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腫瘍選択的増幅型ハイブリッドウイルスベクターの開発とその制御機構の解明

Research Project

Project/Area Number 13218116
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionJichi Medical University

Principal Investigator

岡田 尚已 (岡田 尚巳)  自治医科大学, 医学部, 講師 (00326828)

Project Period (FY) 2001 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥24,200,000 (Direct Cost: ¥24,200,000)
Fiscal Year 2004: ¥6,000,000 (Direct Cost: ¥6,000,000)
Fiscal Year 2003: ¥6,100,000 (Direct Cost: ¥6,100,000)
Fiscal Year 2002: ¥6,000,000 (Direct Cost: ¥6,000,000)
Fiscal Year 2001: ¥6,100,000 (Direct Cost: ¥6,100,000)
Keywordsがん / 自殺遺伝子治療 / ウイルスベクター / ハイブリッドベクター / アデノウイルス / レトロウイルス / アデノ随伴ウイルス / 遺伝子治療 / 遺伝子発現制御 / ハイブリッドウイルスベクター / Cre-loxP / 幹細胞
Research Abstract

癌の遺伝子治療において様々なベクター系が用いられているが、より高い臨床的効果を期待するために、さらなる改良が求められている。腫瘍内で治療遺伝子を増幅させ遺伝子発現増強とベクターの拡散を促すシステムの実用化をめざし、ハイブリッドベクターの開発とアデノウイルス初期遺伝子群の機能解析を行うことを目的とした。
本年度は、引き続きアデノウイルス初期遺伝子群E1、E2、E4、およびVAの機能を応用し、細胞内で治療ベクターの複製を誘導するシステムを推進した。アデノウイルス初期遺伝子群発現ベクターが生体内でサイレンシングを受けにくくするために、MSCV-LTRの抑制性転写因子結合領域欠失レトロウイルスベクターを応用した。HSV-放発現治療ベクターAAVTk、E1B55k欠失E1遺伝子発現ベクターAAVE1、E1B55k遺伝子発現ベクターAAVE1B55、E2遺伝子発現レトロウイルスベクターDNE2、E4-VA遺伝子発現レトロウイルスベクターDNE4VA、およびRep/Cap発現レトロウイルスベクターDNRepCapの混合感染を腫瘍細胞の系で行った。治療遺伝子として搭載されたHSV-tk遺伝子のコピー数を測定し、ベクターの複製効率と感染条件を検討した。さらに、腫瘍細胞における遺伝子発現を向上させてベクターの複製効率を増強させるため、ベクター感染時にHDAC阻害剤を併用し、遺伝子発現増強効果やその作用機構を解析した。

Report

(4 results)
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (27 results)

All 2005 2004 2003 2002 Other

All Journal Article (6 results) Book (1 results) Patent(Industrial Property Rights) (2 results) Publications (18 results)

  • [Journal Article] Regulation of Osteoclast Apoptosis by Ubiquitination of Proapoptotic BH3-only Bcl-2 Family Member Bim.2005

    • Author(s)
      Akiyama, T., et al.
    • Journal Title

      EMBO J. 22・24

      Pages: 6653-6664

    • Related Report
      2004 Annual Research Report
  • [Journal Article] In situ generation of pseudotyped retroviral progeny by adenovirus-mediated transduction of tumor cells enhances the killing effect of HSV-tk suicide gene therapy in vitro and in vivo.2004

    • Author(s)
      Okada T., et al.
    • Journal Title

      J.Gene Med. 6・3

      Pages: 288-299

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The Adenovirus E1A and E1B19K genes provide a helper function for transfection-based AAV vector production.2004

    • Author(s)
      Matsushita, T., et al.
    • Journal Title

      J.Gen.Virol. 85・Pt8

      Pages: 2209-2214

    • Related Report
      2004 Annual Research Report
  • [Journal Article] A soluble CAR-SCF fusion protein improves adenoviral vector-mediated gene transfer to c-Kit-positive hematopoietic cells.2003

    • Author(s)
      Itoh, A., et al.
    • Journal Title

      J.Gene Med. 5・11

      Pages: 929-940

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Interleukin-10-mediated inhibition of angiogenesis and tumor growth in mice bearing VEGF-producing ovarian cancer2003

    • Author(s)
      Kohno, T., et al.
    • Journal Title

      Cancer Res. 63・16

      Pages: 5091-5094

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Enhancement of thymidine kinase-mediated killing of malignant glioma by BimS, a BH3-only cell death activator2003

    • Author(s)
      Yamaguchi, T., et al.
    • Journal Title

      Gene Ther. 10・5

      Pages: 375-385

    • Related Report
      2004 Annual Research Report
  • [Book] Adeno-associated viral vector-mediated gene therapy of ischemia-induced neuronal death (ed.by M.Ian Phillips)2002

    • Author(s)
      Okada, T., et al.
    • Publisher
      Academic Press
    • Related Report
      2004 Annual Research Report
  • [Patent(Industrial Property Rights)] 遺伝子導入効率増強剤2003

    • Inventor(s)
      岡田 尚巳, 小澤 敬也
    • Industrial Property Rights Holder
      藤沢薬品
    • Industrial Property Number
      2003-122968
    • Filing Date
      2003-04-25
    • Related Report
      2004 Annual Research Report
  • [Patent(Industrial Property Rights)] アデノウイルス吸着架橋剤2002

    • Inventor(s)
      伊藤 章, 花園 裕, 岡田 尚巳, 小沢 敬也
    • Industrial Property Rights Holder
      旭化成
    • Industrial Property Number
      2002-299062
    • Filing Date
      2002-10-11
    • Acquisition Date
      2003-07-09
    • Related Report
      2004 Annual Research Report
  • [Publications] Okada T, et al.: "In situ generation of pseudotyped retroviral progeny by adenovirus-mediated transduction of tumer cells enhances the killing effect of HSV-tk suicide gene therapy in vitro and in vivo"J.Gene Med.. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Akiyama T, et al.: "Regulation of Osteoclast Apoptosis by Ubiquitination of Proapoptotic BH3-only Bcl-2Family Member Bim."EMBO J.. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Yamaguchi, et al.: "Enhancement of thymidine kinase-mediated killing of malignant glioma by BimS, a BH3-only cell death activator"Gene Ther.. 10・5. 375-385 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kohno T, et al.: "Interleukin-10-mediated inhibition of angiogenesis and tumor growth in mice bearing VEGR-producing ovarian cancer"Cancer Res.. 63・16. 5091-5094 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kanazawa T, et al.: "Suicide gene therapy using AAV-HSVtk/ganciclovir in combination with irradiation results in regression of human head and neck cancer xenografts in nude mice"Gene Ther.. 10・1. 51-58 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kametaka M, et al.: "Reduction of CTLL-2 cytotoxicity by induction of apoptosis with a Fas-estrogen receptor chimera"Cancer Sci.. 94・7. 639-643 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Okada, T. et al.: "Adeno-associated viral vector-mediated gene therapy of ischemia-induced neuronal death"Methods Ehzymol.. 346. 378-393 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Okada, T. et al.: "Adeno-associated virus vectors for gene transfer to the brain"Methods. 28・2. 237-247 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Wang, L.J.et al.: "Neuroprotective effects of glial cell line-derived neurotrophic factor mediated by an adeno-associated virus vector in a transgenic animal model of amyotrophic lateral sclerosis"J.Neurosci.. 22・16. 6920-6928 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kanazawa, T. et al.: "Suicide gene therapy using AAV-HSVtk/ganciclovir in combination with irradiation results in regression of human head and neck cancer xenografts in nude mice"Gene Ther.. 10・1. 51-58 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamaguchi, T. et al.: "Enhancement of thymidine kinase-mediated killing of malignant glioma by BimS, a BH3-only cell death activator"Gene Ther.. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nomoto, T. et al.: "Distinct patterns of gene transfer to gerbil hippocampus with recombinant adeno-associated virus type 2 and 5"Neurosci.Lett.. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Okada, T., et.al.: "AAV mediated gene transfer for gene therapy of ischemia-induced neuronal death"Method.Enzymol.. 346. 378-393 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Okada, T., et.al.: "Development and characterization of an antisense-mediated regulation system for adeno-associated virus vector production with introduction of Cre recombinase"Biochem.Biophys.Res.Comm.. 288. 62-68 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Okada, T., et.al.: "AV.TK-mediated killing of subcutaneous tumors in situ results in effective immunization against established secondary intracranial tumor deposits"Gene Ther.. 8. 1315-1322 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Muramatsu, M., et.al.: "Reversible Integration of the Dominant Negative Retinoid Receptor Gene for ex Vivo Expansion of Hematopoietic Stem/Progenitor Cells"Biochem.Biophys.Res.Comm.. 285. 891-896 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kanazawa, T., et.al.: "Gamma-rays enhance rAAV-mediated transgene expression and cytocidal effect of AAV-HSVtk/ganciclovir on cancer cells"Cancer Gene Ther.. 8. 99-106 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Wang L., et.al.: "Delivery of AAV-GDNF prevents nigral neurodegeneration and promotes functional recovery in a rat model of Parkinson's disease"Gene Ther.. (in press).

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2018-03-28  

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