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Molecular Pharmacology

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Research ArticleArticle

Antitumor Activity of 2′,3′-Dideoxycytidine Nucleotide Analog Against Tumors Up-Regulating DNA Polymerase β

Thierry Louat, Laurence Servant, Marie-Pierre Rols, Anne Bieth, Justin Teissie, Jean-Sebastien Hoffmann and Christophe Cazaux
Molecular Pharmacology September 2001, 60 (3) 553-558;
Thierry Louat
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Laurence Servant
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Marie-Pierre Rols
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Anne Bieth
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Justin Teissie
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Jean-Sebastien Hoffmann
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Christophe Cazaux
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This article has a correction. Please see:

  • Correction to “Antitumor Activity of 2′,3′-Dideoxycytidine Nucleotide Analog Against Tumors Up-Regulating DNA Polymerase β” - May 01, 2002

Abstract

DNA polymerase β (Pol β), 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 β-transfected B16 melanoma cells, which up-regulate Pol β compared with control isogenic cells. The administration of ddC also increased specifically the survival of mice bearing Pol β-overexpressing B16 melanoma. When the phosphorylated form of ddC was electrotransfered into Pol β-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 β 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 β.

Footnotes

  • This work was supported by l'Association de Recherche sur le Cancer Grant 5446 (to C.C.), la Ligue Nationale Contre le Cancer 31 (to C.C.), la Région Midi-Pyrénées Grants 99001081 (to C.C.) and 99009282 (to J.S.H.), le Centre National de la Recherche Scientifique (Aide Jeunes Equipes), and Electricité de France Grant 14118400 (to J.S.H.).

  • Abbreviations:
    Pol
    DNA polymerase
    BER
    base excision repair
    ddC
    2′,3′-dideoxycytidine
    AZT
    3′-azido-3-thymidine
    ddC-TP
    triphosphorylated 2′,3′-dideoxycytidine
    PBS
    phosphate-buffered saline
    SV40
    simian virus 40
    cytarabine
    4-amino-1-β-d-arabino-furanosyl-2(1H)-pyrimidone
    • Received January 29, 2001.
    • Accepted May 23, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 60 (3)
Molecular Pharmacology
Vol. 60, Issue 3
1 Sep 2001
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Research ArticleArticle

Antitumor Activity of 2′,3′-Dideoxycytidine Nucleotide Analog Against Tumors Up-Regulating DNA Polymerase β

Thierry Louat, Laurence Servant, Marie-Pierre Rols, Anne Bieth, Justin Teissie, Jean-Sebastien Hoffmann and Christophe Cazaux
Molecular Pharmacology September 1, 2001, 60 (3) 553-558;

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Research ArticleArticle

Antitumor Activity of 2′,3′-Dideoxycytidine Nucleotide Analog Against Tumors Up-Regulating DNA Polymerase β

Thierry Louat, Laurence Servant, Marie-Pierre Rols, Anne Bieth, Justin Teissie, Jean-Sebastien Hoffmann and Christophe Cazaux
Molecular Pharmacology September 1, 2001, 60 (3) 553-558;
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