Abstract
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.
Footnotes
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This work was supported by l'Association de Recherche sur le Cancer Grant 5446 (to C.C.), la Ligue Nationale Contre le Cancer 31 (to C.C.), la Région Midi-Pyrénées Grants 99001081 (to C.C.) and 99009282 (to J.S.H.), le Centre National de la Recherche Scientifique (Aide Jeunes Equipes), and Electricité de France Grant 14118400 (to J.S.H.).
- Abbreviations:
- Pol
- DNA polymerase
- BER
- base excision repair
- ddC
- 2′,3′-dideoxycytidine
- AZT
- 3′-azido-3-thymidine
- ddC-TP
- triphosphorylated 2′,3′-dideoxycytidine
- PBS
- phosphate-buffered saline
- SV40
- simian virus 40
- cytarabine
- 4-amino-1-β-d-arabino-furanosyl-2(1H)-pyrimidone
- Received January 29, 2001.
- Accepted May 23, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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