A phase I study of meta-azidopyrimethamine ethanesulphonate (MZPES)--a new dihydrofolate reductase inhibitor.

A total of 68 patients were treated in a phase I study of meta-azidopyrimethamine ethanesulphonate (MZPES)--a novel lipophilic dihydrofolate reductase (DHFR) antagonist. The dose was increased from 5.4 mg/m2 to 460 mg/m2 given as a 1-h infusion, with 460 mg/m2, 600 mg/m2 and 800 mg/m2 given as a 24-h infusion. The dose-limiting toxicity was nausea and vomiting, which was marked at doses above 360 mg/m2 by 1-h infusion and 600 mg/m2 by 24-h infusion. Above 250 mg/m2 patients also described subjective neurological symptoms, although no objective signs were apparent. Myelosuppression was not consistent at any dose level. No objective responses were seen. In view of the lack of anti-folate activity at toxic levels, no phase II trials are currently proposed; toxicological and in vitro studies will continue.