Oncolytic vesicular stomatitis virus in an immunocompetent model of MUC1-positive or MUC1-null pancreatic ductal adenocarcinoma.
Oncolytic vesicular stomatitis virus in an immunocompetent model of MUC1-positive or MUC1-null pancreatic ductal adenocarcinoma.
复制标题
MUC1 阳性或 MUC1 缺失胰腺导管腺癌免疫活性模型中的溶瘤性水泡性口炎病毒。
DOI：
10.1128/jvi.01412-13
复制
发表时间：
2013
影响因子：
5.4
通讯作者：
Grdzelishvili,ValeryZ
中科院分区：
文献类型：
--
作者：
Hastie,Eric;Besmer,DahliaM;Shah,NiravR;Murphy,AndreaM;Moerdyk-Schauwecker,Megan;Molestina,Carlos;Roy,LopamudraDas;Curry,JenniferM;Mukherjee,Pinku;Grdzelishvili,ValeryZ
水泡性口炎病毒（VSV）是一种很有前途的抗肿瘤药物。在此，我们首次在临床相关的免疫活性胰腺导管腺癌（PDA）小鼠模型中检测了VSV体外和体内。我们的系统允许在过表达的情况下研究针对PDA的病毒疗法。在体外，我们测试了三种VSV重组体，野生型VSV，VSV-绿色荧光蛋白（VSV-GFP）和安全的溶瘤VSV-ΔM51-GFP，针对表达人MUC 1或MUC 1无效的5种小鼠PDA细胞系。所有病毒均表现出显著的溶瘤能力，而不依赖于MUC 1的表达，尽管VSV-Δ M51-GFP在两种PDA细胞系中的效果稍差。体内施用VSV-ΔM51-GFP导致测试的小鼠PDA异种移植物（+MUC 1或MUC 1 null）的肿瘤生长显著减少，并且当病毒与化疗药物吉西他滨组合时，抗肿瘤功效进一步提高。在所有试验组中，抗肿瘤作用均为一过性。开发的系统可用于研究涉及各种溶瘤病毒和化疗药物的疗法，目的是诱导肿瘤特异性免疫，同时防止过早清除病毒。
Vesicular stomatitis virus (VSV) is a promising oncolytic agent against various malignancies. Here, for the first time, we tested VSVin vitroandin vivoin a clinically relevant, immunocompetent mouse model of pancreatic ductal adenocarcinoma (PDA). Our system allows the study of virotherapy against PDA in the context of overexpression (80% of PDA patients) or no expression of human mucin 1 (MUC1), a major marker for poor prognosis in patients.In vitro, we tested three VSV recombinants, wild-type VSV, VSV-green fluorescent protein (VSV-GFP), and a safe oncolytic VSV-ΔM51-GFP, against five mouse PDA cell lines that either expressed human MUC1 or were MUC1 null. All viruses demonstrated significant oncolytic abilities independent of MUC1 expression, although VSV-ΔM51-GFP was somewhat less effective in two PDA cell lines.In vivoadministration of VSV-ΔM51-GFP resulted in significant reduction of tumor growth for tested mouse PDA xenografts (+MUC1 or MUC1 null), and antitumor efficacy was further improved when the virus was combined with the chemotherapeutic drug gemcitabine. The antitumor effect was transient in all tested groups. The developed system can be used to study therapies involving various oncolytic viruses and chemotherapeutics, with the goal of inducing tumor-specific immunity while preventing premature virus clearance.