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Study on selective cancer chemotherapy targeting the deficiency of a purine metabolic enzyme

Research Project

Project/Area Number 11557205
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Laboratory medicine
Research InstitutionMie University

Principal Investigator

NOBORI Tsutomu  Mie University, Faculty of Medicine, Professor, 医学部, 教授 (60106995)

Co-Investigator(Kenkyū-buntansha) OSADA Hiroshi  Chugai Pharmaceutical Co., Ltd. Pharmaceutical Research LAB. II, Senior Scientist, 創薬第二研究所, 主任研究員
HORI Hiroki  Mie University, Hospital, Assistant Professor, 医学部・附属病院, 講師 (40252366)
Project Period (FY) 1999 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥12,700,000 (Direct Cost: ¥12,700,000)
Fiscal Year 2001: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2000: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1999: ¥6,800,000 (Direct Cost: ¥6,800,000)
KeywordsMTAP / Taqman PCR / MATP Promoter / DNA methylation / RT-PCR / 遺伝子欠失
Research Abstract

The broad, long-term objectives of this research proposal are to determine the prevalence and clinical characteristics of methylthioadenosine phosphorylase (MTAP) deficiency in human cancers and to develop and apply new methods for the specific treatment of MTAP-negative cancers.
In mammalian cells, methylthioadenosine (MTA) is produced during the synthesis of the polyamines. MTA does not accumulate in normal tissues but is cleaved rapidly to adenine and 5'-methylthioribose 1-phosphate (MTR-1-P) by MTAP. The adenine and MTR-1-P are recycled to purine nucleotides and methionine. respectively. Since all normal cells or tissues are known to contain MTAP, MTAP deficiency in human cancers will enable us to develop tumor-specific chemotherapy, in which MTAP-negative cancer cells will be selectively killed with drugs causing the depletion of purine nucleotides or methionine, under conditions where MTAP-positive normal tissues can be rescued by giving MTA as the sources of purine nucleotides or methionine.
In. order to detect MTAP-negative primary cancers, we have developed quantitative PCR assay to detect homozygous deletion of MTAP gene using Taqman chemistry. This method was able to diagnose MTAP gene deletion even in the samples containing 30 % normal cells. Since MTAP deficiency is not solely attributable to gene deletion, monoclonal antibodies has been generated successfully and are ready for immunohistochemistry. To develop new methods for the selective treatment of MTAP-negative cancers, we used L-alanosine to selectively treat MTAP-negative tumors in animal models.

Report

(4 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report

Research Products

(15 results)

All Other

All Publications

  • [Publications] Tendai J.M'soka, et al.: "Detection of methylthioadenosine phosphorylase (MTAP) and p16 gene deletion in T-cell acute lymphoblastic leukemia by real-time quantitative PCR assay"Leukemia. 14. 935-940 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tuchiya T, et al.: "Analysis of the p16INK4, p14ARF, p15, TP53, and MDM2 Genes and Their Prognostic Implications in Osteosarcoma and Ewing Sarcoma"Cancer Genet Cytogenet. 120. 91-98 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanaka K, et al.: "Mitotic checkpoint protein hsMAD2 as a marker predicting liver metastasis of human gastric cancers"Japanese Journal of Cancer Research. 92. 952-958 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kadariya Y, et al.: "Deletion of Dinucleotide Repeat (Δ14 allele) in the Methylthioadenosine Phosphorylase (MTAP) Promoter and the Allelotype of MTAP Promoter in the Japanese Population"Japanese Journal of Cancer Research. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tendai J. M'soka, et al.: "Detection of methylthioadenosine phosphorylase (MTAP) and p16 gene deletion acute lymphoblastic leukemia by real-time, quantitative PCR assay"Leukemia. 14. 935-940 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tuchiya T. et al.: "Analysis of the p16INK4, p14ARF, p15. TP53, and MDM2 Genes and Their Prognostic Implications in Osteosarcoma and Ewing Sarcoma"Cancer Genet Cytogenet. 120. 91-98 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanaka K. et al.: "Mitotic checkpoint protein hsMAD2 as a marker predicting liver metastasis of human gastric cancers"Japanese Journal of Cancer Research. 92. 952-958 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kadariya Y. et al.: "Deletion of Dinucleotide Repeat (Δ14 allele) in the Methylthioadenosine Phosphorylase (MTAP) Promoter and the Allelotype of MTA15 Promoter in the Japanese Population"Japanese Journal of Cancer Research. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tendai J.M'soka, et al.: "Detection of methylthioadenosine phosphorylase(MTAP)and p16 gene deletion in T-cell acute lymphoblastic leukemia by real-time quantitative PCR assay"Leukemia. 14. 935-940 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tuchiya T, et al.: "Analysis of the p16INK4,p14ARF,p15,TP53,and MDM2 Genes and Their Prognostic Implications in Osteosarcoma and Ewing Sarcoma"Cancer Genet Cytogenet. 120. 91-98 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tanaka K, et al.: "Mitotic checkpoint protein hsMAD2 as a marker predicting liver metastasis of human gastric cancers"Japanese Journal of Cancer Research. 92. 952-958 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kadariya Y, et al.: "Deletion of Dinucleotide Repeat(Δ 14 allele)in the Methylthioadenosine Phosphorylase(MTAP)Promoter and the Allelotype of MTAP Promoter in the Japanese Population"(発表予定).

    • Related Report
      2001 Annual Research Report
  • [Publications] Tendai J.M'soka, et al.: "Detection of methylthioadenosine phosphorylase (MTAP) and p16 gene deletion in T-cell acute lymphoblastic leukemia by real-time quantitative PCR assay."Leukemia. 14. 935-940 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Y.F.Wong,et al.: "Methylation of p16^<INK4A> in primary gynecologic malignancy"Cancer Letters. 136. 231-235 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Tendai J.M'soka, et al.: "Detection of Methylthioadenosine Phosphorylase(MTAP) and p16 Gene Deletion in T-cell Acute Lymphoblastic Leukemia by Real-Time Quantitative PCR Assay"Leukemia発表予定. (2000)

    • Related Report
      1999 Annual Research Report

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Published: 1999-03-31   Modified: 2016-04-21  

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