Selective modulation of 5-fluorouracil action in patients with colorectal carcinoma.

Attempts to modulate by normal metabolites the intracellular metabolism of 5-fluorouracil (FU) via the ribonucleotide pathway leading to increased incorporation of the drug into RNA have been shown to potentiate host toxicity but not the therapeutic efficacy of this agent in preclinical model systems and in patients with advanced colorectal carcinomas. Recent advances aimed at the modulation of FU metabolism by CF via the deoxyribonucleotide pathway leading to prolonged inhibition of dTMPS activity indicates that the therapeutic efficacy of FU can be enhanced significantly in patients with advanced colorectal carcinoma. Pharmacokinetic studies of FU and CF revealed large intrasubject variations. In this presentation, rationale and the results of approaches taken at the preclinical and clinical levels in an attempt to selectively modulate the therapeutic efficacy of fluoropyrimidine will be discussed. This includes the importance of integration of information concerning pharmacokinetics and cellular metabolism in the design of optimal combination chemotherapy of FU with metabolic modulators.