Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients

Abstract

Purpose [corrected] Capecitabine (Xeloda) is a novel fluoropyrimidine carbamate rationally designed to generate 5-fluorouracil (5-FU) preferentially in tumors. The purpose of this study was to demonstrate the preferential activation of capecitabine, after oral administration, in tumor in colorectal cancer patients, by the comparison of 5-FU concentrations in tumor tissues, healthy tissues and plasma. Methods Nineteen patients requiring surgical resection of primary tumor and/or liver metastases received 1,255 mg/m2 of capecitabine twice daily p.o. for 5-7 days prior to surgery. On the day of surgery, samples of tumor tissue, adjacent healthy tissue and blood samples were collected simultaneously from each patient, 2 to 12 h after the last dose of capecitabine had been administered. Concentrations of 5-FU in various tissues and plasma were determined by HPLC. The activities of the enzymes (CD, TP and DPD) involved in the formation and catabolism of 5-FU were measured in tissue homogenates, by catabolic assays. Results The ratio of 5-FU concentrations in tumor to adjacent healthy tissue (T/H) was used as the primary marker for the preferential activation of capecitabine in tumor. In primary colorectal tumors, the concentration of 5-FU was on average 3.2 times higher than in adjacent healthy tissue (P = 0.002). The mean liver metastasis/healthy tissue 5-FU concentration ratio was 1.4 (P = 0.49, not statistically different). The mean tissue/plasma 5-FU concentration ratios exceed…