Development of companion diagnostics and molecular target therapy in malignancy : a model of the purine metabolic enzyme deficiency

恶性肿瘤伴随诊断和分子靶向治疗的发展：嘌呤代谢酶缺乏的模型

• 批准号: 20390166
• 负责人: NOBORI Tsutomu
• 金额: $ 10.32万
• 依托单位: Mie University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20390166/
• 关键词: 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

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.

甲硫腺苷磷酸化酶(MTAP)是一种参与嘌呤和蛋氨酸代谢的酶。对MTAP阴性肿瘤细胞系的遗传分析表明，除1株外，所有酶阴性细胞系均存在MTAP基因的部分或全部缺失。用5‘-脱氮胞苷作用于该细胞株，RT-PCR检测到MTAP基因的表达，提示启动子高甲基化是MTAP基因缺失在恶性肿瘤中的机制之一。除了用抗人MTAP单抗进行IHC和Western blotting外，FACS分析还被发现对白血病细胞系MTAP缺陷的诊断有用。由于MTAP缺乏症在多种原发肿瘤中的发生率较高，人们可以利用正常细胞和癌细胞之间的这种代谢差异来开发选择性化疗。此外，MTAP缺乏作为分子靶点与选择性化疗相结合是伴随诊断的一个很好的例子。

项目成果

Personalized treatment in the eradication therapy for Helicobacter pylori.

幽门螺杆菌根除治疗中的个体化治疗。

• 发表时间: 2010
• 期刊: International Journal of Molecular Medicine 27
• 作者: Jinda S;Nakatani K;Nishioka J;Yasuda K;Soya Y;Hayashi A;Wada H;Nobori T
• 通讯作者: Nobori T

Prospective evaluation of three different diagnostic criteria for disseminated intravascular coagulation

• DOI: 10.1160/th10-05-0293
• 发表时间: 2011-01-01
• 期刊: THROMBOSIS AND HAEMOSTASIS
• 影响因子: 6.7
• 作者: Takemitsu, Tetsushi;Wada, Hideo;Nobori, Tsutomu
• 通讯作者: Nobori, Tsutomu

MTHFR遺伝子、アディポネクチン遺伝子多型を用いたインスリン抵抗性の予測

利用MTHFR基因和脂联素基因多态性预测胰岛素抵抗

• 发表时间: 2009
• 作者: 中谷中;他
• 通讯作者: 他

Prevention of venous thromboembolism according to the guidelines of a domestic manual.

按照国内手册的指导方针预防静脉血栓栓塞。

• 发表时间: 2010
• 期刊: Int J Hematol
• 影响因子: 2.1
• 作者: Kaneko T;et al.
• 通讯作者: et al.

造血幹細胞移植レシピエントにおける日和見感染原因ウイルス定量システムの有用性

量化导致造血干细胞移植受者机会性感染的病毒系统的实用性

• 发表时间: 2010
• 作者: 安田和成;他
• 通讯作者: 他