| Project/Area Number |
11557205
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Laboratory medicine
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| Research Institution | Mie University |
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Principal Investigator |
NOBORI Tsutomu Mie University, Faculty of Medicine, Professor, 医学部, 教授 (60106995)
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| 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)
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| Project Period (FY) |
1999 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| 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)
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| Keywords | MTAP / Taqman PCR / MATP Promoter / DNA methylation / RT-PCR / 遺伝子欠失 |
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| 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.
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