Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts

Abstract

Thymidine phosphorylase (dThdPase) is an essential enzyme for the activation of the cytostatics capecitabine (N(4)-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) and its intermediate metabolite [5'-deoxy-5-fluorouridine (5'-dFUrd)] to 5-fluorouracil in tumors. We have tried to identify the best partners of capecitabine in combination therapy, such as dThdPase up-regulators, which may enhance the efficacy of this compound. Among various cytostatics studied with the WiDr human colon cancer xenograft model, Taxol, Taxotere, and mitomycin C greatly increased levels of human dThdPase in tumors, and cyclophosphamide slightly increased the enzyme level. These cytostatics simultaneously increased the levels of human tumor necrosis factor alpha (TNFalpha), which is an up-regulator of dThdPase. In cultures of the WiDr cells, however, Taxol did not up-regulate TNFalpha to a detectable level and only slightly enhanced levels of dThdPase. These results suggest that Taxol might indirectly elevate TNFalpha in tumor cells, which in turn up-regulated dThdPase in the tumor cells in the WiDr cancer xenograft. In the combination therapy, the efficacy of Taxol and Taxotere with either capecitabine or 5'-dFUrd was more than just additive. In contrast, Taxol and either 5-fluorouracil or UFT (a mixture of tegafur and uracil) in combination showed only additive activity. Taxol and Taxotere might enhance the efficacy of capecitabine and 5'-dFUrd, probably by modulating dThdPase activity in tumor tissues.