Combinatory use of replication-competent adenoviruses and chemotherapeutic agents produces anti-tumor effects on human esophageal carcinoma cells

• Project/Area Number: 23591951
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Chiba Cancer Center (Research Institute)
• Principal Investigator: TAGAWA Masatoshi 千葉県がんセンター(研究所), がん治療開発グループ, 部長 (20171572)
• Co-Investigator(Kenkyū-buntansha): SHIMADA Hideaki 東邦大学, 医学部, 教授 (20292691)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2011: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 遺伝子 / ウイルス / 癌 / 受容体 / 化学療法 / CD46 / 抗腫瘍効果 / 食道がん / アデノウイルス / 細胞死 / p５３ / 食道癌 / CD46分子 / 細胞周期

Research Abstract

We examined a novel therapeutic strategy for intractable cancer in particular esophageal carcinoma. We replaced a transcriptional regulatory region of the E1 region-encoded genes in adenoviruses (Ad) with a 5' region of a gene that was highly expressed in human tumors but not in normal tissues such as midkine, survivin and cyclooxygenase-2. We also changed the fiber region of conventional type 5 Ad, which played a key role in infecting target cells, with a type 35-derived fiber region. The modification increased the viral infectivity since an expression level of the CAR molecules, which were a cellular receptor of type 5 Ad, were often down-regulated in human tumors. In contract, the expression of CD46 molecules, which are the major receptor of type 35 Ad, is rather up-regulated in human tumors. The fiber replacement greatly enhanced Ad infectivity in CAR-low tumors and subsequently enhanced the Ad-mediated cytotoxicity, and produced combinatory effects with anti-cancer agents.

Research Products

• [Journal Article] Combination of adenoviruses expressing melanoma differentiation-associated gene-7 and chemotherapeutic agents produces enhanced cytotoxicity on esophageal carcinoma. (2014)
  • Author(s): Ma, G., Kawamura, K., Yang, S., Okamoto, S., Li, Q., Namba, M., Shingyoji, M., Tada, Y., Tatsumi, K., Hiroshima, K., Shimada, H. and Tagawa, M.
  • Journal Title: Cancer Gene Ther. Volume: 21 Issue: 1 Pages: 31-37
  • DOI: 10.1038/cgt.2013.79
  • Peer Reviewed
• [Journal Article] Fiber-substituted conditionally replicating adenovirus Ad5F35 induces oncolysis of human bladder cancer cells in in vitro analysis. (2013)
  • Author(s): Gotoh A, Nagaya H, Kanno T, Tagawa M, Nishizaki T.
  • Journal Title: Urology. Volume: 81 Issue: 4 Pages: 920.e7-920.e11
  • DOI: 10.1016/j.urology.2012.12.023
  • Peer Reviewed
• [Journal Article] Gene therapy for malignant mesothelioma: Current prospects and challenges. (2013)
  • Author(s): Tagawa, M., Tada, Y., Shimada, H. and Hiroshima, K.
  • Journal Title: Cancer Gene Ther. Volume: 20 Issue: 3 Pages: 150-156
  • DOI: 10.1038/cgt.2013.1
  • Peer Reviewed
• [Journal Article] Enhanced antitumor efficacy of fiber-modified, midkine promoter-regulated oncolytic adenovirus in human malignant mesothelioma (2013)
  • Author(s): Takagi-Kimura, M., Yamano, T., Tamamoto, A., Okamura, N., Okamura, H., Hashimoto-Tamaoki, T., Tagawa, M., Kasahara, N. and Kubo, S.
  • Journal Title: Cancer Sci. Volume: 104 Issue: 11 Pages: 1433-1439
  • DOI: 10.1111/cas.12267
  • Peer Reviewed
• [Journal Article] Antitumor effect of chondroitin sulfate-coated ternary granulocyte macro phage-colony-stimulating factor plasmid complex for ovarian cancer (2012)
  • Author(s): Katsuyuki Hamada, 他
  • Journal Title: JOURNAL OF GENE MEDICINE Volume: 14 Issue: 2 Pages: 120-127
  • DOI: 10.1002/jgm.1647
  • Peer Reviewed
• [Journal Article] Expression of a murine homolog of apoptosis-inducing human IL-24/MDA-7 in murine tumors fails to induce apoptosis or produce anti-tumor effects (2012)
  • Author(s): Nagakawa H, Shimozato O, 他9名
  • Journal Title: Cellular Immunol Volume: 275 Issue: 1-2 Pages: 90-97
  • DOI: 10.1016/j.cellimm.2012.02.010
  • Peer Reviewed
• [Journal Article] Impact of serum biomarkers on esophageal squamous cell carcinoma (2012)
  • Author(s): Shimada H, Yajima S, Oshima Y, Hiwasa T, Tagawa M, Matsushita K, Nomura F
  • Journal Title: Esophagus Volume: 9(3) Issue: 3 Pages: 131-140
  • DOI: 10.1007/s10388-012-0332-x
  • NAID: 40019427695
  • Peer Reviewed
• [Journal Article] Fiber-substituted conditionally replicating adenovirus for oncolysis of human renal carcinoma cells (2012)
  • Author(s): Nagaya, H., Tagawa, M., Hiwasa, K., Terao, S., Kanno, T., Nishizaki, T. and Gotoh, A.
  • Journal Title: Anticancer Res. Volume: 32 Pages: 2985-2990
  • URL: http://ar.iiarjournals.org/content/32/7/2985.abstract
  • Peer Reviewed
• [Journal Article] Upregulated p53 expression activates apoptotic pathways in wild-type p53-bearing mesothelioma and enhances cytotoxicity of cisplatin and pemetrexed (2012)
  • Author(s): Li, Q., Kawamura, K., Okamoto, S., Yamanaka, M., Yang, S., Yamauchi, S., Fukamachi, T., Kobayashi, H., Tada, Y., Takiguchi, Y., Tatsumi, K., Shimada, H., Hiroshima, K. and Tagawa, M.
  • Journal Title: Cancer Gene Ther Volume: 19 Issue: 3 Pages: 218-228
  • DOI: 10.1038/cgt.2011.86
  • Peer Reviewed
• [Journal Article] Fiber-substituted conditionally replicating adenovirus for oncolysis of human renal carcinoma cells. (2012)
  • Author(s): Nagaya, H., Tagawa, M., Hiwasa, K., Terao, S., Kanno, T., Nishizaki, T. and Gotoh, A.
  • Journal Title: Anticancer Res. Volume: 32 Pages: 2985-2990
  • Peer Reviewed
• [Journal Article] A possible anti-cancer agent, type III interferon, activates cell death pathways and produces anti-tumor effects (2011)
  • Author(s): Tagawa, M., Kawamura, K., Li, Q., Tada, Y., Hiroshima, K. and Shimada, H.
  • Journal Title: Clin. Dev. Immunol Volume: 2011 Pages: 1-6
  • DOI: 10.1155/2011/479013
  • Peer Reviewed
• [Journal Article] Antitumor activity of type III interferon alone or in combination with type I interferon against human non-small-cell lung cancer (2011)
  • Author(s): Fujie, H., Tanaka, T., Tagawa, M., Kaijun, N., Watanabe, M., Suzuki, T., Nakayama, K. and Numasaki, M.
  • Journal Title: Cancer Sci. Volume: 102 Pages: 1977-1990
  • NAID: 120005518441
  • Peer Reviewed
• [Journal Article] Adenoviruses-mediated transduction of human esophageal carcinoma cells with the interferon-lambda genes produced anti-tumor effects (2011)
  • Author(s): Li, Q., Kawamura, K., Okamoto, S., Fujie, H., Numasaki, M., Namba, M., Nagata, M., Shimada, H., Kobayashi, H. and Tagawa, M.
  • Journal Title: Br. J. Cancer Volume: 105 Issue: 9 Pages: 1302-1312
  • DOI: 10.1038/bjc.2011.379
  • Peer Reviewed
• [Journal Article] Antitumor activity of type III interferon alone or in combination with type I interferon against human non-small cell lung cancer (2011)
  • Author(s): Fujie H、 Tanaka T、Tagawa M、 Kaijun N、 Watanabe M、 Suzuki T、 Nakayama K、 Numasaki M
  • Journal Title: Cancer Sci Volume: 102 Issue: 11 Pages: 1977-1990
  • DOI: 10.1111/j.1349-7006.2011.02079.x
  • NAID: 120005518441
  • Peer Reviewed
• [Presentation] An HSP90 inhibitor, which blocks p53 degradation, suppresses adenoviruses-mediated p53 production and the apoptosis (2013)
  • Author(s): 柴寛, その他
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜市
  • Year and Date: 2013-10-05
• [Presentation] Updated gene therapy for malignant mesothelioma : Challenges for the intractable caner (2013)
  • Author(s): Masatoshi Tagawa, その他
  • Organizer: 19th annual meeting of Japan Society of Gene Therapy
  • Place of Presentation: Okayama
  • Year and Date: 2013-07-06
• [Presentation] Midkine promoter-driven oncolytic adenovirus with Ad35 fiber modification achieves enhanced transduction of human osteosarcoma cells (2013)
  • Author(s): Shuji Kubo, その他
  • Organizer: 19th annual meeting of Japan Society of Gene Therapy
  • Place of Presentation: Okayama
  • Year and Date: 2013-07-06
• [Presentation] A Cancer-targeting ligand strongly enhances oncolytic activity of a conditionally replicative adenovirus (2013)
  • Author(s): Yuki Yamamoto, その他
  • Organizer: 16th annual meeting of American Society of Gene and Cell Therapy
  • Place of Presentation: Salt Lake City, USA
  • Year and Date: 2013-05-18
• [Presentation] Development of doubly regulated oncolytic adenovirus for human malignant mesothelioma (2013)
  • Author(s): Shuji Kubo, その他
  • Organizer: 16th annual meeting of American Society of Gene and Cell Therapy
  • Place of Presentation: Salt Lake City, USA
  • Year and Date: 2013-05-18
• [Presentation] A Cancer-targeting ligand strongly enhances oncolytic activity of a conditionally replicative adenovirus. (2013)
  • Author(s): Yuki Yamamoto, Naoko Goto, Shumpei Ohnami, Masatoshi Tagawa and Kazunori Aoki
  • Organizer: 16th annual meeting of American Society of Gene and Cell Therapy
  • Place of Presentation: Salt Lake City, USA
• [Presentation] Development of doubly regulated oncolytic adenovirus for human malignant mesothelioma. (2013)
  • Author(s): Shuji Kubo, Misato Takagi-Kimura, Atsuko Tamamoto, Tomoko Hashimoto-Tamaoki, Noriyuki Kasahara and Masatoshi Tagawa
  • Organizer: 16th annual meeting of American Society of Gene and Cell Therapy
  • Place of Presentation: Salt Lake City, USA
• [Presentation] Updated gene therapy for malignant mesothelioma: Challenges for the intractable caner. (2013)
  • Author(s): Masatoshi Tagawa, Yuji Tada, Hideaki Shimada and Kenzo Hiroshima
  • Organizer: 19th annual meeting of Japan Society of Gene Therapy
  • Place of Presentation: Okayama, Japan
• [Presentation] Midkine promoter-driven oncolytic adenovirus with Ad35 fiber modification achieves enhanced transduction of human osteosarcoma cells. (2013)
  • Author(s): Shuji Kubo, Misato Takagi-Kimura, Atsuko Tamamoto, Nobutaka Okamura, Masatoshi Tagawa, Noriyuki Kasahara, Haruki Okamura and Tomoko Hashimoto-Tamaoki
  • Organizer: 19th annual meeting of Japan Society of Gene Therapy
  • Place of Presentation: Okayama, Japan
• [Presentation] An HSP90 inhibitor, which blocks p53 degradation, suppresses adenoviruses-mediated p53 production and the apoptosis (2013)
  • Author(s): 柴 寛、荻野 敦史、多田 裕司、関根 郁夫、滝口 裕一、巽 浩一郎、島田 英昭、廣島 健三、加藤 和則、山口 直人、田川 雅敏
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Gene therapy for malignant mesothelioma with restored p53 functions (2012)
  • Author(s): Masatoshi Tagawa, その他
  • Organizer: International Society for Cell and Gene Therapy of Cancer2012 Singapore Conference
  • Place of Presentation: Singapore
  • Year and Date: 2012-10-05
• [Presentation] Cytotoxicity of replication-competent adenoviruses in esophageal carcinoma was enhanced by forced p53 expression (2012)
  • Author(s): 楊珊, その他
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市
  • Year and Date: 2012-09-20
• [Presentation] Development of doubly regulated oncolytic adenovirus for human malignant mesothelioma (2012)
  • Author(s): 久保秀司, その他
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市
  • Year and Date: 2012-09-20
• [Presentation] Analysis of serum anti-galectin-1 antibody in stage I/II gastroenterological carcinomas (2012)
  • Author(s): 島田英昭, その他
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市
  • Year and Date: 2012-09-20
• [Presentation] Bisphosphonates induce apoptosis through the suppression of Rab and produce combinatory effects with anti-cancer agents (2012)
  • Author(s): 田川雅敏, その他
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市
  • Year and Date: 2012-09-20
• [Presentation] Cytotoxicity of replication-competent adenoviruses in esophageal carcinoma was enhanced by forced p53 expression. (2012)
  • Author(s): 楊珊、川村希代子、江媛媛、柴 寛、久保秀司、山口直人、多田裕司、滝口裕一、巽浩一郎、島田英昭、廣島健三、田川雅敏
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市
• [Presentation] Development of doubly regulated oncolytic adenovirus for human malignant mesothelioma. (2012)
  • Author(s): 久保秀司、山野智基、吉川良恵、森永伴法、玉置知子、田川雅敏、笠原典之
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市
• [Presentation] Analysis of serum anti-galectin-1 antibody in stage I/II gastroenterological carcinomas. (2012)
  • Author(s): 島田英昭、谷島 聡、小池淳一、田川雅敏、日和佐隆樹、松下一之、野村文夫
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市
• [Presentation] Bisphosphonates induce apoptosis through the suppression of Rab and produce combinatory effects with anti-cancer agents. (2012)
  • Author(s): 田川雅敏、川村希代子、楊珊、江媛媛、柴 寛、久保秀司、山口直人、多田裕司、滝口裕一、巽浩一郎、島田英昭、廣島健三
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市
• [Presentation] Gene therapy for malignant mesothelioma with restored p53 functions. (2012)
  • Author(s): Masatoshi Tagawa, Kiyoko Kawamura, Shan Yang, Yuanyuan Jiang, Kuan Chai, Naoto Yamaguchi, Yuji Tada, Yuichi Takiguchi, Koichiro Tatsumi, Hideaki Shimada, Kenzo Hiroshima.
  • Organizer: Internatinal Socieity for Cell and Gene Therapy of Cancer 2012
  • Place of Presentation: シンガポール
  • Invited
• [Presentation] Promoter-mediated replication of adenoviruses induces apoptosis-independent cell death in p53-null pancreatic carcinoma cells (2011)
  • Author(s): Masatoshi Tagawa, その他
  • Organizer: 14th annual meeting of American Society of Gene and Cell Therapy
  • Place of Presentation: Seattle、USA
  • Year and Date: 2011-05-21
• [Presentation] Up-regulated p53 expression activates apoptotic pathways in wild-type p53-bearing mesothelioma and enhances cytotoxicity of the first-line chemotherapeutic agents (2011)
  • Author(s): Masatoshi Tagawa, その他
  • Organizer: 19th Annual Congress of the European Society of Gene and Cell Therapy
  • Place of Presentation: Brighton, UK
• [Presentation] Promoter-mediated replication of adenoviruses induces apoptosis-independent cell death in p53-null pancreatic carcinoma cells. (2011)
  • Author(s): Tagawa, M., その他
  • Organizer: 14th annual meeting of American Society of Gene and Cell Therapy
  • Place of Presentation: シアトル、アメリカ
• [Presentation] Up-regulated p53 expression activates apoptotic pathways in wild-type p53-bearing mesothelioma and enhances cytotoxicity of the first-line chemotherapeutic agents. (2011)
  • Author(s): Tagawa, M., その他
  • Organizer: 19th Annual Congress of the European Society of Gene and Cell Therapy
  • Place of Presentation: ブライトン、英国
• [Book] Mesotheliomas-synonyms and definition, epidemiology, etiology, pathogenesis, cyto-histopathological features, clinic, diagnosis, treatment, prognosis. (2012)
  • Author(s): Fukamachi, T., Saito, H., Tagawa, M. and Kobayashi, H.
  • Total Pages: 244
  • Publisher: InTech
• [Book] Midkine: From embryogenesis to pathogenesis and therapy. (2012)
  • Author(s): Tagawa, M., Kawamura, K., Yu, L., Tada, Y., Hiroshima, K. and Shimada, H.
  • Total Pages: 319
  • Publisher: Springer-Verlag Gmbh
• [Book] Type III interferon family-mediated anti-tumor responses through multiple mechanisms. In : Cellular and genetic practices for translational medicine. ed. by Jong-Young Kwak and Jin-Yeong Han (2011)
  • Author(s): Tagawa, M., Tada, Y., Hiroshima, K. and Shimada, H.
  • Publisher: Research Signpost
• [Book] Cellular and genetic practices for translational medicine. (2011)
  • Author(s): Tagawa, M., その他
  • Total Pages: 260
  • Publisher: Research Signpost
• [Remarks]
  • URL: http://www.pref.chiba.lg.jp/gan/kenkyujo/institute/organization/cell-therapy/index.html
• [Remarks]
  • URL: http://www.pref.chiba.lg.jp/gan/kenkyujo/institute/projects/007.html