THE ROLE OF LOW-DOSE PALA IN BIOCHEMICAL MODULATION

Phosphonacetyl-L-aspartate (PALA) is a rationally-synthesized analog of the transition-state intermediate in the formation of carbamyl aspartate from carbamyl phosphate and aspartic acid by aspartate carbamyl transferase (ACTase). PALA is thus a potent inhibitor of the enzyme (K(i) about 10-8 M for ACTases of various origins), which in whole cells blocks the de novo synthesis of pyrimidines. In vivo, low doses of PALA inhibit whole body pyrimidine synthesis. While this action is cytotoxic in vitro, extensive human testing demonstrates that PALA alone is devoid of selective antitumor activity. Recent interest in the therapeutic action of PALA derives from the demonstration that its action potentiates the cytotoxicity of several cytotoxic drugs, notably 5-fluorouracil (5-FU). Results from clinical trials of PALA and 5-FU in combination in colorectal cancer suggest that biochemical modulation with regimens which follow the principles determined in preclinical studies may enhance the efficacy of current therapy.