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

目的：胞苷脱氨酶参与新的嘧啶类似物卡培他滨((N^4-pentyloxycarbonyl-5‘-deoxy-5-fluorocytidine)和吉西他滨(2’，2‘-二氟脱氧胞苷)的代谢。本研究的目的是与吉西他滨比较，直接研究CDD在肿瘤细胞自身在调节对卡培他滨敏感性中的作用。方法：用脂质体转染法将人CDD2基因导入人膀胱癌T24细胞。结果：CDD2基因不影响胸苷磷酸化酶(TP)、二氢嘧啶脱氢酶(DPD)和胸苷合成酶(TS)的活性，但显著提高CDD活性(p&lt；0.01)。强制表达CD使T24在体外对5‘-脱氧-5-氟胞苷(5’-DFCR)敏感，在体内对卡培他滨敏感，但在体内和体外均对吉他滨耐药。CDD特异性抑制剂四氢尿苷(清华)可阻断CDD2基因对5‘DFCR和吉西他滨体外敏感性的影响。5‘-DFCR处理细胞后，CDD2基因的表达水平显著升高(p&lt；0.01)，TS活性显著降低(p&lt；0.01)。结论：本研究清楚地表明肿瘤细胞中的CDD对卡培他滨和吉西他滨的敏感性有直接的贡献。

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.