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ENHANCEMENT OF BYSTANDER EFFECTS WITH THE COMBINATION OF IMMUNO-GENE THERAPY AND PRO-DRUG GENE THERAPY

Research Project

Project/Area Number 13671653
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

KUMON Hiromi  Okayama University, Graduate School of Medicine and Dentistry, Professor, 大学院・医歯学総合研究科, 教授 (30144760)

Co-Investigator(Kenkyū-buntansha) NASU Yasutomo  Okayama University Hospital, Associate Professor, 医学部附属病院, 講師 (20237572)
TSUSHIMA Tomoyasu  Okayama University, Graduate School of Medicine and Dentistry, Associate Professor, 大学院・医歯学総合研究科, 助教授 (20135990)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2001: ¥2,000,000 (Direct Cost: ¥2,000,000)
Keywordsgene therapy / pro-drug gene therapy / Bladder cancer / prostate cancer / 5-fluorouracil / Uracil phosphoribosy 1 transferas / adenovirus vector / Uracil phosphoribosy1 transferase
Research Abstract

In this research, enhancement of bystander effects with the combination of immuno-gene therapy and pro-drug gene therapy was analyzed. As a main portion of this project, effects of UPRT (uracil phosphoribosyltransferase) gene therapy (new type of pro-drug gene therapy) for bladder cancer was analyzed. Here we show the summary of them.
Objective : We evaluated whether adenovirus-mediated UPRT genes could generate sensitized antitumor effect of 5-FU on experimental bladder cancer.
Material and Method : Human bladder cancer cell T24 was used for in vitro and in vivo study. Two recombinant replication-deficient adeno virus vectors, AdCA-LacZ and AdCA-UPRT, were constructed from a serotype 5 wild-type adenovirus (Ad5) by inserting CAG promoter with an E. coli LacZ gene and an E. coli UPRT gene, respectively, into the EIA region of the genome, deleting the E1B and E3 region. For in vitro chemosensitivity assay, T24 cells were seeded in 96-well plates at a density of 1000 cells/well, infected w … More ith AdCA-LacZ or AdCA-UPRT (MOI :0-100), and then exposed to 5-FU. Six days later, the sensitivity was assessed with MTT assay. For in vivo tumor treatment, subcutaneous tumors were employed by injection of T24 cells (10^7 cells). Twelve days after tumor cell injection (day 12) when tumor becomes palpable with mean estimated weight 147mg (108 -199mg), mouse were randomized to be directly injected with AdCA-LacZ or AdC A-UPRT (1X10^8 pfu/10ul) subsequently (two days later : day14) with either saline or 5-FU(2Omg/kg) intraperitoneally for 10days (from day14 to 23).
Results : AdCA-UPRT infection increased the sensitivity of T24 cells to 5-FU in a MOI-dependent manner. IC50 to 5-FU shifted from 5,М in, control cells to 0.05М in AdCA-UPRT-infected cells at MOI of 50 indicating 100 fold sensitization by AdCA-UPRT infection. Consistent with in vitro studies, administration of AdCA-UPRT into the tumor of T24 cells, together with systemic 5-FU administration, resulted in sup pression of tumor growth at day28, compared with the control tumor groups : Among control groups, difference was not observed in comparis on with the presence or absence of 5-FU administration
Conclusion : These results suggest that UPRT gene therapy with 5-FU can sensitize the antitumor effect of 5-FU. Consequently, this approach is a new chemosensitizing strategy for cancer gene therapy and a more feasible modality for the treatment of bladder cancer. Less

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (27 results)

All Other

All Publications (27 results)

  • [Publications] Nasu Y: "Combination gene therapy with adenoviral vector-mediated HSV-tk+GCV and IL-12 in an orthotopic mouse model for prostate cancer."Prostate Cancer and Prostatic Diseases. 4. 44-55 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] T.Kurashige: "NY-ESO-1 expression and immunogenicity associated with transitional cell carcinoma : Correlation with tumor gradel"Cancer Research. 61. 4671-4674 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] T.Ono: "Identification of proacrosin binding proteinsp32 precursor as a human cancer/testis antigen."Proc.Natl.Acad.Sci.USA. 98. 3282-3287 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kraaji R.: "Validation of transrectal ultrasonographic volumetry for orthotopic prostate tumours in mice"Lab Anim. 36(2). 165-172 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ebara S: "Gene therapy for prostate cancer : toxicological profile of four HSV-tk transducing adenoviral vectors regulated by different promoters"Prostate Cancer Prostatic Dis. 5(4). 316-325 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 那須保友: "前立腺癌遺伝子治療の現状と展望"岡山医学会雑誌. 114. 173-177 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 那須保友: "前立腺癌の遺伝子治療-臨床研究における最近の動向"医学のあゆみ. 203(5). 323-327 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 那須保友: "前立腺癌の遺伝子診断と遺伝子治療"日本臨床. 60(Suppl 1). 28-32 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Y, Nasu: "Combination, gene therapy with adenoviral vector-mediated HSV-tk+GCV and IL-12 in an orthotopic mouse model for prostate cancer."Prostate Cancer and Prostatic Diseases. 4. 44-55 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] T.Kurashige: "NY-ESO-1 expression and immunogenicity, associated with transitional cell carcinoma : Correlation with tumor grade 1"Cancer Research. 61. 4671-4674 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] T.Ono: "Identification. of proacrosin binding proteinsp32 precursor as a human cancer/testis antigen."Proc.Natl.Acad.Sci.USA. 98. 3282-3287 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kraaji R: "Validation of transrectal ultrasonographic volumetry for orthotopic prostate tumours in mice"Lab Anim. 36(2). 165-172 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] S, Ebara: "Gene therapy for prostate cancer : toxicological profile of four HSV-tk transducing adenoviral vectors regulated by different promoters."Prostate Cancer Prostatic Diseases. 5(4). 316-325 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Y, Nasu: "Current status and future prospect of prostate cancer gene therapy"Acta Medica Okayama. 114. 173-177 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Y, Nasu: "Current status and future prospect of prostate cancer gene therapy"Igaku no Ayumi. 203(5). 323-327 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Y, Nasu: "Molecular Diaganosis and Gene Therapy for Prostate Cancer"Nippon Rinsho. 60(supp1). 28-32 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kraaji R.: "Validation of transrectal ultrasonographic volumetry for orthotopic prostate tumours in mice"Lab Anim. 36(2). 165-172 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ebara S: "Gene therapy for prostate cancer : toxicological profile of four HSV-tk transducing adenoviral vectors regulated by different promoters"Prostate Cancer Prostatic Dis. 5(4). 316-325 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 那須保友, 公文裕巳: "前立腺癌遺伝子治療の現状と展望"岡山医学会雑誌. 114. 173-177 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 那須保友: "前立腺癌の遺伝子治療-臨床研究における最近の動向"医学のあゆみ. 203(5). 323-327 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 那須保友: "前立腺癌の遺伝子診断と遺伝子治療"日本臨床. 60(Suppl). 28-32 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kumon H: "Gene Therapy in the 21 century"Molecular Urology. 5(2). 45-46 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ono T: "Identification of proacrosin binding protein sp32 precursor as a human cancer/testis antigen"Proc.Natl.Acad.Sci USA. 98(6). 3282-3287 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nasu Y: "Combination gene therapy with adenoviral vector-mediated HSV-tk+GCV and IL-12 in an orthotopic mouse model for prostate cancer"Prostate Cancer and Prostatic Diseases. 4. 44-55 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Likun Li: "Caveolin-1 mediates testosterone-stimulated survival/clonal growth and promotes metastatic activities in prostate cancer cells"Cancer Research. 61. 4386-4392 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tsushima T: "Optimal starting time for flutamide to prevent disease flare in prostate cancer patients treated with a gonadotropin-releasing hormone agonist"Urologia Internationalis. 66. 135-139 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ebara S: "Therapeutic Potential Of AdenovirusMediated Interleukin-12 Gene Therapy For Prostate Cancer.In : Growth Factors And Their Receptors In Cancer Metastasis"Jiang WG, Matsumoto K, Nakamura T. 303 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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