NYU Cancer Institute and the NYU Gene Therapy Center, Department of Pathology, NYU School of Medicine, New York University, New York, NY 10016, USA.
Cancer Gene Ther. 2010 Apr;17(4):244-55. doi: 10.1038/cgt.2009.70. Epub 2009 Oct 2.
Genetic instability of cancer cells generates resistance after initial responses to chemotherapeutic agents. Several oncolytic viruses have been designed to exploit specific signatures of cancer cells, such as important surface markers or pivotal signaling pathways for selective replication. It is less likely for cancer cells to develop resistance given that mutations in these cancer signatures would negatively impact tumor growth and survival. However, as oncolytic viral vectors are large particles, they suffer from inefficient extravasation from tumor blood vessels. Their ability to reach cancer cells is an important consideration in achieving specific oncolytic targeting and potential vector replication. Our previous studies indicated that the Sindbis viral vectors target tumor cells by the laminin receptor. Here, we present evidence that modulating tumor vascular leakiness, using VEGF and/or metronomic chemotherapy regimens, significantly enhances tumor vascular permeability and directly enhances oncolytic Sindbis vector targeting in tumor models. Because host-derived vascular endothelium cells are genetically stable and less likely to develop resistance to chemotherapeutics, a combined metronomic chemotherapeutics and oncolytic vector regimen should provide a new approach for cancer therapy. This mechanism could explain the synergistic treatment outcomes observed in clinical trials of combined therapies.
癌细胞的遗传不稳定性会在对化疗药物产生初始反应后产生耐药性。已经设计了几种溶瘤病毒来利用癌细胞的特定特征，例如重要的表面标志物或关键信号通路，以进行选择性复制。由于这些癌症特征的突变会对肿瘤生长和存活产生负面影响，因此癌细胞产生耐药性的可能性较小。然而，由于溶瘤病毒载体是大颗粒，它们从肿瘤血管中渗出的效率较低。它们到达癌细胞的能力是实现特异性溶瘤靶向和潜在载体复制的重要考虑因素。我们之前的研究表明，辛德比斯病毒载体通过层粘连蛋白受体靶向肿瘤细胞。在这里，我们提供的证据表明，使用 VEGF 和/或节拍化疗方案调节肿瘤血管通透性，可显著增强肿瘤血管通透性，并直接增强肿瘤模型中的溶瘤辛德比斯病毒载体靶向。由于宿主来源的血管内皮细胞具有遗传稳定性，并且不太可能对化疗药物产生耐药性，因此联合节拍化疗和溶瘤载体方案应为癌症治疗提供新方法。这种机制可以解释联合治疗临床试验中观察到的协同治疗结果。
