RT Journal Article
SR Electronic
T1 Antitumor Activity of 2′,3′-Dideoxycytidine Nucleotide Analog Against Tumors Up-Regulating DNA Polymerase β
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 553
OP 558
VO 60
IS 3
A1 Thierry Louat
A1 Laurence Servant
A1 Marie-Pierre Rols
A1 Anne Bieth
A1 Justin Teissie
A1 Jean-Sebastien Hoffmann
A1 Christophe Cazaux
YR 2001
UL http://molpharm.aspetjournals.org/content/60/3/553.abstract
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