Oncolytic vesicular stomatitis virus for treatment of orthotopic hepatocellular carcinoma in immune-competent rats.
Oncolytic vesicular stomatitis virus for treatment of orthotopic hepatocellular carcinoma in immune-competent rats.
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发表时间：
2003-07
期刊：
影响因子：
11.2
通讯作者：
O. Ebert;K. Shinozaki;Tian-gui Huang;M. Savontaus;A. García-Sastre;S. Woo
中科院分区：
文献类型：
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作者：
O. Ebert;K. Shinozaki;Tian-gui Huang;M. Savontaus;A. García-Sastre;S. Woo
肿瘤靶向复制型病毒作为一类新型的溶瘤剂正在开发中。水泡性口炎病毒（VSV）是一种负链RNA病毒，由于其减弱的抗病毒反应，对肿瘤细胞具有固有的复制特异性。VSV作为一种溶瘤病毒特别有吸引力，因为它在肿瘤细胞中的复制速率非常快，使得溶瘤作用可以在宿主中潜在的中和性抗病毒免疫应答开始之前最大限度地显现。为了容易地监测VSV复制，我们已经拯救了表达绿色荧光蛋白（GFP）基因的重组VSV（rVSV）载体（rVSV-GFP）。使用这种表达GFP的病毒，我们已经证明了VSV对人和大鼠肝细胞癌（HCC）的溶瘤潜力。我们发现rVSV-GFP在培养的人和大鼠HCC细胞中有效复制，而正常人和大鼠肝细胞是难治性的。当将单剂量的载体瘤内注射到免疫活性大鼠中的大原位植入的HCC中时，rVSV-GFP在整个实体瘤块中有效地和选择性地复制，而没有明显的肝毒性，引起肿瘤破坏，并抑制肿瘤生长，这导致动物存活的显著延长。我们的研究结果表明，VSV是一种有效的溶瘤剂对肝癌的免疫功能正常的主机，并保证进一步发展为未来的治疗肝癌患者。
Tumor-targeted replicating viruses are being developed as a novel class of oncolytic agents. Vesicular stomatitis virus (VSV) is a negative-strand RNA virus with inherent specificity for replication in tumor cells due to their attenuated antiviral responses. VSV as an oncolytic virus is particularly appealing for its exceptionally rapid replication rate in tumor cells, such that the oncolytic effects could be maximally manifested before the onset of potentially neutralizing antiviral immune responses in the host. To easily monitor VSV replication, we have rescued a recombinant VSV (rVSV) vector expressing the green fluorescent protein (GFP) gene (rVSV-GFP). Using this GFP-expressing virus, we have demonstrated the oncolytic potential of VSV against human and rat hepatocellular carcinoma (HCC). We found that rVSV-GFP replicated efficiently in cultured human and rat HCC cells, whereas normal human and rat hepatocytes were refractory. When a single dose of the vector was injected intratumorally into large orthotopically implanted HCC in immune-competent rats, rVSV-GFP effectively and selectively replicated throughout the solid tumor mass without apparent hepatotoxicity, caused tumor destruction, and inhibited tumor growth, which led to significant prolongation of animal survival. Our results show that VSV is an effective oncolytic agent against HCC in immune-competent hosts and warrants further development for future therapy in patients with HCC.