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

Purpose: Capecitabine (Xeloda) is a novel fluoropyrimidine carbamate ration ally designed to generate 5-fluorouracil (5-FU) preferentially in tumors. T he purpose of this study was to demonstrate the preferential activation of capecitabine, after oral administration, in tumor in colorectal cancer pati ents, by the comparison of 5-FU concentrations in tumor tissues, healthy ti ssues and plasma. Methods: Nineteen patients requiring surgical resection o f primary tumor and/or liver metastases received 1,255 mg/m(2) of capecitab ine 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 col lected simultaneously from each patient, 2 to 12 h after the last dose of c apecitabine had been administered. Concentrations of 5-FU in various tissue s 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 concen trations 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 high er than in adjacent healthy tissue (P = 0.002). The mean liver metastasis/h ealthy tissue 5-FU concentration ratio was 1.4 (P = 0.49, not statistically different). The mean tissue/plasma 5-FU concentration ratios exceeded 20 f or colorectal tumor and ranged from 8 to 10 for other tissues. Conclusions: The results demonstrated the preferential activation of capecitabine to 5- FU in colorectal tumor, after oral administration to patients. This is expl ained to a great extent by the activity of TP in colorectal tumor tissue, ( the enzyme responsible for the conversion of 5'-DFUR to 5-FU), which is app roximately four times that in adjacent healthy tissue. In the liver, TP act ivity is approximately equal in metastatic and healthy tissue, which explai ns the lack of preferential activation of capecitabine in these tissues.