PHASE-I TRIAL OF FLUOROURACIL MODULATION BY N-PHOSPHONACETYL-L-ASPARTATE AND 6-METHYLMERCAPTOPURINE RIBONUCLEOSIDE (MMPR), AND LEUCOVORIN IN PATIENTS WITH ADVANCED CANCER

The results of several clinical trials support the hypothesis that bio chemical modulation may enhance the antitumor activity of 5-Fluorourac il (5-FU). We have performed a phase I trial using a combination of th ree different biochemical modulators at the optimal dose established i n previous clinical trials. The modulators include: phosphonacetyl-1-a spartate (PALA), which may increase 5-FU incorporation into RNA; leuco vorin, which potentiates thymidylate synthase inhibition; and 6-methyl mercaptopurine riboside (MMPR), which promotes the intracellular reten tion of fluorinated nucleotides. The treatment regimen consisted of PA LA 250 mg/m(2) day 1, followed 24h later by MMPR 150 mg/m(2) as an iv bolus, and the initiation of a 24-hour infusion of 5-FU along with leu covorin 50 mg/m(2). This regimen was repeated weekly. Doses of 5-FU we re escalated in cohorts of four or more patients from 2,000 to 2,600 m g/m(2). Among 20 patients entered, the majority had colorectal cancer, and most had received prior 5-FU treatment. Toxicity was predominantl y gastrointestinal, and diarrhea was dose-limiting at a 5-FU dose of 2 600 mg/m(2). There were three partial remissions observed, two of whom had colorectal cancer. Emerging data that casts doubt on the modulati on value of PALA at this dose and schedule suggests that revision of t his regimen be considered before Phase II trial.