Development of companion diagnostics and molecular target therapy in malignancy : a model of the purine metabolic enzyme deficiency
| Project/Area Number |
20390166
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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 | 一般 |
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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, 大学院・医学系研究科, 教授 (60106995)
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| Co-Investigator(Kenkyū-buntansha) |
NATATANI Kaname 三重大学, 医学部附属病院, 講師 (80237304)
TAKAO Motoshi 三重大学, 医学部附属病院, 准教授 (30263007)
SHIRAISHI Taizou 三重大学, 大学院・医学系研究科, 教授 (30162762)
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| Project Period (FY) |
2008 – 2010
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| Project Status |
Completed (Fiscal Year 2010)
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| Budget Amount *help |
¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000)
Fiscal Year 2010: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2009: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2008: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
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| Keywords | MTA酵素欠損 / プリン代謝 / 免疫組織染色 / 選択的化学療法 / DNAメチル化 / MTAP / 抗ヒトMTAPモノクローナル抗体 / FACS解析 / 急性Tリンパ性白血 / 治療選択遺伝子検査 / CYP3A5 / 脱メチル化剤 / メチル化 / 遺伝子発現抑制 / MTAP欠損 / モノクローナル抗体 / 分子標的治療 / エピトープマッピング |
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| Research Abstract |
Methylthioadenosine phosphorylase (MTAP) is an enzyme involved in the metabolism of purine and methionine. Genetic analysis of the MTAP-negative cancer cell lines indicated that the all enzyme-negative cell lines but one had the partial or total deletion of MTAP gene. When this exceptional cell line was incubated with 5'-deazacytidine, the MTAP gene expression was confirmed by RT-PCR, indicating that the promoter hypermethylation is one of the mechanisms for MTAP deficiency in malignancy. In addition to IHC and Western blotting with anti-human MTAP monoclonal antibody, FACS analysis was found to be useful for the diagnosis of MTAP deficiency in leukemic cell lines.
In conclusions, MTAP deficiency will be diagnosed more precisely with IHC and FACS analysis than with the genetic test alone. Since the frequency of MTAP deficiency in a variety of primary tumors is relatively high, one could exploit this metabolic difference between normal and cancer cells for the development of the selective chemotherapy. Furthermore, the combination of MTAP deficiency as a molecular target and the selective chemotherapy is a good example of companion diagnostics.
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Report
(4 results)
Research Products
(35 results)
