Dose-dependent inhibition of aspartate carbamoyltransferase in peripheral blood mononuclear cells in patients receiving N-(phosphonacetyl)-L-asparate

J. L. Grem, N. McAtee, J. C. Drake, S. Steinberg, C. J. Allegra

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Forty-eight patients with adenocarcinoma of the gastrointestinal tract were treated on this trial. The MTD of 5-FU given as a 72 hour infusion with high-dose leucovorin was initially determined to be 2000 mg/m2/d. Patients were treated at PALA dose levels ranging from 250 to 2848 mg/m2. Biochemical assessment of target enzyme activity was performed at each PALA dose level. We conclude that compared to each patient's own baseline, PALA at 250 mg/m2 failed to appreciably inhibit ACTase activity at 24 hours in most patients. More consistent inhibition of ACTase activity was seen with PALA at or above 1266 mg/m2, but toxicity was prohibitive with 2848 mg/m2 PALA. Even with the highest PALA doses, ACTase activity was back to baseline by 96 hours in most patients. PALA at 1266 mg/m2 given 24 hours prior to the start of 72 hour infusional 5-FU plus high-dose leucovorin was associated with acceptable toxicity and did not appear to compromise 5-FU dose-intensity. Finally, because of interpatient variability in the degree of ACTase inhibition following PALA, biochemical monitoring of target enzyme activity may permit more rational adjustment of the PALA dose in individual patients.

Original languageEnglish (US)
Pages (from-to)119-123
Number of pages5
JournalAdvances in experimental medicine and biology
Volume339
DOIs
StatePublished - 1993

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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