Increased radiosensitivity of aerobic mammalian cells following pre-incubation with misonidazole in hypoxia.

The effect of pre-incubation of CHO cells with misonidazole in hypoxia on the aerobic radiosensitivity of these same cells was observed and analyzed according to the concepts of independent and additive interaction. It was found that the sensitivity of cells irradiated in air, in the presence or absence of misonidazole, increased when the cells had been pre-incubated with misonidazole in hypoxia at 37 degrees C. This increase in aerobic radiosensitivity was evident as a loss of the shoulder of the survival curve, and the data were consistent with an additive, rather than an independent interaction mechanism. The effect was also observed when the cells were washed prior to irradiation. These data are consistent with our previous work with hypoxic cells, and support the hypothesis that a toxic metabolite of the sensitizer is produced during hypoxic incubation, whose effect is manifested as an additional increment of cell killing equivalent to an additional dose of radiation. Given the possibility of a diffusible toxic product of sensitizer nitroreduction, the hypoxic cell toxicity of nitroimidazoles, generally perceived to be of importance only in hypoxic cells, may be a factor in the radiosensitivity of non-hypoxic cells in tumours.