Cytotoxicity of misonidazole in vivo under conditions of prolonged contact of drug with the tumour cells

A single high dose of misonidazole (> = 1 mg/g) given to BALB/c mice bearing EMT6 tumours killed approximately 90% of the tumour cells. No cytotoxicity, however, can be demonstrated at more clinically relevant dose levels (< = 0.3 mg.g). The plasma half-life of misonidazole is approximately 12 hours in man. An attempt has been made to simulate the human situation in the BALB/c mouse by performing bilateral kidney ligations prior to injection of misonidazole. This extended the apparent plasma half-life of misonidazole plus its O-demethylated metabolite after an injection of 0.1 mg/g of misonidazole from approximately one hour to seven hours. Despite finding extensive killing of tumour cells at the high dose of misonidazole of 1.2 mg/g, no detectable cytotoxicity was observed in the low dose (0.1 mg/g) mice in which the plasma half-life had been extended to seven hours. This suggests that misonidazole will produce little, if any, cytotoxicity to human tumours. (author)