文章：

雷帕霉素和溶瘤呼肠孤病毒的协同抗肿瘤作用

Synergistic antitumour effects of rapamycin and oncolytic reovirus 

原文发布日期：2018-05-03 

英文摘要：

There are currently numerous oncolytic viruses undergoing clinical trial evaluation in cancer patients and one agent, Talimogene laherparepvec, has been approved for the treatment of malignant melanoma. This progress highlights the huge clinical potential of this treatment modality, and the focus is now combining these agents with conventional anticancer treatments or agents that enhance viral replication, and thereby oncolysis, in the tumour microenvironment. We evaluated the combination of reovirus with rapamycin in B16F10 cell, a murine model of malignant melanoma, based on potential mechanisms by which mTOR inhibitors might enhance viral oncolysis. Rapamycin was not immunomodulatory in that it had no effect on the generation of an antireovirus-neutralising antibody response in C57/black 6 mice. The cell cycle effects of reovirus (increase G0/G1 fraction) were unaffected by concomitant or sequential exposure of rapamycin. However, rapamycin attenuated viral replication if given prior or concomitantly with reovirus and similarly reduced reovirus-induced apoptotic cell death Annexin V/PI and caspase 3/7 activation studies. We found clear evidence of synergistic antitumour effects of the combination both in vitro and in vivo, which was sequence dependent only in the in vitro setting. In conclusion, we have demonstrated synergistic antitumour efficacy of reovirus and rapamycin combination. 

摘要翻译： 

目前有多种溶瘤病毒正在癌症患者中进行临床试验评估，其中Talimogene laherparepvec已被批准用于治疗恶性黑色素瘤。这一进展凸显了该治疗模式的巨大临床潜力，当前的研究重点是将这些制剂与常规抗癌治疗或能增强肿瘤微环境中病毒复制（从而增强溶瘤作用）的药物联用。基于mTOR抑制剂可能增强病毒溶瘤作用的潜在机制，我们在恶性黑色素瘤小鼠模型B16F10细胞中评估了呼肠孤病毒与雷帕霉素的联合治疗效果。雷帕霉素不具有免疫调节作用，对C57BL/6小鼠抗呼肠孤病毒中和抗体反应的产生没有影响。呼肠孤病毒的细胞周期效应（增加G0/G1期比例）不受雷帕霉素同时或序贯给药的影响。然而，若在呼肠孤病毒给药前或同时使用雷帕霉素，则会减弱病毒复制，并类似地减少呼肠孤病毒诱导的凋亡性细胞死亡（Annexin V/PI及caspase 3/7活化实验证实）。我们在体外和体内实验中均发现该联合方案具有协同抗肿瘤作用的明确证据，但仅体外实验中显示出给药时序依赖性。综上所述，我们证实了呼肠孤病毒与雷帕霉素联用具有协同抗肿瘤功效。

原文链接：

Synergistic antitumour effects of rapamycin and oncolytic reovirus