POSITIVE CORRELATION BETWEEN THE EFFICACY OF CAPECITABINE AND DOXIFLURIDINE AND THE RATIO OF THYMIDINE PHOSPHORYLASE TO DIHYDROPYRIMIDINE DEHYDROGENASE-ACTIVITIES IN TUMORS IN HUMAN CANCER XENOGRAFTS

Capecitabine (N-4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is new fluoropyrimidine carbamate, which is converted to 5-fluorouracil (5-FU ra) selectively in tumors through the intermediate metabolite 5'-deoxy -5-fluorouridine (5'-dFUrd, doxifluridine). 5'-dFUrd is metabolized to 5-FUra by thymidine phosphorylase (dThdPase) located in high levels i n various types of solid tumors from patients, whereas 5-FUra generate d is catabolized to dihydrofluorouracil by dihydropyrimidine dehydroge nase (DPD). The present study investigated whether the efficacy of cap ecitabine and its intermediate metabolite 5'-dFUrd correlates with lev els of these enzymes in various human cancer xenograft models, Capecit abine and 5'-dFUrd were highly effective and inhibited tumor growth by more than 50% in 18 of 24 xenograft lines (75%) and 15 of 24 xenograf t lines (63%), respectively, whereas 5-FUra and a mixture of tegafur a nd uracil were effective only in 1 of 24 (4.2%) and 5 of 24 (21%), res pectively, The efficacy of capecitabine correlated with dThdPase activ ity, However, capecitabine was effective even in tumors with lower lev els of dThdPase if DPD levels were also lower. In contrast, it was not as effective even in tumors with sufficient levels of dThdPase if DPD levels were very high. The efficacy of capecitabine consequently corr elated very well with and depended on the ratio of these two enzymes i n tumors, These results indicate that capecitabine might exert its eff icacy through 5-FUra generated in tumor tissues but not through that g enerated in normal organs, On the other hand, there was no correlation between the efficacy of a mixture of tegafur and uracil and these enz yme activities in tumors, The efficacy of capecitabine would be optimi zed by selecting patients who have tumors with a high ratio of dThdPas e to DPD activities.