The enhanced sensitivity of mammalian cells to killing by X rays after prolonged exposure to several nitroimidazoles.

Electron affinic compounds, such as misonidazole, preferentially sensitize hypoxic cells to killing by X rays, and are also preferentially cytotoxic to cells deficient in oxygen. Prolonged exposure of cells to misonidazole prior to irradiation results in an increased radiosensitization. This is expressed as the Extra Enhancement Ratio (EER), defined as the ratio of the doses delivered immediately after the addition of the sensitizer or after prolonged incubation, that produce a given biological effect. Chinese hamster V79 cells have been used to investigate this prolonged incubation effect for a variety of 2-nitroimidazoles including misonidazole, desmethylmisonidazole and SR-2508 and as well as two ortho-substituted-4-nitroimidazoles with a bromine or sulfonamide group substituted in the 5-position. A considerable variation was observed in the magnitude of the Extra Enhancement Ratio (EER) produced by pre-incubation with different compounds at concentrations that produce the same sensitizing effect. There is a good correlation between the EER and the measured rate at which the various sensitizers deplete cells of non-protein sulfhydryl compounds. There is also a good correlation between the EER and the fraction of cells killed by the pre-incubation period in the drug.