title: Phase II trial of PALA and 6-methylmercaptopurine riboside (MMPR) in combination with 5-fluorouracil in advanced pancreatic cancer.
abstract: The biochemical modulators PALA, an inhibitor of aspartate transcarbamylase which depletes uridine nucleotide pools, and 6-methylmercaptopurine riboside (MMPR) which inhibits purine metabolism, selectively potentiate the antitumor activity of 5-fluorouracil (5-FU) in preclinical models. Based on a phase I trial of this combination, we performed a phase II trial in patients with advanced pancreatic cancer. PALA 250 mg/m2 was administered i.v. on day 1, followed 24h later by MMPR 150 mg/m2 as a bolus i.v. injection, and 5-FU 2300 mg/m2 by 24h infusion. Treatments were repeated weekly. Seventeen patients, all previously untreated with chemotherapy, were entered, of whom 14 are evaluable for response. Toxicity > or = grade 2 included nausea (6/17), vomiting (4/17), diarrhea (3/17), stomatitis (5/17), and neurotoxicity (2/17). Among 14 evaluable patients there were no partial responses, and two patients with stable disease. Pretreatment with PALA and MMPR is insufficient to enhance the activity of 5-FU in pancreatic cancer.
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: I
authors.initials: I
authors.lastname: Redei
authors.forename: F
authors.initials: F
authors.lastname: Green
authors.forename: J P
authors.initials: JP
authors.lastname: Hoffman
authors.forename: L M
authors.initials: LM
authors.lastname: Weiner
authors.forename: R
authors.initials: R
authors.lastname: Scher
authors.forename: P J
authors.initials: PJ
authors.lastname: O'Dwyer
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001221:Aspartate Carbamoyltransferase / Q000037:antagonists & inhibitors; D001224:Aspartic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008778:Methylthioinosine / Q000008:administration & dosage; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010746:Phosphonoacetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D001224:Aspartic Acid; D008778:Methylthioinosine; C013195:sparfosic acid; D001221:Aspartate Carbamoyltransferase; D010746:Phosphonoacetic Acid; D005472:Fluorouracil