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Experimental Efficacy of Genechemotherapy for Biliary cancer using molecular target gene transduction method.

Research Project

Project/Area Number 21790648
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeSingle-year Grants
Research Field Gastroenterology
Research InstitutionUniversity of Tsukuba

Principal Investigator

FUKUDA Kuniaki  筑波大学, 医学医療系, 講師 (50447257)

Project Period (FY) 2009 – 2011
Project Status Completed (Fiscal Year 2011)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2011: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2009: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords胆道学 / 遺伝子治療 / 消化器内科学
Research Abstract

Biliary cancers are highly malignant diseases with poor prognosis and thus development of new treatments such as gene therapy is necessary. Although adenovirus vectors are widely used for cancer gene therapy, conventional adenoviral vectors infect not only cancer cells but also normal cells. Therefore, a new method that allow more specific gene delivery to cancer cells needs to be developed to obtain more efficient anti-tumor effect and safety. We explored methods of retargeting adenovirus vectors for targeted gene therapy of human biliary cancers using the Ad incorporating an IgG Fc binding motif (Z33) from the Staphylococcus protein A (Ad-FZ33) combined with tumor specific antibodies. Flow cytometry analysis revealed high expression levels of epithelial cell adhesion molecule (EpCAM) and epidermal growth factor receptor (EGFR) on human biliary cancer cells. Ad-FZ33 expressing LacZ combined with antibodies against EpCAM or EGFR, followed by β-gal assay, demonstrated highly efficient gene transduction in these biliary cancer cells, compared with the treatment with control antibody or without antibody. Ad-FZ33 expressing uracil phosphoribosyl transferase (UPRT), an enzyme which greatly enhances the toxicity of 5-fluorouracil (FU), combined with antibodies against EpCAM or EGFR, remarkably enhanced the sensitivity of biliary cancer cells to 5-FU. By contrast, the treatment didn't affect 5-FU sensitivity of the cells not expressing EpCAM or EGFR including normal hepatocytes. Finally, treatments with the UPRT-expressing Ad-FZ33 with antibodies against EpCAM or EGFR, followed by 5-FU administration, were significantly suppressed the growth of biliary cancer xenografts in nude mice. These results indicate that the molecular target genechemotherapy mediated by the Z33 fiber-modified adenovirus with anti-EpCAM or anti-EGFR antibodies offers a potentially effective therapeutic modality against biliary cancers, and can be expected in clinical applications fairly.

Report

(4 results)
  • 2011 Annual Research Report   Final Research Report ( PDF )
  • 2010 Annual Research Report
  • 2009 Annual Research Report
  • Research Products

    (8 results)

All 2011 2009 Other

All Journal Article (3 results) (of which Peer Reviewed: 1 results) Presentation (4 results) Remarks (1 results)

  • [Journal Article] EpCAM-and EGFRtargetedselective gene therapy for biliarycancers using Z33-fiber modified adenovirus2011

    • Author(s)
      Kawashima R, Abei M, Fukuda K, NakamuraK, Murata T, Wakayama M, Seo E, Hasegawa N, Mizuguchi H, Obata Y, Hyodo I, Hamada H, Yokoyama KK
    • Journal Title

      Int. J Cancer

      Volume: 129(5) Pages: 1244-1253

    • Related Report
      2011 Final Research Report
  • [Journal Article] EpCAM- and EGFR-targeted selective gene therapy for biliary cancers using Z33-fiber modified adenovirus2011

    • Author(s)
      Kawashima R, Abei M, Fukuda K, Nakamura K, Murata T, Wakayama M, Seo E, Hasegawa N, Mizuguchi H, Obata Y, Hyodo I, Hamada H, Yokoyama KK
    • Journal Title

      International Journal of Cancer

      Volume: 129 Pages: 1244-1253

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] E1A, E1B double-restricted replicative adenovirus at low dose greatly augments tumor-specific suicide gene therapy for gallbladder cancer2009

    • Author(s)
      Fukuda K, Abei M, Ugai H, Kawashima R, Seo E, Wakayama M, Murata T, Endo S, Hamada H, Hyodo I, Yokoyama KK
    • Journal Title

      Cancer Gene Ther

      Volume: 16(2) Pages: 126-36

    • Related Report
      2011 Final Research Report
  • [Presentation] Targeted gene therapy for cancers by using Z33 fiber modified adenovirus vector with tumor specific antibodies2009

    • Author(s)
      Kawashima R, Fukuda K, Abei M, Nakamura K, Murata T, Yokoyama KK, Hamada H, Hyodo I
    • Organizer
      20th Asia Pacific Cancer Conference
    • Place of Presentation
      つくば
    • Year and Date
      2009-11-12
    • Related Report
      2011 Final Research Report
  • [Presentation] Targeted gene therapy for cancers by using Z33 fiber modified adenovirus vector with tumor specific antibodies2009

    • Author(s)
      Rei Kawashima
    • Organizer
      20^<th> Asia Pacific Cancer Conference
    • Place of Presentation
      つくば市
    • Year and Date
      2009-11-12
    • Related Report
      2009 Annual Research Report
  • [Presentation] Z33アデノウイルスと腫瘍特異抗体を用いた胆道癌の標的化遺伝子治療の開発2009

    • Author(s)
      川島玲,安部井誠人,福田邦明,村田武英,濱田洋文,兵頭一之介
    • Organizer
      第45回日本胆道学会
    • Place of Presentation
      千葉
    • Year and Date
      2009-09-19
    • Related Report
      2011 Final Research Report
  • [Presentation] Effective gene therapy for biliary cancers by using Z33 fiber modified adenovirus with tumor specific antibodies2009

    • Author(s)
      Kawashima R, Abei M, Fukuda K, Nakamura K, Murata T, Hyodo I, Hamada H, Obata Y, Yokoyama KK
    • Organizer
      第15回日本遺伝子治療学会
    • Place of Presentation
      大阪
    • Year and Date
      2009-07-10
    • Related Report
      2011 Final Research Report
  • [Remarks]

    • URL

      http://www.md.tsukuba.ac.jp/clinical-med/gastroenterology/daigakuin.html

    • Related Report
      2010 Annual Research Report

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Published: 2009-04-01   Modified: 2016-04-21  

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