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.
Highlights
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 have previously shown in mice that MISO prolonged the initial plasma elimination half-life of CCNU, which in turn led to an increase in peak CCNU tumour concentration and we proposed this as a mechanism of chemosensitization for this combination (Lee & Workman, 1983)
More definitive evidence for this mode of action of MISO is needed to establish that the increase in tumour toxicity does directly parallel the increase in tumour drug concentration
Summary
All drugs used were gifts: MISO from Roche Products Ltd.; CCNU from the Drug Synthesis and Chemistry Branch of the National Cancer Institute, USA, and from Lundbeck; and the monohydroxylated metabolites of CCNU from Dr T.P. Johnston of the Southern Research Institute, Alabama, USA
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