PHASE-1 AND CLINICAL PHARMACOLOGICAL EVALUATION OF BIOCHEMICAL MODULATION OF 5-FLUOROURACIL WITH N-(PHOSPHONACETYL)-L-ASPARTIC ACID

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (5) , 2324-2329
Abstract
5-Fluorouracil (FUra) is a clinically useful antineoplastic agent. Preclinical studies suggest that the therapeutic effects of FUra can be enhanced by pretreatment with N-(phosphonacetyl)-L-aspartic acid (PALA), an inhibitor of aspartate transcarbamylase. The objective of treatment with PALA is to increase the activation of FUra by inhibiting the normal pathway of de novo pyrimidine biosynthesis. Theoretically, the optimal dose of PALA should produce effective blockade of this pathway without increasing toxic effects of FUra. Using pyrazofurin-induced orotic aciduria and orotidinuria as a measure of this pathway, it was determined that PALA (250 mg/sq m) is effective in inhibiting total-body pyrimidine synthesis. Adult patients (68) with cancer were treated with combinations of PALA and FUra. High doses of PALA (1-2 g/sq m) prevented the use of full doses of FUra; however, PALA (250 mg/sq m) can be administered 24 h before FUra (750 mg/sq m) once weekly for at least 3 wk. The toxicity observed using that combination of doses was mild to moderate myelosuppression, mucositis, diarrhea, nausea and vomiting. Further clinical studies are warranted.