PT  - JOURNAL ARTICLE
AU  - Thierry Louat
AU  - Laurence Servant
AU  - Marie-Pierre Rols
AU  - Anne Bieth
AU  - Justin Teissie
AU  - Jean-Sebastien Hoffmann
AU  - Christophe Cazaux
TI  - Antitumor Activity of 2′,3′-Dideoxycytidine Nucleotide Analog Against Tumors Up-Regulating DNA Polymerase β
DP  - 2001 Sep 01
TA  - Molecular Pharmacology
PG  - 553--558
VI  - 60
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/60/3/553.short
4100  - http://molpharm.aspetjournals.org/content/60/3/553.full
SO  - Mol Pharmacol2001 Sep 01; 60
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics