title: An oncolytic adenovirus regulated by a radiation-inducible promoter selectively mediates hSulf-1 gene expression and mutually reinforces antitumor activity of I131-metuximab in hepatocellular carcinoma.
abstract: Gene therapy and antibody approaches are crucial auxiliary strategies for hepatocellular carcinoma (HCC) treatment. Previously, we established a survivin promoter-regulated oncolytic adenovirus that has inhibitory effect on HCC growth. The human sulfatase-1 (hSulf-1) gene can suppress the growth factor signaling pathways, then inhibit the proliferation of cancer cells and enhance cellular sensitivity to radiotherapy and chemotherapy. I(131)-metuximab (I(131)-mab) is a monoclonal anti-HCC antibody that conjugated to I(131) and specifically recognizes the HAb18G/CD147 antigen on HCC cells. To integrate the oncolytic adenovirus-based gene therapy and the I(131)-mab-based radioimmunotherapy, this study combined the CArG element of early growth response-l (Egr-l) gene with the survivin promoter to construct a radiation-inducible enhanced promoter, which was used to recombine a radiation-inducible oncolytic adenovirus as hSulf-1 gene vector. When I(131)-mab was incorporated into the treatment regimen, not only could the antibody produce radioimmunotherapeutic effect, but the I(131) radiation was able to further boost adenoviral proliferation. We demonstrated that the CArG-enhanced survivin promoter markedly improved the proliferative activity of the oncolytic adenovirus in HCC cells, thereby augmenting hSulf-1 expression and inducing cancer cell apoptosis. This novel strategy that involved multiple, synergistic mechanisms, including oncolytic therapy, gene therapy and radioimmunotherapy, was demonstrated to exert an excellent anti-cancer outcome, which will be a promising approach in HCC treatment.
authors.affiliation: Department of Cancer Radiotherapy, Nanjing Second Hospital and Second Affiliated Hospital of Southeast University, Nanjing 210003, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Lin
authors.initials: L
authors.lastname: Fang
authors.forename: Quan'an
authors.initials: Q
authors.lastname: Zhang
authors.forename: Qin
authors.initials: Q
authors.lastname: Zheng
authors.forename: Jinlong
authors.initials: J
authors.lastname: Tong
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Fu
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Jiang
authors.forename: Changqing
authors.initials: C
authors.lastname: Su
authors.forename: Junnian
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000528:radiation effects; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D059248:Chemoradiotherapy; D005822:Genetic Vectors / Q000235:genetics / Q000528:radiation effects / Q000627:therapeutic use; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000235:genetics* / Q000528:radiation effects; D011401:Promoter Regions, Genetic / Q000528:radiation effects; D016499:Radioimmunotherapy / Q000379:methods; D015238:Sulfotransferases / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; C511207:metuximab; C470791:SULF1 protein, human; D015238:Sulfotransferases