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Anti-angiogenesis gene therapy utilizing viral vectors

Research Project

Project/Area Number 10671325
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Cerebral neurosurgery
Research InstitutionJikei University School of Medicine

Principal Investigator

TANAKA Toshihide  Department of Neurosurgery, Jikei University School of Medicine, Clinical fellow, 医学部, 助手 (90301530)

Co-Investigator(Kenkyū-buntansha) AKASAKI Yasuharu  Department of Neurosurgery, Jikei University School of Medicine, Clinical fellow, 脳神経外科, 助手 (00256322)
MANOME Yoshinobu  Department of Microbiology 1, Jikei University School of Medicine, Assistant Professor, 第一細菌学, 講師 (30219539)
Project Period (FY) 1998 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2001: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2000: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1999: ¥500,000 (Direct Cost: ¥500,000)
KeywordsAngiogenesis / Gene Therapy / Viral Vectors / Tumor Dormancy / angiostatin / endostatin / endothelial cells / apoptosis / ascites tumor / glioma / endostain
Research Abstract

The aim of this study is to verify whether viral vector mediated transduction of angiogenesis inhibitor genes containing signal peptide is effective for therapeutics of brain tumor and ascites tumor models.
VEGF (vascular endothelial growth factor) plays a major role as stimulator as well as vascular permeability, which result in peritumoral edema, ascites and pleural effusion. First of all, the transduction efficiency to tumor cells and endothelial cells by adenoviral vector expressing β galactosidase was examined. Endothelial cells as well as tumor cells tunied out to be attractive target for gene transduction. Then adenoviral vectors encoding angiogenesis inhibitor such as platelet factor 4 (PF4), angiostatin and endostatin fused to signal peptide was assessed. Vectors mediated therapy against brain and ascites tumor models led to prolonged survival and inhibition of angiogenesis and tumor growth. Secretable form of PF4 (sPF4) was the most effective inhibitor of tumor growth among the all of the angiogenesis inhibitors.
In addition, interestingly, gene therapy by sPF4 not only inhibited ascites formation, but also turned bloody tumor associated ascites into yellow and serous fluid. Immunohi stochemical analyzes showed the decreased microvascular density and induction of apoptosis by transduction of angiogenesis inhibitor genes, however, they did not have any effects on growth potency of tumor cells.
These results suggest that viral vector mediated anti angiogenesis gene therapy achieved to maintain tumor dormancy. These studies were published in Nature Medicine, Cancer Research, Neurologia Medico-Chirurgica, and Human Gene Therapy.
In the future, we will continue to develop further system utilizing other angiogenesis inhibitors such as soluble form of VEGF and Tie-2 receptor to examine whether they have more potent inhibitory effect on tumor growth.

Report

(5 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (30 results)

All Other

All Publications (30 results)

  • [Publications] Hampl M, Tanaka T, Fine HA.: "Treatment of malignant ascites with adenoviral vectors expressing antiangiogcnie genes"Molecular Therapy. 1(5). S155 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hampl M, Tanaka T, Fine HA.: "Adenoviral mediated antiangiogenic gene therapy of malignant ascites in breast and ovarian cancer"Journal of Society Gynecological Investion. 196A (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hanpl M, Tanaka T, Fine HA.: "Therapeutic effects of viral vector-mediated antiangiogenic gene transfer in malignant ascites"Human Gene Therapy. 12. 1713-1729 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanaka T, Cao Y, Fine HA.: "Viral vector-targeted "Anti-Angiogenic" gene therapy utilizing an angiostatin complementary DNA"Cancer Research. 58. 3362-3369 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanaka T: "Effect of adenoviral-mediated thymidine kinase transudation and ganciclovir therapy on tumor associated endothelial cells"Neurologica Medico-Chirurgica. 37. 730-738 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanaka T, Manome Y, Fine HA.: "Viral vector-mediated transudation of a modified platelet factor 4 cDNA inhibites angiogenesis and tumor growth"Nature Medicine. 3. 437-442 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanaka T, Cao Y, Folkman J, Fine HA.: "Viral vector-targeted "Anti-Angiogenic" gene therapy utilizing an angiostatin complementary DNA."Cancer Res,. 58. 3362-3369 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanaka T.: "Angiogenesis inhibitor and anti-angiogenesis therapy・"Experimental Medicine-Molecular Medicine for Vascular Biology (in Japanese). 16 (5). 645-650 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanaka T.: "Anti-angiogenesis tharapy."Modern Medicine(in Japanese). 30 (7). 2032-2040 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanaka T.: "Angiogenesis targeted gene therapy."Molccular Medicine(in Japanese). 35 (10). 1270-1279 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanaka T.: "Vascular targeted anti-cancer therapy."The Tissue Culture Engineering(in Japanese). 25 (5). 186-191 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanaka T.: "Clinical application on anti-angiogenesis therapy."Journal of clinical and Experimental Medicine(in Japanese). 191 (5). 619-625 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanaka T.: "Antiangiogenesis therapy-A development of gene therapy."In : Yasufumi Sato, editor. Current Topics for Angiogenesis Research : Mechanism, Pathogenesis, and Therapy.(in Japanese) Tokyo : Yoko-sha. 148-161 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanaka T.: "Antiangiogenic gene therapy. In : Seiitsu Murota and Yasufumi Sato, editor."Development of Angiogenesis Research.(in Japanese)Tokyo : Iyaku Journal-sha. 330-340 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanaka T.: "Clinical application on angiogenesis research."Jan J Thron Hemost(in Japanese). 11 (2). 131-138 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hampl M, Tanaka T, Fine HA.: "Treatment of malignant ascites with adenoviral vectors expressing antiangiogenic genes."Molecular Therapy.. 1 (5). S155 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hampl M, Tanaka T, Fine HA.: "Adenoviral mediated antiangiogenic gene therapy of malingnant ascites in breast and ovarian cancer."J. Soc. GynecolInvest. 8 (1) (suppl). 196A (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hampl M, Tanaka T, Fine HA et al.: "Therapeutic effects of viral vector-mediated antiangiongenic gene transfer in malingnant ascites."Hum Gene Thr. 12. 1713-1729 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hampl M, Tanaka T, Fine HA.: "Treatment of malignant ascites with adenoviral vectors expressing antiangiogenic genes"Molecular Therapy. 1(5). S155 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hampl M, Tanaka T, Fine HA.: "Adenoviral mediated antiangiogenic gene therapy of malignant ascites in breast and ovarian cancer"Journal of Society Gynecological Investion. 196A (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hampl M, Tanaka T, Fine HA.: "Therapeutic effects of viral vector-mediated antiangiogenic gene transfer in malignant ascites"Human Gene Therapy. 12. 1713-1729 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 田中俊英: "血管新生研究の新展開"医薬ジャーナル社. 11 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 田中 俊英: "血管をターゲットにした腫瘍治療"組織培養工学. 25(5). 186-191 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 田中 俊英: "血管新生とその臨床応用"医学のあゆみ. 191(5). 619-625 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 田中 俊英: "血管新生の最前線-そのメカニズムと病態/治療"佐藤靖史編. 14 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] T.Tanaka: "Effect of adenoviral-mediated thymidine kinase transduction and ganciclovir therapy on tumor associated endothelial cells." Neurologia Medico-Chirurgica. 37. 730-738 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] T.Tanaka: "Viral vector-mediated transduction of a modified platelet factor 4 cDNA inhibits angiogenesis and tumor growth." Nature Medicine. 3. 437-442 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] T.Tanaka: "Viral vector-targeted“Anti-Angiogenic" gene therapy utilizing an angiostatin complementary DNA." Cancer Research. 58. 3362-3369 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 田中俊英: "抗血管新生療法" 現代医療. 30(7). 2032-2040 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 田中俊英: "血管新生の遺伝子治療" Molecular Medicne. 35(10). 1270-1279 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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