title: The combination of an oxygen-dependent degradation domain-regulated             adenovirus expressing the chemokine RANTES/CCL5 and NK-92 cells exerts enhanced             antitumor activity in hepatocellular carcinoma.
abstract: Oncolytic adenoviruses are modified based on adenovirus serotype 5 (Ad5),             which belongs to subgroup C and depends on Coxsackie-adenovirus receptor (CAR)             to recognize target cells. However, expression of CAR is generally low or lost             in certain tumors including hepatocellular carcinoma (HCC). By contrast, CD46             is highly expressed in various types of malignant tumor cells. Therefore, we constructed             an adenovirus vector expressing the human RANTES/CCL5 gene regulated by oxygen-dependent             degradation domain (ODD) and analyzed its antitumor effects in vitro and in vivo.             The human RANTES/CCL5 gene was fused with ODD by PCR and the recombinant oncolytic             adenovirus containing RANTES-ODD, SG511-CCL5-ODD, was constructed by the Gateway             system, which infected cells by binding CD46. Viral replication experiments were             performed to evaluate the selective replication ability of SG511-CCL5-ODD. RANTES             expression was determined by ELISA. The chemotactic test was used to analyze the             ability of the expressed RANTES to recruit NK92 cells. The antitumor effects of             SG511-CCL5-ODD were examined in HCC xenografts in nude mice. A chimeric oncolytic             adenovirus, SG511-CCL5-ODD, was constructed successfully. Cells infected with             the recombinant virus were able to express RANTES selectively in different environments             controlled by ODD and the expressed RANTES was able to recruit NK92 cells by its             chemotactic effect in vitro and improve the anticancer immune response in HCC             xenografts in nude mice. The chimeric adenovirus SG511-CCL5-ODD highly expressed             the RANTES-ODD fusion gene in the hypoxia of HCC under the control of the ODD             and effectively attracted NK92 cells and a high number of immunocytes. These factors             had complementary advantages and, in combination, exerted enhanced antitumor efficacy.
authors.affiliation: Laboratory of Viral and Gene Therapy, Eastern Hepatobiliary Surgical Hospital and Institute, The Second Military Medical University, Shanghai 200438, PR China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Linfang
authors.initials: L
authors.lastname: Li
authors.forename: Hongping
authors.initials: H
authors.lastname: Wu
authors.forename: Chunhong
authors.initials: C
authors.lastname: Wang
authors.forename: Zi
authors.initials: Z
authors.lastname: Yan
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Changqing
authors.initials: C
authors.lastname: Su
authors.forename: Huajun
authors.initials: H
authors.lastname: Jin
authors.forename: Fuping
authors.initials: F
authors.lastname: Zhou
authors.forename: Mengchao
authors.initials: M
authors.lastname: Wu
authors.forename: Qijun
authors.initials: Q
authors.lastname: Qian
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000502:physiology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival; D018946:Chemokine CCL5 / Q000096:biosynthesis* / Q000235:genetics; D002633:Chemotaxis; D003131:Combined Modality Therapy; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000276:immunology / Q000637:transplantation; D008113:Liver Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D047368:Tumor Burden; D014779:Virus Replication
chemical_list: C483024:CCL5 protein, human; D018946:Chemokine CCL5; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011993:Recombinant Fusion Proteins