Modulation of fluorouracil by N-(phosphonacetyl)-L-asparate: a review

N-(phosphonacetyl)-L-asparate (PALA), a potent inhibitor of de novo pyrimidine synthesis, was demonstrated in preclinical studies to enhance the therapeutic activity of fluorouracil (5-FU). However, the initial clinical trials with the combination failed to conform to these experimental findings. Very recent clinical studies, employing for the first time the principles for the enhanced therapeutic interaction determined in the preclinical studies, have now reported enhanced efficacy with the PALA-FU combination. Reviewing the lessions of the PALA-FU experience, this article explains the potential benefits as well as the need for biochemical modulation in cancer chemotherapy, the need for the appropriate dosage ratio between agents in modulation-based clinical trials, and the necessity to determine in patients, by direct biochemical measurements at the tissue level, the dose and temporal relationship between agents that reproduces the pertinent biochemical changes in human tumors that produced the therapeutic success of that particular drug combination in the preclinical model.