Antitumor activity of 2',3'-dideoxycytidine nucleotide analog against tumors up-regulating DNA polymerase beta

Mol Pharmacol. 2001 Sep;60(3):553-8.


DNA polymerase beta (Pol beta), an error-prone DNA-synthesizing enzyme tightly down-regulated in healthy somatic cells, has been shown to be overexpressed in many human tumors. In this study, we show that treatment with the 2',3'-dideoxycytidine (ddC) nucleoside analog inhibited in vitro and in vivo the proliferation of Pol beta-transfected B16 melanoma cells, which up-regulate Pol beta compared with control isogenic cells. The administration of ddC also increased specifically the survival of mice bearing Pol beta-overexpressing B16 melanoma. When the phosphorylated form of ddC was electrotransfered into Pol beta-transfected melanoma, the cell growth inhibition was strengthened, strongly suggesting that the cytotoxic effect results from incorporation of the chain terminator into DNA. Using in vitro single- and double-stranded DNA synthesis assays, we demonstrated that excess Pol beta perturbs the replicative machinery, favors ddC-TP incorporation into DNA, and consequently promotes chain termination. Therefore, the use of chain terminator anticancer agents could be suitable for the treatment of tumors with a high level of Pol beta.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Cell Division / drug effects
  • Cell Extracts / pharmacology
  • Cell Survival / drug effects
  • DNA / biosynthesis
  • DNA / drug effects*
  • DNA Polymerase beta / drug effects
  • DNA Polymerase beta / metabolism*
  • Deoxycytosine Nucleotides / pharmacology
  • Dideoxynucleotides
  • Enzyme Activation
  • Melanoma, Experimental / drug therapy
  • Melanoma, Experimental / enzymology*
  • Mice
  • Neoplasm Transplantation
  • Simian virus 40 / drug effects
  • Simian virus 40 / physiology
  • Tumor Cells, Cultured
  • Up-Regulation
  • Virus Replication / drug effects
  • Zalcitabine / chemistry
  • Zalcitabine / metabolism
  • Zalcitabine / pharmacology*
  • Zalcitabine / therapeutic use


  • Antineoplastic Agents
  • Cell Extracts
  • Deoxycytosine Nucleotides
  • Dideoxynucleotides
  • 2',3'-dideoxycytidine 5'-triphosphate
  • Zalcitabine
  • DNA
  • DNA Polymerase beta