Forced expression of cytidine deaminase confers sensitivity to capecitabine

Oncology. 2003;65(3):267-74. doi: 10.1159/000074480.

Abstract

Objective: 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). 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Capecitabine
  • Cell Survival / drug effects
  • Cytidine Deaminase / genetics*
  • DNA, Complementary / genetics
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / therapeutic use*
  • Dihydrouracil Dehydrogenase (NADP) / metabolism
  • Disease Models, Animal
  • Drug Screening Assays, Antitumor
  • Enzyme-Linked Immunosorbent Assay
  • Fluorouracil / analogs & derivatives
  • Gene Expression Regulation, Enzymologic / physiology*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Thymidine Phosphorylase / metabolism
  • Thymidylate Synthase / metabolism
  • Transfection
  • Tumor Cells, Cultured / transplantation
  • Urinary Bladder Neoplasms / drug therapy*
  • Urinary Bladder Neoplasms / enzymology
  • Urinary Bladder Neoplasms / pathology
  • Xenograft Model Antitumor Assays

Substances

  • Antimetabolites, Antineoplastic
  • DNA, Complementary
  • Deoxycytidine
  • Capecitabine
  • 5'-deoxy-5-fluorocytidine
  • gemcitabine
  • Dihydrouracil Dehydrogenase (NADP)
  • Thymidylate Synthase
  • Thymidine Phosphorylase
  • Cytidine Deaminase
  • Fluorouracil