title: Phase I trial of fluorouracil modulation by N-phosphonacetyl-L-aspartate and 6-methylmercaptopurine ribonucleoside (MMPR), and leucovorin in patients with advanced cancer.
abstract: The results of several clinical trials support the hypothesis that biochemical modulation may enhance the antitumor activity of 5-Fluorouracil (5-FU). We have performed a phase I trial using a combination of three different biochemical modulators at the optimal dose established in previous clinical trials. The modulators include: phosphonacetyl-l-aspartate (PALA), which may increase 5-FU incorporation into RNA; leucovorin, which potentiates thymidylate synthase inhibition; and 6-methylmercaptopurine riboside (MMPR), which promotes the intracellular retention of fluorinated nucleotides. The treatment regimen consisted of PALA 250 mg/m2 day 1, followed 24 h later by MMPR 150 mg/m2 as an iv bolus, and the initiation of a 24-hour infusion of 5-FU along with leucovorin 50 mg/m2. This regimen was repeated weekly. Doses of 5-FU were escalated in cohorts of four or more patients from 2,000 to 2,600 mg/m2. Among 20 patients entered, the majority had colorectal cancer, and most had received prior 5-FU treatment. Toxicity was predominantly gastrointestinal, and diarrhea was dose-limiting at a 5-FU dose of 2600 mg/m2. There were three partial remissions observed, two of whom had colorectal cancer. Emerging data that casts doubt on the modulation value of PALA at this dose and schedule suggests that revision of this regimen be considered before Phase II trial.
authors.affiliation: Fax Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: A
authors.initials: A
authors.lastname: Hageboutros
authors.forename: G R
authors.initials: GR
authors.lastname: Hudes
authors.forename: F
authors.initials: F
authors.lastname: Greene
authors.forename: F P
authors.initials: FP
authors.lastname: LaCreta
authors.forename: J
authors.initials: J
authors.lastname: Brennan
authors.forename: P J
authors.initials: PJ
authors.lastname: O'Dwyer
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D001224:Aspartic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008778:Methylthioinosine / Q000008:administration & dosage / Q000494:pharmacology*; D008875:Middle Aged; D010746:Phosphonoacetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000964:Antimetabolites, Antineoplastic; D001224:Aspartic Acid; D008778:Methylthioinosine; C013195:sparfosic acid; D010746:Phosphonoacetic Acid; D002955:Leucovorin; D005472:Fluorouracil