The toxicity of the radiosensitizer misonidazole towards hypoxic cellsin vitro: a model for mouse and man

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Abstract
The drug misonidazole, which is currently undergoing clinical trials as a radiosensitizer, is much more toxic towards hypoxic cells than to those which are aerobic. This toxicity occurs at drug concentrations that might be used clinically for radiotherapy treatment. Consequently, if an enhancement of the radiation response is seen when misonidazole is used clinically, this may not only be due to radiosensitization of hypoxic cells but may also be due, in part, to the cytotoxic action of the drug alone. The contribution of cytotoxicity to total radiosensitization is likely to be greater in man than in mouse. Evidence supporting this was obtained using Chinese hamster V79 cells, an in vitro mammalian cell system was described. The technique permits measurement of the cytotoxicity of misonidazole under conditions where the concentration of drug given to the cells can be progressively reduced. This is achieved by gradual addition of hypoxic medium to the suspension culture containing drug at 37.degree. C. This is an attempt to simulate the conditions in vivo where hypoxic cells in tumors are exposed to a continually decreasing drug concentration. Results provide indirect evidence that toxicity to hypoxic cells may well contribute significantly to overall radiosensitization in man to an extent much greater than has been demonstrated in mouse.