Oncolytic Activity of Vesicular Stomatitis Virus Is Effective against Tumors Exhibiting Aberrant p53, Ras, or Myc Function and Involves the Induction of Apoptosis

We have recently shown that vesicular stomatitis virus (VSV) exhibits potent oncolytic activity both in vitro and in vivo (S. Balachandran and G. N. Barber, IUBMB Life 50:135–138, 2000). In this study, we further demonstrated, in vivo, the efficacy of VSV antitumor action by showing that tumors that are defective in p53 function or transformed with myc or activated ras are also susceptible to viral cytolysis. The mechanism of viral oncolytic activity involved the induction of multiple caspase-dependent apoptotic pathways was effective in the absence of any significant cytotoxic T-lymphocyte response, and occurred despite normal PKR activity and eIF2α phosphorylation. In addition, VSV caused significant inhibition of tumor growth when administered intravenously in immunocompetent hosts. Our data indicate that VSV shows significant promise as an effective oncolytic agent against a wide variety of malignant diseases that harbor a diversity of genetic defects.

我们此前的研究已证实，水泡性口炎病毒（vesicular stomatitis virus, VSV）在体外（in vitro）与体内（in vivo）均具有强效溶瘤活性（S. Balachandran及G. N. Barber, IUBMB Life 50:135–138, 2000）。本研究进一步通过体内实验验证了VSV的抗肿瘤功效：p53功能缺陷或经myc癌基因、激活型ras（activated ras）转化的肿瘤，同样对病毒介导的细胞裂解作用易感。病毒溶瘤活性的核心机制涉及诱导多条半胱天冬酶依赖的细胞凋亡通路（caspase-dependent apoptotic pathways），该通路可在未引发显著细胞毒性T淋巴细胞（cytotoxic T-lymphocyte）应答的情况下发挥作用，且即便蛋白激酶R（Protein Kinase R, PKR）活性与真核翻译起始因子2α（eukaryotic translation initiation factor 2α, eIF2α）磷酸化水平正常，该溶瘤过程仍可正常发生。此外，在免疫健全宿主（immunocompetent hosts）中经静脉给药时，VSV可显著抑制肿瘤生长。本研究数据表明，VSV作为一种高效溶瘤制剂，对携带多种遗传缺陷的各类恶性疾病均具有良好的应用前景。