Vol. 60, Issue 3, 553-558, September 2001

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

Thierry Louat, Laurence Servant, Marie-Pierre Rols, Anne Bieth, Justin Teissie, Jean-Sebastien Hoffmann, and Christophe Cazaux

Institut de Pharmacologie et Biologie Structurale, Instabilité Génétique et Cancer (T.L., L.S., A.B., J.-S.H., C.C.) and Biophysique Cellulaire (M.-P.R., J.T.), UMR Centre National de la Recherche Scientifique 5089, Toulouse, France

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