title: Cytotoxic effects of replication-competent adenoviruses on human esophageal carcinoma are enhanced by forced p53 expression.
abstract: BACKGROUND
  Improvement of transduction and augmentation of cytotoxicity are crucial for adenoviruses (Ad)-mediated gene therapy for cancer. Down-regulated expression of type 5 Ad (Ad5) receptors on human tumors hampered Ad-mediated transduction. Furthermore, a role of the p53 pathways in cytotoxicity mediated by replication-competent Ad remained uncharacterized.
  
  
  METHODS
  We constructed replication-competent Ad5 of which the E1 region genes were activated by a transcriptional regulatory region of the midkine or the survivin gene, which is expressed preferentially in human tumors. We also prepared replication-competent Ad5 which were regulated by the same region but had a fiber-knob region derived from serotype 35 (AdF35). We examined the cytotoxicity of these Ad and a possible combinatory use of the replication-competent AdF35 and Ad5 expressing the wild-type p53 gene (Ad5/p53) in esophageal carcinoma cells. Expression levels of molecules involved in cell death, anti-tumor effects in vivo and production of viral progenies were also investigated.
  
  
  RESULTS
  Replication-competent AdF35 in general achieved greater cytotoxic effects to esophageal carcinoma cells than the corresponding replication-competent Ad5. Infection with the AdF35 induced cleavages of caspases and increased sub-G1 fractions, but did not activate the autophagy pathway. Transduction with Ad5/p53 in combination with the replication-competent AdF35 further enhanced the cytotoxicity in a synergistic manner. We also demonstrated the combinatory effects in an animal model. Transduction with Ad5/p53 however suppressed production of replication-competent AdF35 progenies, but the combination augmented Ad5/p53-mediated p53 expression levels and the downstream pathways.
  
  
  CONCLUSIONS
  Combination of replication-competent AdF35 and Ad5/p53 achieved synergistic cytotoxicity due to enhanced p53-mediated apoptotic pathways.
authors.affiliation: Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, 260-8717, Chiba, Japan. yswish2009@163.com.|Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan. yswish2009@163.com.
authors.forename: Shan
authors.initials: S
authors.lastname: Yang
authors.affiliation: Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, 260-8717, Chiba, Japan. kkawamur@chiba-cc.jp.
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Kawamura
authors.affiliation: Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, 260-8717, Chiba, Japan. sokamoto@chiba-cc.jp.|Department of Biochemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan. sokamoto@chiba-cc.jp.|Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan. sokamoto@chiba-cc.jp.
authors.forename: Shinya
authors.initials: S
authors.lastname: Okamoto
authors.affiliation: Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, 260-8717, Chiba, Japan. mr_children4hero@yahoo.co.jp.|Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan. mr_children4hero@yahoo.co.jp.
authors.forename: Suguru
authors.initials: S
authors.lastname: Yamauchi
authors.affiliation: Division of Respirology, Chiba Cancer Center, Chiba, Japan. mshingyoji@chiba-cc.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Shingyoji
authors.affiliation: Division of Respirology, Chiba Cancer Center, Chiba, Japan. isekine@chiba-u.jp.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Sekine
authors.affiliation: Department of Biochemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan. hiroshi.k@mx6.ttcn.ne.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan. ytada25@yahoo.co.jp.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tada
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan. tatsumi@faculty.chiba-u.jp.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tatsumi
authors.affiliation: Department of Pathology, Tokyo Women's Medical University Yachiyo Medical Center, Chiba, Japan. kenzo@tymc.twmu.ac.jp.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Hiroshima
authors.affiliation: Department of Surgery, School of Medicine, Toho University, Tokyo, Japan. hideaki.shimada@med.toho-u.ac.jp.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Shimada
authors.affiliation: Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, 260-8717, Chiba, Japan. mtagawa@chiba-cc.jp.|Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan. mtagawa@chiba-cc.jp.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Tagawa
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D012333:RNA, Messenger / Q000096:biosynthesis; D014161:Transduction, Genetic; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53