Misonidazole protects mouse tumour and normal tissues from the toxicity of oral CCNU

Abstract

Because the nitrosourea CCNU is given exclusively by the oral route in man, we have carried out studies in mice on the antitumour activity, acute toxicity and pharmacokinetics of oral CCNU, either alone or in combination with the chemosensitizer misonidazole. In both plasma and KHT tumour the peak concentration and "early" AUC for total nitrosoureas were about 1.4-1.5 fold greater for the oral compared to the i.p. route. These differences were reflected in the roughly twofold greater antitumour activity for the oral route. In contrast, acute toxicity tests showed that oral CCNU was 1.45 times less toxic to normal tissue, although the dose-limiting organ may be different for the two routes. Misonidazole reduced the antitumour activity of oral CCNU by dose modifying factors (DMF) of 0.58-0.71. Similarly, the acute toxicity was also diminished by a DMF of 0.74. Misonidazole has a complex effect on oral CCNU pharmacokinetics. The plasma and tumour total nitrosourea peak concentrations were reduced by 1.5 and 1.7 fold respectively. Misonidazole also reduced the "early" nitrosourea AUC, with the extent of the reduction depending on the minimum effective concentration (MEC) chosen. For example, the plasma nitrosourea AUC was reduced by factors of 1.05 and 9.6 for MEC values of 1 and 2 micrograms ml-1 respectively. We propose these pharmacokinetic changes to be the underlying mechanism for the reduction of oral CCNU cytotoxicity by misonidazole. Clinical trials of such combinations should be accompanied by detailed pharmacokinetic evaluation.