Phase II trial of PALA and 6-methylmercaptopurine riboside (MMPR) in combination with 5-fluorouracil in advanced pancreatic cancer

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 p...

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Bibliographic Details
Published in:Investigational new drugs 1994-01, Vol.12 (4), p.319-321
Main Authors: REDEI, I, GREEN, F, HOFFMAN, J. P, WEINER, L. M, SCHER, R, O'DWYER, P. J
Format: Article
Language:English
Subjects:
Adenocarcinoma - drug therapy
Adenocarcinoma - secondary
Adult
Aged
Antineoplastic agents
Antineoplastic Combined Chemotherapy Protocols - adverse effects
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Aspartate Carbamoyltransferase - antagonists & inhibitors
Aspartic Acid - administration & dosage
Aspartic Acid - analogs & derivatives
Biological and medical sciences
Chemotherapy
Female
Fluorouracil - administration & dosage
Humans
Male
Medical sciences
Methylthioinosine - administration & dosage
Middle Aged
Pancreatic Neoplasms - drug therapy
Pharmacology. Drug treatments
Phosphonoacetic Acid - administration & dosage
Phosphonoacetic Acid - analogs & derivatives
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Summary: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.
ISSN:0167-6997
1573-0646
DOI:10.1007/BF00873047