity, while not affecting the radiosensitivity of aerated cells. If the drug is incubated with the cells for a period of time at 37°C prior to irradiation, both aerated and hypoxic cells show an increase in radiosensitivity. Under these conditions the radiosensitizing effectiveness towards hypoxic cells appears to be particularly anomalous, inasmuch as enhancement ratios similar to misonidazole can be obtained at concentrations 50 to 100 times lower. The isomer SK-21981 (1-methyl-4-sulfonamide-5-nitroimidazole) does not behave in this anomalous way, but sensitizes to an extent predictable from its electron affinity. These compounds differ in the rate at which they react spontaneously and intracellularly with NPSH compounds such as glutathione. It is suggested that MJL sensitizes by two mechanisms; the first a function of its electron affinity and the second a function of its rapid reaction with endogenous radioprotective and chemotherapeutic compounds in the cell.