Trimetrexate: clinical development of a nonclassical antifolate.

Trimetrexate is a 2,4-diaminoquinazoline inhibitor of dihydrofolate reductase (DHFR) which is cytotoxic in vitro and in vivo to several tumors resistant to methotrexate. It is more lipophilic than the parent antifolate, and is not transported by the reduced folate carrier. These features promise activity greater than that of methotrexate in the clinic; its inability to undergo polyglutamylation may also enhance the therapeutic index. In preclinical models, the activity of trimetrexate was highly schedule dependent, being superior on repeated dose schedules. Phase I studies have demonstrated that myelosuppression is the major toxic effect of trimetrexate on all schedules tested in man. Phase II studies will evaluate a 5-day schedule initially; trials in multiple tumor types and examination of the role of schedule are already under way.