Forced Expression of Cytidine Deaminase Confers Sensitivity to Capecitabine

Abstract

Objective: Cytidine deaminase (CDD) is involved in the metabolism of new pyrimidine analogues, capecitabine (N⁴-pentyloxycarbonyl-5′-deoxy-5-fluorocytidine) and gemcitabine (2′,2′-difluorodeoxycytidine). The purpose of the present study was to directly examine the role of CDD in tumor cells themselves in mediating the sensitivity to capecitabine compared with gemcitabine. Methods: The human bladder cancer cell line T24 was transfected with human CDD2 cDNA by the lipofectin method. Results: Transfection of CDD2 cDNA did not change the levels of thymidine phosphorylase, dihydropyrimidine dehydrogenase and thymidylate synthase (TS) but increased the CDD activity significantly (p < 0.01). Forced expression of CDD made T24 sensitive to 5′-deoxy-5-fluorocytidine (5′DFCR) in vitro and capecitabine in vivo, but resistant to gemcitabine both in vitro and in vivo. Tetrahydrouridine, a specific CDD inhibitor, abrogated the changes in the in vitro sensitivity to 5′DFCR and gemcitabine by transfection of CDD2 cDNA. Transfection of CDD2 cDNA resulted in a significant increase in cellular 5-fluorouracil level (p < 0.01) and inhibition of TS activity (p < 0.01) after treatment with 5′DFCR in vitro. Conclusions: The present study clearly showed direct evidence for the contribution of CDD in tumor cells themselves to the sensitivities to capecitabine and gemcitabine.