Syncytia induction enhances the oncolytic potential of vesicular stomatitis virus in virotherapy for cancer
Syncytia induction enhances the oncolytic potential of vesicular stomatitis virus in virotherapy for cancer
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DOI：
10.1158/0008-5472.can-03-3753
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发表时间：
2004-05-01
期刊：
影响因子：
11.2
通讯作者：
Woo, SLC
中科院分区：
文献类型：
--
作者：
Ebert, O;Shinozaki, K;Woo, SLC
水泡性口炎病毒;（VSV）选择性地在肿瘤中复制，但不在正常细胞中复制，并且正在被开发为用于癌症治疗的溶瘤剂。在这里，我们报告的重组VSV的建设能够诱导肿瘤细胞之间的合胞体形成，通过膜融合在中性pH值，这导致增强溶瘤特性对多灶性肝细胞癌（HCC）在肝脏的免疫活性大鼠。通过在其基因组中插入表达源自纽卡斯尔病病毒的对照或融合蛋白的转录单位来构建重组VSV载体。重组融合VSV载体对人和大鼠肝癌细胞的体外表征显示出广泛的合胞体形成和显著增强的细胞毒性作用。在体内，将融合性VSV给药到肝脏中带有同系多灶性HCC病变的布法罗大鼠的肝动脉中导致合胞体仅在肿瘤内形成，并且对邻近的肝实质没有附带损害。与非融合对照病毒相比，融合VSV在给药动物中也具有显著的存活优势（P = 0.0078，对数秩检验）。结果表明，融合VSV可以发展成为一种有效和安全的治疗药物，用于癌症患者的治疗，包括那些患有肝脏多灶性HCC的患者。
Vesicular stomatitis virus; (VSV) selectively replicates in tumor but not in normal cells and is being developed as an oncolytic agent for cancer therapy. Here we report the construction of a recombinant VSV capable of inducing syncytia formation between tumor cells through membrane fusion at neutral pH, which led to enhanced oncolytic properties against multifocal hepatocellular carcinoma (HCC) in the livers of immunocompetent rats. Recombinant VSV vectors were constructed by insertion into their genome a transcription unit expressing a control or fusion protein derived from Newcastle disease virus. In vitro characterization of the recombinant fusogenic VSV vector on human and rat HCC cells showed extensive syncytia formation and significantly enhanced cytotoxic effects. lit vivo, administration of fusogenic VSV into the hepatic artery of Buffalo rats bearing syngeneic multifocal HCC lesions in their livers resulted in syncytia formation exclusively within the tumors, and there was no collateral damage to the neighboring hepatic parenchyma. The fusogenic VSV also conferred a significant survival advantage over a nonfusogenic control virus in the treated animals (P = 0.0078, log-rank test). The results suggest that fusogenic VSV can be developed into an effective and safe therapeutic agent for cancer treatment in patients, including those with multifocal HCC in the liver.