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 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 beta-transfected B16 melanoma cells, which up-regulate Pol beta compared with control isogenic cells. The administration of ddC also increased specifically the survival of mice bearing Pol beta-overexpressing B16 melanoma. When the phosphorylated form of ddC was electrotransfered into Pol beta-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 beta 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 beta.
Louat
T
T
Institut de Pharmacologie et Biologie Structurale, Instabilité Génétique et Cancer, UMR Centre National de la Recherche Scientifique 5089, Toulouse, France.
Servant
L
L
Rols
M P
MP
Bieth
A
A
Teissie
J
J
Hoffmann
J S
JS
Cazaux
C
C
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D002457:Cell Extracts / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects*; D019951:DNA Polymerase beta / Q000187:drug effects / Q000378:metabolism*; D003845:Deoxycytosine Nucleotides / Q000494:pharmacology; D054306:Dideoxynucleotides; D004789:Enzyme Activation; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000201:enzymology*; D051379:Mice; D009368:Neoplasm Transplantation; D013539:Simian virus 40 / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D014779:Virus Replication / Q000187:drug effects; D016047:Zalcitabine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D002457:Cell Extracts; D003845:Deoxycytosine Nucleotides; D054306:Dideoxynucleotides; C037406:2',3'-dideoxycytidine 5'-triphosphate; D016047:Zalcitabine; D004247:DNA; D019951:DNA Polymerase beta