Department of Surgery, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Cancer Gene Ther. 2011 Dec;18(12):837-49. doi: 10.1038/cgt.2011.49. Epub 2011 Sep 2.
M protein mutant vesicular stomatitis virus is an attractive candidate oncolytic virus for the treatment of metastatic colorectal cancer due to its ability to kill cancer cells that are defective in their antiviral responses. The oncolytic activity of recombinant wild-type and M protein mutant vesicular stomatitis viruses was determined in RKO, Hct116 and LoVo colorectal cancer cells, as well as in human fibroblast and hepatocyte primary cultures. RKO and Hct116 cells were sensitive to both viruses, whereas LoVo cells were resistant. [(35)S]methionine labeling experiments and viral plaque assays showed that sensitive and resistant colorectal cancer cells supported viral protein and progeny production after infection with either virus. Colorectal cancer cells were pretreated with β-interferon and infected with vesicular stomatitis virus to evaluate the extent to which interferon signaling is downregulated in colorectal cancer cells. Although colorectal cancer cells retained some degree of interferon signaling, this signaling did not negatively impact the oncolytic effects of either virus in sensitive cells. Murine xenografts of RKO cells were effectively treated by intratumoral injections with M protein mutant virus, whereas LoVo xenografts were resistant to treatment with this virus. These results suggest that M protein mutant vesicular stomatitis virus is a good candidate oncolytic virus for the treatment of selected metastatic colorectal cancers.
M 蛋白突变型水疱性口炎病毒由于能够杀死抗病毒反应有缺陷的癌细胞，因此是一种有吸引力的溶瘤病毒候选药物，可用于治疗转移性结直肠癌。重组野生型和 M 蛋白突变型水疱性口炎病毒在 RKO、Hct116 和 LoVo 结直肠癌细胞以及人成纤维细胞和肝细胞原代培养物中的溶瘤活性。RKO 和 Hct116 细胞对两种病毒均敏感，而 LoVo 细胞则具有抗性。[(35)S]甲硫氨酸标记实验和病毒斑形成实验表明，感染两种病毒后，敏感和耐药结直肠癌细胞均支持病毒蛋白和子代的产生。用β-干扰素预处理结直肠癌细胞，然后用水疱性口炎病毒感染，以评估干扰素信号在结直肠癌细胞中下调的程度。尽管结直肠癌细胞保留了一定程度的干扰素信号，但这种信号并未对敏感细胞中两种病毒的溶瘤作用产生负面影响。通过肿瘤内注射 M 蛋白突变型病毒有效治疗了 RKO 细胞的鼠异种移植物，而 LoVo 异种移植物对该病毒的治疗具有抗性。这些结果表明，M 蛋白突变型水疱性口炎病毒是治疗选定转移性结直肠癌的良好溶瘤病毒候选药物。
