Clinical and laboratory reevalution of dichloromethotrexate.

Clinical and pharmacologic effects of dichloromethotrexate (DCM) were reevaluated by an intermittent intravenous large dose schedule in patients with advanced malignancies. DCM was tolerated without Leucovorin (calcium folinate) in man, even when the initial immunoassayable DCM level approached 10(-3) M. Hepatic dysfunction occurred more frequently at high doses. Hematologic toxicity was not dose-limiting. Plasma decay of DCM was comparable to that of methotrexate (MTX). Of 50 patients treated, five including two with hepatic metastasis from colon carcinoma, responded with more than 50% regression of tumor. In vitro comparison of DCM and MTX in Molt 3 cells revealed that DCM was slightly more inhibitory than MTX on an equimolar basis. In the presence of 2.5 g/dl of human serum albumin (HA), however, inhibitory effects of DCM decreased markedly. The decreased biologic effects of DCM compared to those of MTX are due to much higher binding to HA by DCM. This phenomenon appears to explain all of the clinical and pharmacologic characteristics of DCM.