Huang Qian, Zhang Xiuwu, Wang He, Yan Bin, Kirkpatrick John, Dewhrist Mark W, Li Chuan-Yuan
Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Clin Cancer Res. 2004 Feb 15;10(4):1439-45. doi: 10.1158/1078-0432.ccr-03-0122.
To develop a novel conditionally replicative adenovirus vector that targets telomerase-positive cancer cells.
A telomerase gene-derived promoter was used to control the expression of the E1a gene so that the E1a gene is only expressed in telomerase-positive tumor cells. In addition, a reporter gene was also engineered into the vector so that its infection and replication can be monitored easily.
A novel recombinant adenovirus vector that could selectively replicate in telomerase-positive cancer cells was made successfully. This vector showed active replication in a panel of cancer cells and minimal replication in normal human fibroblast or epithelial cells. The recombinant vector could effectively lyse various cultured tumor cells even at very low multiplicity of infection. The replication efficiency in tumor cells is over 10(3)-fold more than normal fibroblast and epithelial cells. In s.c. tumor models, the newly developed telomerase-selective adenovirus vectors exhibited significantly more virus replication and reporter gene expression.
The telomerase-targeted adenovirus vector has significant potential as an oncolytic virus as well as a tumor-specific therapeutic gene delivery vehicle.
开发一种靶向端粒酶阳性癌细胞的新型条件性复制腺病毒载体。
使用端粒酶基因衍生的启动子来控制E1a基因的表达，使得E1a基因仅在端粒酶阳性肿瘤细胞中表达。此外，还在载体中构建了一个报告基因，以便能够轻松监测其感染和复制情况。
成功制备了一种新型重组腺病毒载体，该载体能够在端粒酶阳性癌细胞中选择性复制。该载体在一组癌细胞中显示出活跃复制，而在正常人成纤维细胞或上皮细胞中复制极少。即使在非常低的感染复数下，重组载体也能有效裂解各种培养的肿瘤细胞。其在肿瘤细胞中的复制效率比正常成纤维细胞和上皮细胞高10³倍以上。在皮下肿瘤模型中，新开发的端粒酶选择性腺病毒载体表现出显著更多的病毒复制和报告基因表达。
端粒酶靶向腺病毒载体作为一种溶瘤病毒以及肿瘤特异性治疗性基因递送载体具有巨大潜力。
