We have studied the effect of misonidazole (MISO) on the antitumour activity, normal tissue toxicity and pharmacokinetics of four bifunctional nitrogen mustards: chlorambucil (CHL); phenylacetic acid mustard (PAAM), a metabolite of CHL; beta, beta-difluorochlorambucil (beta-F2CHL), an analogue which is metabolized less efficiently by the beta-oxidation pathway; and melphalan (MEL). MISO (2.5 mmol/kg) increased the response of the KHT tumour to CHL, PAAM and beta-F2CHL by dose-modifying factors (DMFs) of 1.55-1.85, 1.35-1.65 and 1.5-1.8, respectively. In contrast, the activity of MEL was not altered. However, with 5.0 mmol/kg MISO an enhanced response to MEL was observed (DMF = 1.35-1.55). Similarly, for CHL and PAAM, but not MEL, acute toxicity was also increased by 2.5 mmol/kg MISO. The increase in toxicity with CHL and PAAM was similar to the increase in antitumour activity, and their therapeutic indices were unchanged. Effective chemosensitizers were shown to be powerful inhibitors of drug clearance. Thus, potent chemosensitizers such as MISO, the lipophilic analogue benznidazole (BENZO), the microsomal enzyme inhibitor SKF 525A, and the parent heterocycle imidazole all reduced the plasma clearance of CHL and its metabolites and therefore increased drug exposure (AUC). Conversely, the hydrophilic MISO metabolite Ro 05-9963 was a poor chemosensitizer and produced only very weak pharmacokinetic effects. As the DMFs for chemosensitization agreed very well with those for increased AUC, it seems likely that pharmacokinetic changes are the major cause of the enhancement of tumour response to CHL. For MEL, chemosensitization also appears to be related to pharmacokinetic changes. MISO at a dose of 2.5 mmol/kg produced no change in MEL pharmacokinetics and no enhancement of tumour response, whereas 5.0 mmol/kg MISO was effective on both counts.
Summary 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 2pgml-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.
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