ANTITUMOR ACTIVITIES OF A NOVEL FLUOROPYRIMIDINE, N-4-PENTYLOXYCARBONYL-5'-DEOXY-5-FLUOROCYTIDINE (CAPECITABINE)

Capecitabine (N-4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a no vel fluoropyrimidine carbamate that was synthesized for the purpose of finding antitumor drugs with improved safety and efficacy profiles co mpared with those of 5-fluorouracil (5-FUra) and doxifluridine (5'-deo xy-5-fluorouridine, 5'-dFUrd). The present study compared the antitumo r activities of the compound with those of other fluoropyrimidines in 12 human cancer xenograft models and their antimetastatic activities i n murine tumor models. The antitumor efficacy of capecitabine was grea ter than those of 5'-dFUrd, UFT (a mixture of tegafur and uracil) and 5-FUra. Capecitabine was also much safer, particularly much less toxic to the intestinal tract, than the other compounds, indicating higher therapeutic indices. The therapeutic indices of capecitabine, 5'-dFUrd and 5-FUra were >40, >20 and 2.0 against the human CXF280 colon cance r xenograft, the most sensitive line to the fluoropyrimidines so far t ested, and 5.1, 1.5, and <1.5 against the human HCT116 colon cancer xe nograft with ordinary sensitivity, respectively. In addition, capecita bine, as well as 5'-dFUrd, selectively suppressed the spontaneous meta stasis of mouse Lewis lung carcinoma in mice at extremely low doses, 3 2-64 fold lower than their minimum effective dose (MED) against the pr imary tumor growth, Capecitabine was even more antimetastatic than 5'- dFUrd. These results indicate that capecitabine has high therapeutic p otential.