Liu Ying, Wang Hongjie, Yumul Roma, Gao Wentao, Gambotto Andrea, Morita Takashi, Baker Andrew, Shayakhmetov Dmitry, Lieber André
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Hum Gene Ther. 2009 Jun;20(6):621-9. doi: 10.1089/hum.2008.142.
Inefficient tumor transduction with targeted adenoviral vectors is largely due to unspecific virus sequestration by blood components, including coagulation factor X, and Kupffer cell scavenging. In this study, we show that preinjection of snake venom factor X-binding protein (X-bp) reduces hepatocyte transduction and increases the circulation time in blood of an intravenously injected, fiber-chimeric Ad5/35 vector. X-bp pretreatment resulted in improved Ad5/35 transduction of liver metastases and increased the antitumor efficacy of an Ad5/35-based oncolytic adenovirus. Furthermore, we demonstrate that a vector based on adenoviral serotype 35, which is less sequestered by factor X, is efficient in tumor targeting. This gives a rationale for using Ad35-based vectors in virotherapy of cancer.
靶向腺病毒载体对肿瘤的转导效率低下，很大程度上是由于血液成分（包括凝血因子X）对病毒的非特异性隔离以及库普弗细胞的清除作用。在本研究中，我们发现预先注射蛇毒因子X结合蛋白（X-bp）可减少肝细胞转导，并延长静脉注射的纤维嵌合型Ad5/35载体在血液中的循环时间。X-bp预处理可改善肝转移灶的Ad5/35转导，并提高基于Ad5/35的溶瘤腺病毒的抗肿瘤疗效。此外，我们证明基于腺病毒血清型35的载体较少被因子X隔离，在肿瘤靶向方面效率较高。这为在癌症病毒治疗中使用基于Ad35的载体提供了理论依据。
