title: A tumor-specific conditionally replicative adenovirus vector expressing TRAIL for gene therapy of hepatocellular carcinoma.
abstract: We constructed a novel hepatocellular carcinoma-specific conditionally replicative adenovirus (CRAd). This adenovirus, designated Ad.HS4.AFP.E1A/TRAIL, expresses E1A to mediate viral replication and TRAIL to enhance HCC-killing efficacy under the control of a modified AFP promoter. An insulator HS-4 was placed in front of the AFP promoter to enhance the fidelity of the heterologous promoter. This virus was shown to have specific cytolytic activity in AFP-expressing HCC cells in vitro. Furthermore, the replication efficiency of Ad.HS4.AFP.E1A/TRAIL correlated well with AFP expression of the host cells, showing a 100-fold and 1 000 000-fold decrease in the low-and non-AFP-expressing HCC cells, respectively, compared to the high AFP-expressing HCC cells. An increase in mRNA of TRAIL and the elevated Caspase-3 activity were also observed in Ad.HS4.AFP.E1A/TRAIL-infected HCC cells. These results indicated that TRAIL expression from the viral vector activated the Caspase-3 enzymatic capacity and the HCC cells were sensitive to TRAIL. In vivo, Ad.HS4.AFP.E1A/TRAIL effectively prevented the growth of low AFP-expressing BEL-7404 xenografts. These results indicate that Ad.HS4.AFP.E1A/TRAIL could provide a new strategy of gene therapy for HCC.
authors.affiliation: Shanghai Sunway Biotech Co., Ltd, Pudong, Shanghai, China.
authors.forename: X-W
authors.initials: XW
authors.lastname: Ren
authors.forename: M
authors.initials: M
authors.lastname: Liang
authors.forename: X
authors.initials: X
authors.lastname: Meng
authors.forename: X
authors.initials: X
authors.lastname: Ye
authors.forename: H
authors.initials: H
authors.lastname: Ma
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.forename: J
authors.initials: J
authors.lastname: Guo
authors.forename: N
authors.initials: N
authors.lastname: Cai
authors.forename: H-Z
authors.initials: HZ
authors.lastname: Chen
authors.forename: S-L
authors.initials: SL
authors.lastname: Ye
authors.forename: F
authors.initials: F
authors.lastname: Hu
mesh_terms: D000256:Adenoviridae; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000628:therapy*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003124:Colorimetry; D017931:DNA Primers; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand; D013778:Tetrazolium Salts; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D000509:alpha-Fetoproteins / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D017931:DNA Primers; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D013778:Tetrazolium Salts; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000509:alpha-Fetoproteins; C042207:4-anisyltetrazolium blue; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases