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Targeting gene therapy for prostate cancer using prostate specific antigen (PSA)

Research Project

Project/Area Number 09470352
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section一般
Research Field Urology
Research InstitutionKeio University

Principal Investigator

MURAI Masaru  Keio University School of Medicine Professor, 医学部, 教授 (90101956)

Co-Investigator(Kenkyū-buntansha) NAKASHIMA Jun  Keio University School of Medicine, Assistant Professor, 医学部, 専任講師 (10167546)
ASAKURA Hirotaka  Keio University School of Medicine, Assistant Professor, 医学部, 専任講師 (50175840)
OYAMA Masafumi  Keio University School of Medicine, Instructor, 医学部, 助手 (70276351)
OHIGASHI Takashi  Keio University School of Medicine, Assistant Professor, 医学部, 専任講師 (80185371)
橘 政昭  慶應義塾大学, 医学部, 助教授 (70129526)
西山 徹  慶應義塾大学, 医学部, 助手 (60255536)
中村 薫  慶應義塾大学, 医学部, 講師 (10146673)
馬場 志郎  慶應義塾大学, 医学部, 助教授 (00051889)
Project Period (FY) 1997 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥11,700,000 (Direct Cost: ¥11,700,000)
Fiscal Year 2000: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1999: ¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1998: ¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1997: ¥6,800,000 (Direct Cost: ¥6,800,000)
Keywordsprostate cancer / PSA / gere therapy / プロモーター / 5-fluorocytosine / Cytosine deminase
Research Abstract

As a new treatment of prostate cancer, we are investigating a gene therapy model that utilizes a suicide gene cytosine deaminase (CD) that metabolizes non-toxic 5-fluorocytosine (5-FC) into toxic 5-fluorouracil (5-FU) in a LNCaP human prostate cancer model. The vector pC/CD was used to transfect LNCaP cells. 5 -FC showed a significantly lower ID50 value against the clones LN/CD than the control cells transfected with an empty vector, which was sensitive to 5-FU.Tumors made with LN/CD inoculation in nude mice were shown to regress after i.p.administration of 5-FC.The expression of the CD gene was effective in therapy of the LNCaP prostate cancer model both in vitro and in vivo. We used regulatory elements from the PSMA gene to develop a construct that could be used to control expression of a CD gene in a gene therapy approach against this disease. We recently cloned the promoter of the PSMA gene, which can drive prostate-specific expression of a luciferase reporter gene.
NF κ B inhibitors, pyrrolidine dithiocarbamate (PDTC) and NF κ B decoy, continuously inhibited TNF-α-induced NF κ B activation. Prostate cancer cells treated with TNF-α (20 ng/ml) plus NF κ B inhibitors showed significant growth inhibition. The combination of TNF-α and NF κ B inhibitors was suggested to be an effective therapy for prostate cancer.
We evaluate the antitumoral effect of a conditionally-replicating herpes simplex virus 1 (HSV-1) vector, G207, against prostate cancer in vitro and in vivo. DU145 and PC3 were efficiently destroyed by G207 within 7 days. The viral yields of G207 increased time-dependently. In vivo, the intraneoplastic inoculation of G207 induced a significant inhibition of the tumor growth. In a pathological study, a large number of lacZ positive cells were diffusely present in the G207-treated tumors. G207 thus may be considered a useful agent for the treatment of prostate cancer.

Report

(5 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (23 results)

All Other

All Publications (23 results)

  • [Publications] Sumitomo M,Murai M, et al.: "An essential role for nucler factor kappa B in preventing TNF-α-induced cell death in prostate cancer cells."J.Urol.. 161(2). 674-679 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Saimoto A,Murai M, et al.: "Prostate-specific membrane antigen-derived primers in a nested reverse transcription polymerase chain reaction for detecting prostatic cancer cells.,"Jpn.J.Cancer Res.. 90. 233-239 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sumitomo M,Murai M, et al: "Over expression of IL-1rageneup-regulatesinterleukin-1β concerting enzyme (ICE) gene expression : possible mechanism underlying IL-1β-resistance of cancer cells."Br.J.Cancer. 81(2). 277-286 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Oyama M,Murai M, et al: "Apprication of condetionally replicating herpes vector for gene therapy treatment of urologic neoplasms."Molecular Urology. 4(2). 83-87 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nakashima J,Murai M, et al: "Serm interleukin 6 as a prognostic factor in patients with prostatic cancer."Clin.Cancer Res.. 6. 2702-2706 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Oyama M,Murai M, et al: "T.: Oncolytic viraltherapy for human prostate cancer by conditionally replicating herpes simplex virus 1 vector G207.."Jpn.J.Cancer Res.. 91. 1339-1344 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sumitomo M, Murai M, et al.: "An essential role for nucler factor kappa B in preventing TNF-α-induced cell death in prostate cancer cells"J.Urol.. 161(2). 674-679 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] SAIMOTO A , Murai M, et al.: "Prostate-specific membrance antigen-derived primers in a nested reverse transcription polymerase chain reaction for detecting prostatic cancer cells."Jpn.J.Cancer Res. 90. 233-239 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sumitomo M, Murai M, et al.: "Overexpression of IL-lra gene up-regulates interletukin-1β converting enzyme (ICE) gene expression : possible mechanism underlying IL-1 β-resistance of cancer cells."Br.J.Cancer. 81(2). 277-286 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] OYAMA M, Murai M, et al.: "Apprication of condetionally replicating herpes vector for gene therapy treatment of urologic neoplasms."Molecular Urology. 4(2). 83-87 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] NAKASHIMAJ., Murai M,et al.: "Serm interleukin 6 as a prognostic factor in patients with prostatic cancer."Clin.Cancer Res. 6. 2702-2706 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] OYAMA M, Mural M, et al.: "Oncolytic viral therapy for human prostate cancer by conditionally replicating herpes simplex virus l vector G207.Jpn"Jpn.J.Cancer Res.. 91. 1339-1344 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Oyama,M.,Murai,M., et al.: "Intra-vesical and intravenous therapy of human bladder cancer by the herpes vector G207."Human Gene Therapy. 11. 1683-1893 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Oyama,M.,Murai,M., et al.: "Oncolytic viral therapy for human prostate cancer by conditionally replicating herpes simplex virus vector G207."Japanese Journal of Cancer Research. 91. 1339-1344 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nakashima,J.,Murai,M., et al.: "Serum interleukin 6 as a prognostic factor in patients with prostate cancer."Clinical Cancer Research. 6. 2702-2706 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nakashima,J.,Murai,M., et al.: "Prognosis value of alkaline phosphatase flare in patients with metastatic prostate cancer treated with endocrine therapy."Urology. 56. 843-847 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Oyama,M.,Murai,M., et al.: "Application of conditionally replicating herpes vector for gene therapy treatment of urologic neoplasms."Molecular Urology. 4. 83-87 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sumitomo M.,Tachibana M.et al.: "An essential role for nucler factor kappa B in preventing TNF-α-induced cell death in prostate cancer cells"The Journal of Urology. 161(2). 674-679 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Saimoto A.,Murai M.,et al.: "Prostate-specific membrance antigen-derived primers in a nested reverse transcription polymerase chain reaction for detecting prostagic cancer cells"Jpn.J.Cancer Res.. 90. 233-239 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Sumitomo M.,Murai M.,et al.: "Overexpression of IL-1ra gene up-regulates interleukin-1 βconverting enzyme(ICE)gene expression:possible mechanism underlying IL-1 β-resistance of cancer cells"British Journal of Cancer. 81(2). 277-286 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nakashima j.,Murai M.,et al.: "Association between tumor necrosis factor in serm and cachexia in patients with prostate cancer." Clinical Cancer Research. 4. 1743-1748 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ohigashi T.,Ueno M.,et al.: "Suppression of default apoptosis in androgen-dependent cells by testosterone-mediated bcl-2 expression." International Journal of Urology. 6. 147-153 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Shiro Saito, Masaru Murai, et al.: "Therapy of bladder cancer with genes for interleukin-2 and granulocyte-macrophage colonystimulating factor:Experimental study." Molecular Urol.1・4. 273-277 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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