Role of cytidine deaminase as a parameter for anticancer drug sensitivity in the tailor-made therapy

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Objctive: Cytidine deaminase (CDD) is involved in the metabolism of new pyrimidine analogues, capecitabine (N^4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine ) and gemcitabine (2',2'-difluorodeoxycytidine: dFdC). The purpose of present study is to directly examine the role of CDD in tumor cells themselves in mediating the sensitivity to capecitabine as compared with gemcitabine. Methods: 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 (TP), dihydropyrimidine dehydrogenase (DPD), and thymidylate synthase (TS) but increased the CDD activity significantly (p<0.01). Forced expression of CCD made T24 sensitive to 5'-deoxy-5-fluorocyidine (5'DFCR) in vitro and capecitabine in vivo, but resistant to gemitabine both in vitro and in vivo. Tetrahydrouridine (THU), 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 significant increase in cellular 5-fluorouracil (5FU) level (p<0.01) and inhibition of TS activity (p<0.01) after treatment with 5'DFCR in vitro. Conclusion: The present study clearly showed direct evidence for the contribution of CDD in tumor cells themselves to the sensitivities to capecitabine and gemcitabine.