ABSTRACT
This was an open lable, pilot translational clinical pharmacology study of a brief (7 day) course of UFT, 300 mg/m2/day, in combination with leucovorin, 90 mg/day, in six patients with newly diagnosed advanced colorectal cancer. The primary objectives of the study were to examine the impact of this treatment course on the UFT targets which are thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD). The rate of tumoral TS inhibition after the 7-day UFT treatment sequence varied from 5% up to 31%. UFT treatment induced a constant and variable decrease in tumor DPD activity ranging from 13% to 60%. UFT treatment induced a constant increase in uracil concentrations both in plasma and tumors. FT, 5-FU and the metabolite fluoro-beta-alanine (FBAL) were found in plasma and tumors at variable concentrations; the highest drug concentrations were those of FBAL in plasma. The present translational clinical study provides data related to the in vivo pharmacological effects of UFT with a description of its impact on cellular targets.
