Alonso Marta M, Jiang Hong, Yokoyama Tomohisa, Xu Jing, Bekele Nebiyou B, Lang Frederick F, Kondo Seiji, Gomez-Manzano Candelaria, Fueyo Juan
Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Mol Ther. 2008 Mar;16(3):487-93. doi: 10.1038/sj.mt.6300400. Epub 2008 Feb 5.
Novel therapies are clearly needed for the treatment of gliomas, and strategies that involve combining oncolytic vectors with chemotherapy hold out significant hope for a more effective treatment of this malignancy. Whether chemotherapy acts directly on tumor cells by inducing cell arrest or cell death, or indirectly by blocking tumor angiogenesis, the resulting delay in tumor growth may provide the oncolytic virus with a wider window of opportunity to overcome the challenge imposed by the growth kinetics of the tumor. In this study we sought to determine whether the oncolytic adenovirus Delta-24-RGD, in combination with everolimus (RAD001), would result in an enhanced anti-glioma effect in vivo. Viability assays showed that Delta-24-RGD antitumoral activity is synergistically enhanced by combination with RAD001. Interestingly, combination treatment of Delta-24-RGD with RAD001 induced autophagy in vitro. We showed that Delta-24-RGD improved survival of tumor-bearing animals in a dose-dependent manner. A significant finding was that RAD001 enhanced the anti-glioma effect of Delta-24-RGD and resulted in the long-term survival of 80% of the experimental animals. Immunostaining of the treated tumors showed upregulation of Atg5, thereby indicating the therapeutic induction of autophagy. This is the first report showing that Delta-24-RGD plus RAD001 causes autophagic cell death, and dramatically increases long-term survival rates of glioma-bearing animals.
显然需要新的疗法来治疗神经胶质瘤，将溶瘤载体与化疗相结合的策略为更有效地治疗这种恶性肿瘤带来了巨大希望。无论化疗是通过诱导细胞停滞或细胞死亡直接作用于肿瘤细胞，还是通过阻断肿瘤血管生成间接作用，由此导致的肿瘤生长延迟都可能为溶瘤病毒提供更广阔的机会窗口，以克服肿瘤生长动力学带来的挑战。在本研究中，我们试图确定溶瘤腺病毒Delta-24-RGD与依维莫司（RAD001）联合使用是否会在体内增强抗神经胶质瘤的效果。活力测定表明，Delta-24-RGD与RAD001联合使用可协同增强其抗肿瘤活性。有趣的是，Delta-24-RGD与RAD001联合治疗在体外诱导了自噬。我们发现Delta-24-RGD以剂量依赖的方式提高了荷瘤动物的存活率。一个重要发现是，RAD001增强了Delta-24-RGD的抗神经胶质瘤效果，并使80%的实验动物长期存活。对治疗后的肿瘤进行免疫染色显示Atg5上调，从而表明自噬的治疗性诱导。这是第一份表明Delta-24-RGD加RAD001可导致自噬性细胞死亡，并显著提高荷神经胶质瘤动物长期存活率的报告。
