Antitumor Activity of 2 (cid:1) ,3 (cid:1) -Dideoxycytidine Nucleotide Analog Against Tumors Up-Regulating DNA Polymerase (cid:1)
Antitumor Activity of 2 (cid:1) ,3 (cid:1) -Dideoxycytidine Nucleotide Analog Against Tumors Up-Regulating DNA Polymerase (cid:1)
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发表时间：
2001
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通讯作者：
T. Louat;L. Servant;M. Rols;A. Bieth;J. Hoffmann;C. Cazaux
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作者：
T. Louat;L. Servant;M. Rols;A. Bieth;J. Hoffmann;C. Cazaux
DNA 聚合酶 (cid:1) (Pol (cid:1) ) 是一种容易出错的 DNA 合成酶，在健康体细胞中受到严格下调，已被证明在许多人类肿瘤中过度表达。在这项研究中，我们发现用 2 (cid:1) ,3 (cid:1) -二脱氧胞苷 (ddC) 核苷类似物处理可在体外和体内抑制 Pol (cid:1) 转染的 B16 黑色素瘤细胞的增殖，与对照同基因细胞相比，该细胞上调 Pol (cid:1)。 ddC 的施用还特别增加了携带 Pol (cid:1) 过度表达 B16 黑色素瘤的小鼠的存活率。当磷酸化形式的 ddC 电转移到 Pol (cid:1) 转染的黑色素瘤中时，细胞生长抑制作用增强，强烈表明细胞毒性作用是由链终止子掺入 DNA 引起的。使用体外单链和双链 DNA 合成测定，我们证明过量的 Pol (cid:1) 会扰乱复制机制，有利于 ddC-TP 掺入 DNA，从而促进链终止。因此，使用链AZT，3(cid:1)-叠氮基-3-胸苷； ddC-TP，三磷酸化 2 (cid:1) ,3 (cid:1) -二脱氧胞苷； PBS，磷酸盐缓冲盐水； SV40，猿猴病毒40；阿糖胞苷，4-氨基-1-（cid：1）-D-阿拉伯-呋喃糖基-2（1H）-嘧啶酮。
DNA polymerase (cid:1) (Pol (cid:1) ), 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 (cid:1) ,3 (cid:1) -dideoxycyti-dine (ddC) nucleoside analog inhibited in vitro and in vivo the proliferation of Pol (cid:1) -transfected B16 melanoma cells, which up-regulate Pol (cid:1) compared with control isogenic cells. The administration of ddC also increased specifically the survival of mice bearing Pol (cid:1) -overexpressing B16 melanoma. When the phosphorylated form of ddC was electrotransfered into Pol (cid:1) -transfected melanoma, the cell growth inhibition was strengthened, strongly suggesting that the cytotoxic effect re- sults from incorporation of the chain terminator into DNA. Using in vitro single- and double-stranded DNA synthesis assays, we demonstrated that excess Pol (cid:1) perturbs the replicative machinery, favors ddC-TP incorporation into DNA, and conse- quently promotes chain termination. Therefore, the use of chain AZT, 3 (cid:1) -azido-3-thymidine; ddC-TP, triphosphorylated 2 (cid:1) ,3 (cid:1) -dideoxycytidine; PBS, phosphate-buffered saline; SV40, simian virus 40; cytarabine, 4-amino-1- (cid:1) - D -arabino-furanosyl-2(1H)-pyrimidone.