INDUCTION OF THYMIDINE PHOSPHORYLASE-ACTIVITY AND ENHANCEMENT OF CAPECITABINE EFFICACY BY TAXOL TAXOTERE IN HUMAN CANCER XENOGRAFTS/

Thymidine phosphorylase (dThdPase) is an essential enzyme for the acti vation of the cytostatics capecitabine (N-4-pentyloxycarbonyl-5'-deoxy -5-fluorocytidine) and its intermediate metabolite [5'-deoxy-5-fluorou ridine (5'-dFUrd)] to 5-fluorouracil in tumors, We have tried to ident ify the best partners of capecitabine in combination therapy, such as dThdPase up-regulators, which may enhance the efficacy of this compoun d, Among various cytostatics studied with the WiDr human colon cancer xenograft model, Taxol, Taxotere, and mitomycin C greatly increased le vels of human dThdPase in tumors, and cyclophosphamide slightly increa sed the enzyme level. These cytostatics simultaneously increased the l evels of human tumor necrosis factor alpha (TNF alpha), which is an up -regulator of dThdPase. In cultures of the WiDr cells, however, Taxol did not up-regulate TNF alpha to a detectable level and only slightly enhanced levels of dThdPase, These results suggest that Taxol might in directly elevate TNF alpha in tumor cells, which in turn up-regulated dThdPase in the tumor cells in the WiDr cancer xenograft, In the combi nation therapy, the efficacy of Taxol and Taxotere with either capecit abine or 5'-dFUrd was more than just additive. In contrast, Taxol and either fi-fluorouracil or UFT (a mixture of tegafur and uracil) in com bination showed only additive activity, Taxol and Taxotere might enhan ce the efficacy of capecitabine and 5'-dFUrd, probably by modulating d ThdPase activity in tumor tissues.