title: Modification of the early gene enhancer-promoter improves the oncolytic potency of adenovirus 11.
abstract: Oncolytic adenoviruses based on serotype 5 (Ad5) have several shortcomings, including the downregulation of its receptor in cancer cells, high prevalence of neutralizing antibodies and hepatotoxicity. Another adenoviral serotype, Ad11, could overcome these obstacles. Here, we show that human cancer cell lines express higher levels of the Ad11 receptor CD46, resulting in much better infectivity than Ad5. Surprisingly, only 36% (9/25) of the cell lines were more sensitive to Ad11- than to Ad5-mediated cytotoxicity. Investigations revealed that it was the transcription of Ad11 E1A, not CD46 expression or virus infectivity, which determined the cell's sensitivity to Ad11 killing. Ad11 E1A mRNA levels have an effect on viral DNA replication, structural protein synthesis and infectious particle production. To test the hypothesis that increased E1A transcription would lead to improved Ad11 replication in Ad5-sensitive (but Ad11-less sensitive) cells, two Ad11 mutants (Ad11-Ad5-P and Ad11-Ad5-EP) were constructed where either the E1A promoter or enhancer-promoter, respectively, was replaced by that of Ad5. Ad11-Ad5-EP demonstrated increased E1A mRNA levels and replication, together with enhanced oncolytic potency in vitro and in vivo. This effect was found in both the Ad5-sensitive and Ad11-sensitive cancer cells, broadening the range of tumors that could be effectively killed by Ad11-Ad5-EP.
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Han Hsi
authors.initials: HH
authors.lastname: Wong
authors.forename: Guozhong
authors.initials: G
authors.lastname: Jiang
authors.forename: Rathi
authors.initials: R
authors.lastname: Gangeswaran
authors.forename: Pengju
authors.initials: P
authors.lastname: Wang
authors.forename: Jiwei
authors.initials: J
authors.lastname: Wang
authors.forename: Ming
authors.initials: M
authors.lastname: Yuan
authors.forename: Hexiao
authors.initials: H
authors.lastname: Wang
authors.forename: Vipul
authors.initials: V
authors.lastname: Bhakta
authors.forename: Heike
authors.initials: H
authors.lastname: Müller
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Lemoine
authors.forename: Yaohe
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D017500:Adenovirus E1A Proteins / Q000235:genetics*; D000818:Animals; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003588:Cytopathogenic Effect, Viral / Q000235:genetics; D051301:Desmoglein 2 / Q000235:genetics; D004742:Enhancer Elements, Genetic; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006801:Humans; D051916:Membrane Cofactor Protein / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics / Q000401:mortality / Q000628:therapy; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D011401:Promoter Regions, Genetic; D016019:Survival Analysis; D014158:Transcription, Genetic; D014779:Virus Replication / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D017500:Adenovirus E1A Proteins; D036022:Capsid Proteins; D051301:Desmoglein 2; D051916:Membrane Cofactor Protein; C018315:hexon capsid protein, Adenovirus
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