title: Enhanced antitumor efficacy of a novel fiber chimeric oncolytic adenovirus expressing p53 on hepatocellular carcinoma.
abstract: Oncolytic adenoviruses may offer a new treatment option and improve the prognosis for patients with hepatocellular carcinoma (HCC). However, the antitumor efficacy of oncolytic adenoviruses on HCC cells is compromised due to low expression of the adenovirus serotype 5 (Ad5) receptor on the target cells. In this study we showed that all HCC cell lines and clinical samples expressed high level of CD46, the receptor for Adenovirus 35 (Ad35) and constructed new fiber chimeric oncolytic adenoviruses with or without a p53 gene expression cassette, SG635-p53 and SG635, respectively. These variants were derived from the previously described Ad5 vectors SG600-p53 and SG600 by replacing the Ad5 fiber with a chimeric Ad5/35 fiber. It was found that the 5/35 fiber chimeric adenovirus vector (Ad5/35-EGFP) demonstrated significantly improved transduction in all tested HCC cell lines compared with the Ad5 vector (Ad5-EGFP). The new fiber chimeric oncolytic adenoviruses produced more progeny viruses in HCC cells than did the Ad5-based viruses but replicated weakly in normal fibroblast BJ cells. In addition, SG635-p53 mediated a higher level of transgenic expression than SG600-p53 in Hep3B and Huh7 cells and showed a markedly enhanced antitumor effect on HCC cells in vitro compared with SG635 or SG600-p53 without causing significant cytotoxicity to normal cells. Antitumor activity of SG635-p53 was shown in Hep3B subcutaneous xenograft tumor models following intratumoral injection, resulting in significant inhibition of tumor growth and prolonged survival of animals. Our data suggest that SG635-p53, as a fiber chimeric oncolytic adenovirus in combination with p53 expression, may serve as a novel, promising and safe anticancer agent for the treatment of HCC.
authors.affiliation: Liver Transplantation Center, 3rd Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Liver Transplantation Center, 3rd Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Liver Transplantation Center, 3rd Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Guoying
authors.initials: G
authors.lastname: Wang
authors.affiliation: Liver Transplantation Center, 3rd Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Liver Transplantation Center, 3rd Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Chen
authors.affiliation: Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Tai
authors.affiliation: Liver Transplantation Center, 3rd Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Minqiang
authors.initials: M
authors.lastname: Lu
authors.affiliation: Laboratory of Gene and Viral Therapy, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Qijun
authors.initials: Q
authors.lastname: Qian
authors.affiliation: Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China; Cell-gene Therapy Translational Medicine Research Center, 3rd Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. Electronic address: keekee77@126.com.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Liver Transplantation Center, 3rd Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China. Electronic address: chgh1955@263.net.
authors.forename: Guihua
authors.initials: G
authors.lastname: Chen
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000628:therapy*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000628:therapy*; D051916:Membrane Cofactor Protein; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: C497857:CD46 protein, human; D051916:Membrane Cofactor Protein; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53