期刊
GENE THERAPY
卷 18, 期 8, 页码 765-777出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/gt.2011.16
关键词
cancer targeting Gene-Viro-Therapy; dual-regulated oncolytic adenovirus; tumor necrosis factor-related apoptosis-inducing ligand; autophagy; apoptosis
类别
资金
- National Nature Science Foundation of China [30623003]
- Science and Technology Commission of Shanghai Municipality [06DZ22032]
- National Basic Research Program of China (973 Program) [2004 CB51804]
- Hi-Tech Research Development Program of China (863 Program) [2007AA 021006]
- Chinese Academy of Science [KSCX2-YW-R -09, R-04]
- Zhejiang Sci-Tech University [0616033]
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
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