title: Cancer targeting Gene-Viro-Therapy of liver carcinoma by dual-regulated oncolytic adenovirus armed with TRAIL gene.
abstract: 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 (Δ55) (Ad·AFP·D55 for short thereafter) was constructed by replacing the native viral E1A promoter with the simian virus 40 enhancer/α-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.
authors.affiliation: Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Cao
authors.forename: M
authors.initials: M
authors.lastname: Yang
authors.forename: R-C
authors.initials: RC
authors.lastname: Wei
authors.forename: Y
authors.initials: Y
authors.lastname: Zeng
authors.forename: J-F
authors.initials: JF
authors.lastname: Gu
authors.forename: W-D
authors.initials: WD
authors.lastname: Huang
authors.forename: D-Q
authors.initials: DQ
authors.lastname: Yang
authors.forename: H-L
authors.initials: HL
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Ding
authors.forename: N
authors.initials: N
authors.lastname: Wei
authors.forename: K-J
authors.initials: KJ
authors.lastname: Zhang
authors.forename: B
authors.initials: B
authors.lastname: Xu
authors.forename: X-R
authors.initials: XR
authors.lastname: Liu
authors.forename: Q-J
authors.initials: QJ
authors.lastname: Qian
authors.forename: X-Y
authors.initials: XY
authors.lastname: Liu
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D024201:Bystander Effect; D006528:Carcinoma, Hepatocellular / Q000628:therapy*; D045744:Cell Line, Tumor; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008113:Liver Neoplasms / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D000509:alpha-Fetoproteins / Q000235:genetics
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D000509:alpha-Fetoproteins