Initial clinical studies of piritrexim.

Piritrexim (PTX) is a second-generation, lipid-soluble inhibitor of dihydrofolate reductase (DHFR). Metabolic inhibition occurs within seconds after rapid diffusion into human cancer cells. We describe the initial phase I studies with iv and oral forms of this drug given on a daily basis for 5 days to patients with cancer. The dose-limiting toxicity is primarily hematologic (leukopenia, granulocytopenia, thrombocytopenia), but phlebitis is also encountered with iv administration and gastrointestinal problems (nausea, vomiting) with oral administration. Oral toxicity can be reduced by giving the daily dose in 2 divided doses. The maximum tolerated dose (MTD) for the iv route is 170 mg/m2 per day for 5 days; for the oral route it is 480 mg/m2 per day for 5 days. Unlike an earlier lipid-soluble folate antagonist, piritrexim did not cause neurologic or histamine-like disorders.