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Experimental Efficacy of Fiber-modified Cancer-selectively Replicating Adenovirus for Gene Therapy of Biliary Cancers

Research Project

Project/Area Number 16390203
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionUniversity of Tsukuba

Principal Investigator

ABEI Masato  University of Tsukuba, Graduate School of Comprehensive Human Sciences, Assistant Professor (20261802)

Co-Investigator(Kenkyū-buntansha) YOKOYAMA Kazunari  独立行政法人理化学研究所, BioResourse Center, RIKEN Institute, Head of Gene Engineering Division (80182707)
HAMADA Hirofumi  Sapporo Medical University, Department of Molecular Medicine, Professor (00189614)
轟 健  筑波大学, 大学院人間総合科学研究科, 助教授 (70114105)
Project Period (FY) 2004 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥9,200,000 (Direct Cost: ¥9,200,000)
Fiscal Year 2006: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2005: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2004: ¥3,400,000 (Direct Cost: ¥3,400,000)
Keywordsgene therapy / adenovirus / biliary cancer / gallbladder cancer / bile duct cancer / integrin / コクサッキー・アデノウイルス受容体
Research Abstract

Cancers of biliary system represent highly malignant diseases of dismal prognosis. We have previously introduced an E1A, E1B-double restricted oncolytic adenovirus, AxdAdB3, which showed excellent infectivity and oncolytic efficacy in half of the biliary cancer lines with an enhanced safety to normal cells. The purpose of this study was to evaluate whether RGD-fiber modification of AxdAdB3 (AxdAdB3-F/RGD), which enables integrin-dependent infection, can to improve the infectivity and efficacy of AxdAdB3 for biliary cancers. Expressions of adenoviral receptors, coxsackievirus adenovirus receptor (CAR) and integrins (avb3, avb5), were compared with the level of infectivity of LacZ-expressing replication-defective adenoviruses with wild type fibers or RGD-modified fibers in a panel of biliary cancer cell lines in vitro. Viral replication and cytotoxicity of AxdAdB3-F/RGD, a novel E1A, E1B double restricted adenovirus with RGD-modified fibers, in various biliary cancer cells and in normal … More cells, were compared with those of its parent virus, AxdAdB-3, in vitro. Antitumor effects in vivo of these oncolytic viruses were compared in a xenograft tumor model. Expression of CAR significantly correlated with the Ad infectivity, while integrin αvβ5 was abundantly expressed in all biliary cancer cells. While AxdAdB3 effectively replicated and lysed only the biliary cancer cells with a preserved expression of CAR, AxdAdB3-F/RGD exhibited efficient replication and potent oncolysis in both CAR-positive and CAR-negative biliary cancer cells. AxdAdB3-F/RGD showed attenuated replication and little cytopathy in human normal cells (ie ; hepatocytes, WI-38 cells) as well as AxdAdB3. Furthermore, in nude mice with subcutaneous xenografts of CAR-deficient human biliary cancer, i.t. AxdAdB3-F/RGD therapy caused a marked inhibition of tumor growth. In conclusion, the RGD fiber modification strategy exhibited enhanced infectivity, replication, and oncolytic efficacy of the E1A, E1B-double mutated adenovirus for CAR-deficient biliary cancers. In addition, it preserved the merit of excellent safety of the double-restricted virus for normal cells. These results suggest a potential use of this agent for the treatment of biliary cancers. Less

Report

(4 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • Research Products

    (9 results)

All 2007 2005 2004

All Journal Article (9 results)

  • [Journal Article] E1A, E1B double-restricted adenovirus with RGD fiber modification exhibits enhanced oncolysis for CAR-deficient biliary cancers.2007

    • Author(s)
      Mariko Wakayama, et al.
    • Journal Title

      Clinical Cancer Research 13(10)

      Pages: 3043-3050

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] E1A, E1B double-restricted adenovirus with RGD-fiber modification exhibits enhanced oncolysis for CAR-deficient biliary cancers2007

    • Author(s)
      Wakayama M, et al.
    • Journal Title

      Clinical Cancer Research 13(10)

      Pages: 3043-3050

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] E1A, E1B Double-Restricted Adenovirus with RGD Fiber Modification Exhibits Enhanced Oncolysis for CAR-Deficient Biliary Cancers.2007

    • Author(s)
      Mariko Wakayama, et al.
    • Journal Title

      Clinical Cancer Research 印刷中

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Effective gene therapy of biliary cancers by a conditionally replicative adenovirus expressing uracil phosphoribosyltransferase : Significance of 5-fluorouracil administration.2005

    • Author(s)
      Emiko Seo, et al.
    • Journal Title

      Cancer Research 65(2)

      Pages: 546-552

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Effective gene therapy of biliary cancers by a conditionally replicative adenovirus expressing uracil phosphoribosyltransferase : Significance of 5-fluorouracil administration2005

    • Author(s)
      Seo E, et al.
    • Journal Title

      Cancer Research 65(2)

      Pages: 546-552

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Effective Gene Therapy of Biliary Tract Cancers by a Conditionally Replicative Adenovirus Expressing Uracil Phosphoribosyltransferase : Significance of Timing of 5-fluorouracil Administration.2005

    • Author(s)
      Emiko Seo, et al.
    • Journal Title

      Cancer Research 65

      Pages: 546-552

    • Related Report
      2005 Annual Research Report 2004 Annual Research Report
  • [Journal Article] Researches and future perspectives on gene therapy for biliary cancers using tumor-selectively replicating adenoviruses.2004

    • Author(s)
      Masato Abei, et al.
    • Journal Title

      Igaku to yakuri 52(6)

      Pages: 885-893

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Researches and future perspectives on gene therapy for biliary cancers using tumor-selectively replicating adenoviruses2004

    • Author(s)
      Masato Abei, et al.
    • Journal Title

      Igaku to yakuri 52(6)

      Pages: 885-893

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] 腫瘍選択的増殖型アデノウイルスを用いた胆道癌の遺伝子治療の研究とその展望2004

    • Author(s)
      安部井誠人, 他
    • Journal Title

      医学と薬学 52

      Pages: 885-893

    • Related Report
      2004 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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