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

DNA polymerase beta (Pol beta), an error-prone DNA-synthesizing enzyme tigh tly down-regulated in healthy somatic cells, has been shown to be overexpre ssed 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 beta -transfected B16 melanoma cells, which up-re gulate Pol beta compared with control isogenic cells. The administration of ddC also increased specifically the survival of mice bearing Pol beta -ove rexpressing B16 melanoma. When the phosphorylated form of ddC was electrotr ansfered into Pol beta -transfected melanoma, the cell growth inhibition wa s 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 beta perturbs the replicative machinery, favors ddC-TP incorporation into DNA, a nd consequently promotes chain termination. Therefore, the use of chain ter minator anticancer agents could be suitable for the treatment of tumors wit h a high level of Pol beta.