DESIGN OF A NOVEL ORAL FLUOROPYRIMIDINE CARBAMATE, CAPECITABINE, WHICH GENERATES 5-FLUOROURACIL SELECTIVELY IN TUMORS BY ENZYMES CONCENTRATED IN HUMAN LIVER AND CANCER-TISSUE

Capecitabine (N-4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a no vel oral fluoropyrimidine carbamate, which is converted to 5-fluoroura cil (5-FU) selectively in tumours through a cascade of three enzymes. The present study investigated tissue localisation of the three enzyme s in humans, which was helpful for us to design the compound. Carboxyl esterase was almost exclusively located in the liver and hepatoma, but not in other tumours and normal tissue adjacent to the tumours. Cytid ine (Cyd) deaminase was located in high concentrations in the liver an d various types of solid tumours. Finally, thymidine phosphorylase (dT hdPase) was also more concentrated in various types of tumour tissues than in normal tissues. These unique tissue localisation patterns enab led us to design capecitabine. Oral capecitabine would pass intact thr ough the intestinal tract, but would be converted first by carboxylest erase to 5'-deoxy-5-fluorocytidine (5'-dFCyd) in the liver, then by Cy d deaminase to 5'-deoxy-5-fluorouridine (5'-dFUrd) in the liver and tu mour tissues and finally by dThdPase to 5-FU in tumours. In cultures o f human cancer cell Lines, the highest level of cytotoxicity was shown by 5-FU itself, followed by 5'-dFUrd. Capecitabine and 5'-dFCyd had w eak cytotoxic activity only at high concentrations. The cytotoxicity o f the intermediate metabolites 5'-dFCyd and 5'-dFUrd was suppressed by inhibitors of Cyd deaminase and dThdPase, respectively, indicating th at these metabolites become effective only after their conversion to 5 -FU. Capecitabine, which is finally converted to 5-FU by dThdPase in t umours, should be much safer and more effective than 5-FU, and this wa s indeed the case in the HCT116 human colon cancer and the MX-1 breast cancer xenograft models. (C) 1998 Elsevier Science Ltd. All rights re served.