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SUICIDEAND IMMUNE GENE THERAPY USING TUMOR SPECIFIC PROMOTOR FOR BREAST CANCER

Research Project

Project/Area Number 12671190
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General surgery
Research InstitutionCHIBA UNIVERSITY (2001)
Chiba Cancer Center (Research Institute) (2000)

Principal Investigator

MATSUBARA Hisahiro (2001)  Chiba University, University Hospital, Assistant, 医学部・附属病院, 助手 (20282486)

宮内 基博 (2000)  千葉県がんセンター, 研究局・病理研究部, 主任研究員 (70260247)

Co-Investigator(Kenkyū-buntansha) AGAWA Masatoshi  Chiba Cancer Center, Research Institute, Head, 病理研究部, 部長 (20171572)
松原 久裕  千葉大学, 医学部・医学部付属病院, 助手 (20282486)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2001: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2000: ¥2,300,000 (Direct Cost: ¥2,300,000)
KeywordsRREAST CANCER / SUICIDE GENE THERAPY / TUMOR SPECIFIC PROMOTER / midkine / c-erbB-2 / HSV-tk / 腫瘍特異的プロモーター / c-erB2 / 遺伝子治療 / サイトカイン遺伝子 / 自殺遺伝子
Research Abstract

A selective expression of suicide or immune gene(s) in tumor cells should produce a preferential cytotoxic effect on tumors and a useful strategy for cancer treatment. The c-erbB-2 and midkine gene are frequently overexpressed in human breast cancers as a result of gene amplification and/or elevated transcription. We therefore examined a possible usage of promoter regions of the c-erbB-2 and midkine gene to express a suicide gene preferentially in breast cancer cells. The present reporter gene assays using deletion mutants of the c-erbB-2 promoter region demonstrated that the 251-bp (-213/+38 from the transcriplional start site) but not the 125-hp fragment (-87/+38) could direct transcription of the linked luciferase gene better than the SV40 immediate early promoter in breast cancer cells. Also the 1.0 kb promoter region of the midkine gene could activate transcription of a fused reporter gene and suicide gene in human breast cancer cells. In contrast, the 251-bp fragment-mediated pro … More moter activity in nonbreast cancer cells and in normal fibroblasts was lower than the activity by the SV40 promoter. The 126-bp fragment (-213/-87) thereby contains a exacting element(s) which is responsible for the preferential transcriptional activity in breast cancer cells. An electrophoretic mobility shift assay suggested that a possible modification of a transcriptional factor was involved in the tumor specificity. Transaction with the plasmid DNA containing the herpes simplex virus-thymidine kinase gene linked with the 251-bp promoter (p256-TK) resulted in increased sensitivity to ganciclovir (GCV) in breast cancer but not in nonbreast cancer cells. Administration of GCV into nude mice bearing human breast tumors that were transfecled with the p256-TK DNA suppressed subsequent growth of the transplanted tumors. These results suggest that delivery of a suicide gene linked with the these 1.0 kb midkine or 251 bp c-erbB-2 promoter can be a feasible therapeutic strategy specific to breast cancer. Less

Report

(3 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • Research Products

    (15 results)

All Other

All Publications (15 results)

  • [Publications] Maeda T, et al.: "A minimum c-erbB-2 promoter-mediated expression of herpes simplex virus thymidine kinase gene confers selective cytotoxicity of human breast cancer cells to ganciclovir"Cancer Gene Therapy. 8・11. 890-896 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Matsubara H, et al.: "A minimal promoter region of the c-erbB2 gene that can drive the expression of suicide gene preferentially in cancer cells"Cancer Gene Therapy. 8・Supp.2. S17 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yu L, et al.: "Identification of a minimal c-erbB-2 promoter region that mediates preferential expression of a linked foreign gene in humnan breast cancer cells"International Journal of Oncology. 20・3. 607-610 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Maeda T, el al.: "A minimum c-erbB-2 promoter-mediated expression of herpes simplex virus thymidine kinase gene confers selective cytotoxicity of human breast cancer cells to ganciclovir."Cancer Gene Therapy. 8-11. 890-896 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Matsubara H. et al.: "A minimal promoter region of the c-erbB-2 gene that can drive the expression of suicide gene preferentially in cancer cells."Cancer Gene Therapy. 8-Suppl. 2.. S17 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yu L, et al: "Idenlificalion of a minimal c-erbB-2 promoter region that mediates preferential expression of a linked foreign gene in human breast cancer cells"International Journal of Oncology. 20-3. 607-610 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Maeda T, et al.: "A minimum c-erbB-2 promoter-mediated expression of herpes simplex virus thymidine kinase gene confers selective cytotoxicity of human breast cancer cells to ganciclovir"Cancer Gene Therapy. 8・11. 890-896 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Matsubara H, et al.: "A minimal promoter region of the c-erbB2 gene that can drive the expression of suicide gene preferentially in cancer cells"Cancer Gene Therapy. 8・Supp.2. S17 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yu L, et al.: "Identification of a minimal c-erbB-2 promoter region that mediates preferential expression of a linked foreign gene in human breast cancer cells"International Journal of Oncology. 20・3. 607-610 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Matsubara,H.,Tagawa,M. et al: "Radiosensitivity of human breast cancer cells transduced with wild-type p53 gene is influenced by p53 status of parental cells."Anticancer Res. 20. 869-874 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Miyauchi,M.,Tagawa,M. et al: "Transduction of the human deoxycytidine kinase gene in rodent tumor cells induces in vivo growth retardation in syngeneic hosts."Cancer Lett. 156. 151-157 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kawamura,K.,Tagawa,M. et al: "Bystander effect in uracil phosphoribosyltransferase/5-fluorouracil-mediated suicide gene therapy is correlated with the level of intercellular communication"Int J Oncol. 18. 117-120 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kawamura,K.,Tagawa,M. et al: "Expression of Escherichia coli uracil phosphoribosyltransferase gene in murine colon carcinoma cells augments the antitumoral effect of 5-fluorouracil and induces protective immunity."Cancer Gene Ther. 7. 637-643 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Miyauchi,M.,Tagawa,M. et al: "Expression of herpes simplex virus-thymidine kinase gene controlled by a promoter region of the midkine gene confers selective cytotoxicity to ganciclovir in human carcinoma cells."Int J Cancer. 91. 723-727 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Matsubara,H.,Tagawa,M. et al: "Combinatory anti-tumor effects of electroporation-mediated chemotherapy and wild-type p53 gene transfer to human esophageal cancer cells."Int J Oncol. (in press). (2001)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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