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

T Louat1, L Servant, M P Rols

  • 1Institut de Pharmacologie et Biologie Structurale, Instabilité Génétique et Cancer, UMR Centre National de la Recherche Scientifique 5089, Toulouse, France.

Molecular Pharmacology
|August 15, 2001
PubMed

Insights

Certain cancers overexpress DNA polymerase beta (Pol beta). Treating these tumors with the chain terminator 2

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • DNA polymerase beta (Pol beta) is a DNA-synthesizing enzyme.
  • Pol beta is down-regulated in healthy cells but overexpressed in many human tumors.
  • This overexpression suggests a potential therapeutic target in cancer treatment.

Purpose of the Study:

  • To investigate the therapeutic potential of the nucleoside analog 2',3'-dideoxycytidine (ddC) in Pol beta-overexpressing tumors.
  • To elucidate the mechanism by which ddC exerts its cytotoxic effects in the context of Pol beta.
  • To evaluate the efficacy of ddC as a chain terminator anticancer agent for specific tumor types.

Main Methods:

  • In vitro and in vivo proliferation assays using Pol beta-transfected B16 melanoma cells.
  • Administration of ddC and its phosphorylated form via electrotransfer.
  • In vitro DNA synthesis assays to assess Pol beta activity and ddC incorporation.
  • Survival studies in mice bearing Pol beta-overexpressing melanoma.

Main Results:

  • Treatment with ddC inhibited proliferation of Pol beta-transfected B16 melanoma cells both in vitro and in vivo.
  • ddC administration specifically increased the survival of mice with Pol beta-overexpressing melanoma.
  • Electrotransfer of phosphorylated ddC enhanced cell growth inhibition, indicating DNA incorporation.
  • Excess Pol beta was shown to promote ddC-TP incorporation into DNA, leading to chain termination.

Conclusions:

  • The chain terminator 2',3'-dideoxycytidine (ddC) effectively inhibits Pol beta-overexpressing melanoma.
  • The cytotoxic effect of ddC is mediated by its incorporation into DNA, causing chain termination.
  • Chain terminator anticancer agents are a promising therapeutic strategy for tumors with high Pol beta levels.

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