title: E1B-55 kDa-defective adenoviruses activate p53 in mesothelioma and enhance cytotoxicity of anticancer agents.
abstract: BACKGROUND
  Genetic characterization of malignant mesothelioma shows a homozygous deletion of the INK4A/ARF locus, which results in inactivation of the p53 pathways.
  
  
  METHODS
  We examined possible antitumor effects of adenoviruses with a deletion of the E1B-55kD gene (Ad-delE1B55) on mesothelioma and investigated combinatory actions with the first-line chemotherapeutic agents.
  
  
  RESULTS
  Ad-delE1B55 produced cytotoxicity on mesothelioma cells, which was associated with p53 phosphorylation, pRb dephosphorylation, and cleavage of caspases. Ad-delE1B55-infected cells displayed hyperploidy at the cell-cycle analysis and showed enlarged nuclear configurations. Combination of Ad-delE1B55 plus cisplatin or pemetrexed produced antitumor effects in vitro. Furthermore, Ad-delE1B55 and cisplatin showed combinatory effects in an orthotopic animal model.
  
  
  CONCLUSIONS
  Cell death caused by Ad-delE1B55 is attributable to cell-cycle arrest at M-phase checkpoint followed by activated apoptotic pathways, and combination of the first-line chemotherapeutic agents and the oncolytic adenovirus is a potential therapeutic for mesothelioma.
authors.affiliation: Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan; Department of Respirology, Chiba University, Chiba, Japan.
authors.forename: Makako
authors.initials: M
authors.lastname: Yamanaka
authors.affiliation: Department of Respirology, Chiba University, Chiba, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tada
authors.affiliation: Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan.
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Kawamura
authors.affiliation: Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan; Department of Molecular Biology and Oncology, Chiba University, Chiba, Japan.
authors.forename: Quanhai
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Okamoto
authors.affiliation: Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan; Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Kuan
authors.initials: K
authors.lastname: Chai
authors.affiliation: Division of Translational Genomics, Chiba Cancer Center Research Institute, Chiba, Japan.
authors.forename: Sana
authors.initials: S
authors.lastname: Yokoi
authors.affiliation: TOT Shanghai RD Center, Shanghai, China.
authors.forename: Min
authors.initials: M
authors.lastname: Liang
authors.affiliation: Department of Biochemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Fukamachi
authors.affiliation: Department of Biochemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamaguchi
authors.affiliation: Department of Respirology, Chiba University, Chiba, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kitamura
authors.affiliation: Department of Surgery, School of Medicine, Toho University, Tokyo, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Shimada
authors.affiliation: Department of Pathology, Tokyo Women's Medical University, Yachiyo Medical Center, Yachiyo, Japan.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Hiroshima
authors.affiliation: Medical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Takiguchi
authors.affiliation: Department of Respirology, Chiba University, Chiba, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tatsumi
authors.affiliation: Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan; Department of Molecular Biology and Oncology, Chiba University, Chiba, Japan. Electronic address: mtagawa@chiba-cc.jp.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Tagawa
mesh_terms: D000256:Adenoviridae / Q000502:physiology*; D017501:Adenovirus E1B Proteins / Q000172:deficiency*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011003:Ploidies; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D017501:Adenovirus E1B Proteins; D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin