Departments of Surgery and Immunology, Hillman Cancer Center, University of Pittsburgh Cancer Institute, University of Pittsburgh, 5117 Centre Avenue, Pittsburgh, PA 15238, USA.
Gene Ther. 2011 Feb;18(2):164-72. doi: 10.1038/gt.2010.121. Epub 2010 Aug 26.
Recent developments in the field of oncolytic or tumor-selective viruses have meant that the clinical applications of these agents are now being considered in more detail. Like most cancer therapies it is likely that they will be used primarily in combination with other therapeutics. Although several reports have shown that oncolytic viruses can synergize with chemotherapies within an infected cancer cell, it would be particularly important to determine whether factors released from infected cells could enhance the action of chemotherapies at a distance. Here, we demonstrate in vitro synergy between oncolytic vaccinia and taxanes. However, we also show, for the first time, that this synergy is at least partly due to the release of factors from the infected cells that are capable of sensitizing surrounding cells to chemotherapy. Several cellular factors were identified as being mediators of this bystander effect, including type I interferon released soon after infection and high-mobility group protein B1 (HMGB1) released after cell death. This represents the first description of these mechanisms for beneficial interactions between viral and traditional tumor therapies. These data may provide a direct basis for the design of clinical trials with agents currently in the clinic, as well as providing insight into the development of next generation viral vectors.
近年来，溶瘤或肿瘤选择性病毒领域的发展意味着这些药物的临床应用正在被更详细地考虑。与大多数癌症疗法一样，它们很可能主要与其他疗法联合使用。尽管有几项报告表明溶瘤病毒可以在感染的癌细胞内与化疗药物协同作用，但确定感染细胞释放的因子是否可以远距离增强化疗药物的作用将尤为重要。在这里，我们证明了溶瘤痘苗病毒和紫杉烷类药物之间的体外协同作用。然而，我们还首次表明，这种协同作用至少部分是由于感染细胞释放的因子能够使周围细胞对化疗药物敏感。几种细胞因子被鉴定为这种旁观者效应的介导物，包括感染后很快释放的 I 型干扰素和细胞死亡后释放的高迁移率族蛋白 B1（HMGB1）。这代表了病毒和传统肿瘤疗法之间有益相互作用的这些机制的首次描述。这些数据可能为目前正在临床应用的药物的临床试验设计提供直接依据，并为下一代病毒载体的开发提供深入了解。
