Effect of pretreatment with phenobarbital or SKF 525A on the toxicity and antitumor activity of lomustine.

Previous investigations have shown that the combination of the conventional chemotherapeutic agent lomustine (CCNU) and the nitroimidazole radiation sensitizer misonidazole can lead to an improved therapeutic result. To study whether altered CCNU metabolism plays a role in this chemopotentiation, mice were treated with known modifiers of hepatic microsomal enzymes prior to CCNU exposure, and tumor response and systemic toxicity were assessed. KHT sarcoma-bearing C3H/HeJ mice were pretreated with either (a) five daily doses of phenobarbital (80 mg/kg) to induce the microsomal enzymes and then CCNU 48 hours later or (b) a 50-mg/kg dose of the microsomal enzyme inhibitor SKF 525A 1 hour before CCNU. Tumor response and normal tissue toxicity following treatment were measured using a regrowth delay and 30-day lethality assay, respectively. Phenobarbital pretreatment reduced both the antitumor efficacy and toxicity of CCNU (factor of approximately 0.8), while SKF 525A increased the effect of CCNU in both cases (factor of approximately 1.6). Thus, unlike pretreatments with the sensitizer misonidazole, pretreatments with phenobarbital or SKF 525A did not result in a therapeutic advantage for CCNU.