Phase I trial of N-(phosphonacetyl)-L-aspartate, methotrexate, and 5-fluorouracil with leucovorin rescue in patients with advanced cancer. Academic Article uri icon

Overview

abstract

  • Based on an animal model to improve the antitumor activity of 5-fluorouracil (FUra), a Phase I study of N-(phosphonacetyl)-L-aspartate, methotrexate, FUra, and leucovorin was conducted on 44 patients. Methotrexate was given in an intermediate dose (250 mg/m2) to overcome potential drug resistance, and N-(phosphonacetyl)-L-aspartate was given at a low dose (250 mg/m2) in order to allow escalation of FUra to toxicity. These two drugs were given 24 h before FUra to enhance maximal incorporation of FUra into RNA. Two schedules of administration were used; one every other week and one weekly for 2 weeks. The every other week schedule was well tolerated, with minimal gastrointestinal and hematological toxicity. However, the weekly for 2 weeks schedule was more toxic with increased mucositis, diarrhea requiring therapy, and decreased performance status of 20% in 4 of 6 patients. There were no responders in the every other week schedule. There was one partial response and three patients with stable disease in four evaluable patients on the weekly for 2 weeks schedule. At 24 h post-N-(phosphonacetyl)-L-aspartate-methotrexate treatment, PRPP levels were doubled in bone marrow biopsies, and increased 2.5- to 25-fold in tumor biopsies. We have currently added uridine rescue to this combination with the hope of further escalating the dose of FUra.

publication date

  • August 15, 1989

Research

keywords

  • Adenocarcinoma
  • Antineoplastic Combined Chemotherapy Protocols
  • Carcinoma, Squamous Cell
  • Colorectal Neoplasms
  • Head and Neck Neoplasms

Identity

Scopus Document Identifier

  • 0024348362

PubMed ID

  • 2472883

Additional Document Info

volume

  • 49

issue

  • 16