T. Louat et al., Antitumor activity of 2 ',3 '-dideoxycytidine nucleotide analog against tumors up-regulating DNA polymerase beta, MOLEC PHARM, 60(3), 2001, pp. 553-558
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.