Misonidazole and CCNU: Further evidence for a pharmacokinetic mechanism of chemosensitization and therapeutic gain

Abstract

Detailed studies of the effects of misonidazole (MISO) on the pharmacokinetics of CCNU in the KHT tumour, bone marrow and the gut have been carried out in order to elucidate the mechanism of chemosensitisation by MISO, and the therapeutic gain often obtained due to the preferential enhancement of tumour toxicity. In experiments where CCNU concentration and growth delay were both measured in the same transplant group of tumours, we found that tumour response is well correlated with tumour peak CCNU concentration. Further, with MISO treatment the tumour peak CCNU concentration was increased such that the enhancement of tumour response can be entirely accounted for by this increase. The effects of MISO on the CCNU pharmacokinetics in bone marrow and in the gut were different from the tumour in that peak CCNU concentration was not increased. We suggest that this is the explanation for the therapeutic gain.