Wei J, Wahl J, Nakamura T, Stiller D, Mertens T, Debatin K-M, Beltinger C
University Children's Hospital, Ulm, Germany.
Gene Ther. 2007 Nov;14(22):1573-86. doi: 10.1038/sj.gt.3303027. Epub 2007 Sep 27.
Malignant gliomas remain largely incurable despite intensive efforts to develop novel therapies. Replicating oncolytic viruses have shown great promise, among them attenuated measles viruses of the Edmonston B strain (MV-Edm). However, host immune response and the infiltrative nature of gliomas limit their efficacy. We show that human blood outgrowth endothelial cells (BOECs), readily expandable from peripheral blood, are easily infected by MV-Edm and allow replication of MV-Edm while surviving long enough after infection to serve as vehicles for MV-Edm (BOEC/MV-Edm). After intravenous and peritumoral injection, BOEC/MV-Edm deliver the viruses selectively to irradiated orthotopic U87 gliomas in mice. At the tumor, MV-Edm produced by the BOECs infect glioma cells. Subsequent spread from tumor cell to tumor cell leads to focal infection and cytopathic effects that decrease tumor size and, in the case of peritumoral injection, prolong survival of mice. Since MV-Edm within BOECs are not readily neutralized and because BOEC/MV-Edm search and destroy glioma cells, BOEC/MV-Edm constitute a promising novel approach for glioma therapy.
尽管人们为开发新疗法付出了巨大努力，但恶性胶质瘤在很大程度上仍然无法治愈。复制型溶瘤病毒已显示出巨大潜力，其中包括埃德蒙斯顿B株减毒麻疹病毒（MV-Edm）。然而，宿主免疫反应和胶质瘤的浸润性限制了它们的疗效。我们发现，可从外周血中轻松扩增的人血源性内皮祖细胞（BOECs）很容易被MV-Edm感染，并能让MV-Edm复制，同时在感染后存活足够长的时间，充当MV-Edm的载体（BOEC/MV-Edm）。经静脉和瘤周注射后，BOEC/MV-Edm将病毒选择性地递送至小鼠体内经照射的原位U87胶质瘤。在肿瘤部位，BOECs产生的MV-Edm感染胶质瘤细胞。随后从肿瘤细胞到肿瘤细胞的传播导致局部感染和细胞病变效应，从而减小肿瘤大小，并且在瘤周注射的情况下，延长小鼠的生存期。由于BOECs内的MV-Edm不易被中和，且因为BOEC/MV-Edm能寻找并破坏胶质瘤细胞，所以BOEC/MV-Edm构成了一种有前景的胶质瘤治疗新方法。
