In vitro inhibition of misonidazole toxicity and melphalan chemopotentiation by metyrapone.

Overnight exposure of Chinese hamster cells, V-79-753B, to 10(-3)M metyrapone protected them against the hypoxiamediated toxicity of 10(-2)M misonidazole. This protection was accompanied by an increase in radiation resistance. There was no appreciable change in the oxygen-enhancement ratio, nor in the amount of sensitisation produced by 10(-3)M misonidazole. Treatment of cells with metyrapone (10(-3)M) or dexamethasone (1 microgram ml-1 [approximately 2 X 10(-6)M]) prior to exposure first to 5 X 10(-3)M misonidazole in hypoxia and then to melphalan in air, substantially decreased the amount of chemopotentiation produced by the sensitiser, although the toxicity of melphalan alone was not affected in cells treated with either compound. Cells pretreated with either metyrapone or dexamethasone had 2-3 times more glutathione than control cells. This increase in GSH could not explain the change in radiation response, since cells pretreated with 5 X 10(-5)M flurbiprofen, a non-steroidal anti-inflammatory agent, had similarly high GSH levels, but their radiation response is similar to that of untreated cells (Millar et al, 1981). Neither dexamethasone nor flurbiprofen affected cell growth, whilst metyrapone markedly decreased the growth of cells. The results are discussed in terms of possible mechanism(s).