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

Abstract

A single high dose of misonidazole (greater than or equal to 1 mg/g) given to BALB/c mice bearing EMT6 tumours kills approximately 90% of the tumour cells. No cytotoxicity, however, can be demonstrated at more clinically relevant dose levels (less than 0.3 mg/g). However, Stratford and Adams (1978) have shown that extensive killing of hypoxic cells occurs in vitro with low concentrations of misonidazole provided that the contact time is long, such as would occur in man in whom the plasma half-life of misonidazole is approximately 12 hours. We have attempted to simulate the human situation in the BALB/c mouse by performing bilateral kidney ligations prior to injection of misonidazole. This extends 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. This provided a good fit over the first nine hours to the in vitro simulation of the human plasma clearance curve done by Stratford and Adams (1978). However, 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, cytoxocity to human tumours.