Cancer targeting Gene-Viro-Therapy of liver carcinoma by dual-regulated oncolytic adenovirus armed with TRAIL gene

被引:32
作者
Cao, X. [1 ]
Yang, M. [2 ]
Wei, R-C [3 ]
Zeng, Y. [4 ]
Gu, J-F [1 ]
Huang, W-D [1 ]
Yang, D-Q [1 ]
Li, H-L [1 ,5 ]
Ding, M. [1 ]
Wei, N. [1 ]
Zhang, K-J [1 ]
Xu, B. [6 ]
Liu, X-R [1 ]
Qian, Q-J [7 ,8 ]
Liu, X-Y [1 ,7 ]
机构
[1] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Mol Cell Biol Lab, Shanghai 200031, Peoples R China
[2] NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA
[3] Guangxi Normal Univ, Sch Life Sci, Guilin, Peoples R China
[4] Chinese Acad Sci, Inst Pasteur Shanghai, Mol Virol Lab, Shanghai 200031, Peoples R China
[5] Southwestern Univ, Chongqing Engn Res Ctr Floriculture, Dept Hort & Garden, Chongqing, Peoples R China
[6] Tongji Univ, Sch Med, Shanghai Peoples Hosp 10, Dept Gen Surg, Shanghai 200092, Peoples R China
[7] Zhejiang Sci Tech Univ, Xinyuan Inst Med & Biotechnol, Hangzhou, Zhejiang, Peoples R China
[8] Second Mil Med Univ, Eastern Hepatobiliary Surg Hosp, Lab Gene & Virus Therapy, Shanghai, Peoples R China
关键词
cancer targeting Gene-Viro-Therapy; dual-regulated oncolytic adenovirus; tumor necrosis factor-related apoptosis-inducing ligand; autophagy; apoptosis; HUMAN HEPATOCELLULAR-CARCINOMA; PROGRAMMED CELL-DEATH; ANTITUMOR-ACTIVITY; ALPHA-FETOPROTEIN; TUMOR-CELLS; COLORECTAL-CANCER; SURVIVIN PROMOTER; MALIGNANT GLIOMA; HUMAN HEPATOMA; SV40; ENHANCER;
D O I
10.1038/gt.2011.16
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Liver cancer is a common and aggressive malignancy, but available treatment approaches remain suboptimal. Cancer targeting Gene-Viro-Therapy (CTGVT) has shown excellent anti-tumor effects in a preclinical study. CTGVT takes advantage of both gene therapy and virotherapy by incorporating an anti-tumor gene into an oncolytic virus vector. Potent anti-tumor activity is achieved by virus replication and exogenous expression of the anti-tumor gene. A dual-regulated oncolytic adenoviral vector designated Ad.AFP.E1A.E1B (Delta 55) (Ad.AFP.D55 for short thereafter) was constructed by replacing the native viral E1A promoter with the simian virus 40 enhancer/alpha-fetoprotein (AFP) composite promoter (AFPep) based on an E1B-55K-deleted construct, ZD55. Ad.AFP.D55 showed specific replication and cytotoxicity in AFP-positive hepatoma cells. It also showed enhanced safety in normal cells when compared with the mono-regulated vector ZD55. To improve the anti-hepatoma activities of the virus, the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene was introduced into Ad.AFP.D55. Ad.AFP.D55-TRAIL exhibited remarkable anti-tumor activities in vitro and in vivo. Treatment with Ad.AFP.D55-TRAIL can induce both autophagy owing to the Ad.AFP.D55 vector and caspase-dependent apoptosis owing to the TRAIL protein. Therefore, Ad.AFP.D55-TRAIL could be a potential anti-hepatoma agent with anti-tumor activities due to AFP-specific replication and TRAIL-induced apoptosis. Gene Therapy (2011) 18, 765-777; doi:10.1038/gt.2011.16; published online 17 March 2011
引用
收藏
页码:765 / 777
页数:13
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