Pre-operative adjuvant chemotherapy for gastrointestinal cancers : Pharmacogenomic study toward personalized medicine

胃肠癌术前辅助化疗：个性化医疗的药物基因组学研究

• 批准号: 14370390
• 负责人: NISHIYAMA Masahiko
• 金额: $ 6.72万
• 依托单位: HIROSHIMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370390/
• 关键词: Gene Expression Analysis; cDNA microarray; Personalized Medicine; Anticancer Drugs; Normalization; Bioinformatics; Clinical Research; Gastrointestinal Cancers; normalization<標準化>; normalization(標準化)

Efforts to promote personalized medicine have led to better tools for prediction of individual response to drugs, in both toxicity and effect, but enormous tasks remain to be done. For efficacy prediction, very few critical markers have been validated to date, and a laboratory analysis system which can simultaneously predict response to several potent drugs or regimes based on understanding the interplay of multiple prediction markers has not yet been developed.In the present study, we newly developed or demonstrated1)concise, accurate prediction models of the in vitro activity for 8 anticancer drugs (5-FU,CDDP,MMC,DOX,CPT-11,SN-38,TXL, and TXT), along with individual clinical responses to 5 FU using expression data of 12 genes,2)novel normalization methods of expression levels in CDNA microarray,3)important roles of methylation and AP-1 in the transcriptional regulation of DPYD gene, a key gene related to fuluoropyrmidines resoponse,4)biological roles of BCL-2,DEC1,DEC2, and HIFIα in tumor response to various stress.,5)genes related to tumor immortalization,6)roles of CYP3A4,CYP2C8, and UGT1A1 polymorphisms in drug response,and7)therapeutic potential of TXT/S-1 in gastric cancer.These development of a potent therapy and identification of new indicators of individual response to drugs may present the opportunity to establish a novel chemotherapeutic strategy, personalized medicine, which would allow selection of an optimal regimen for each individual based on gene expression profile and/or genomic make-up, in pre-operative adjuvant chemotherapy for gastrointestinal cancers. In parallel with the development of the prediction models for clinical responses to several active combination chemotherapies using clinical samples, a prospective clinical study to clarify the value of the prediction formulae and newly suggested indicators will commence soon.

促进个性化医疗的努力已经导致了更好的工具来预测个体对药物的反应，无论是毒性还是效果，但仍有大量的工作要做。对于疗效预测，迄今为止，只有很少的关键标志物被验证，并且还没有开发出基于理解多个预测标志物的相互作用而能够同时预测对几种有效药物或方案的反应的实验室分析系统。在本研究中，我们新开发或演示了1）简明、准确的8种抗癌药物体外活性预测模型（5-FU、CDDP、MMC、DOX、CPT-11、SN-38、TXL和TXT），沿着使用12个基因的表达数据的对5-FU的个体临床应答，2）cDNA微阵列中表达水平的新标准化方法，3）甲基化和AP-1在DPYD基因转录调节中的重要作用，DPYD基因是与氟代嘧啶应答相关的关键基因，4）BCL-2的生物学作用，DEC 1、DEC 2和HIFIα在肿瘤对各种应激反应中的作用5)肿瘤永生化相关基因，CYP 3A 4、CYP 2C 8和UGT 1A 1多态性在药物反应中的作用，以及TXT/S-1在胃癌中的治疗潜力。其允许在胃肠癌的术前辅助化疗中基于基因表达谱和/或基因组组成为每个个体选择最佳方案。在使用临床样本开发几种活性联合化疗临床反应预测模型的同时，不久将开始一项前瞻性临床研究，以阐明预测公式和新建议指标的价值。

项目成果

Concise prediction models of anticancer efficacy of 8 drugs using expression data from 12 selected genes

• DOI: 10.1002/ijc.20289
• 发表时间: 2004-09
• 期刊: International Journal of Cancer
• 影响因子: 6.4
• 作者: Tomotaka Tanaka;K. Tanimoto;K. Otani;K. Satoh;M. Ohtaki;Kazuhiro Yoshida;T. Toge;H. Yahata;Shinji Tanaka;K. Chayama;Y. Okazaki;Y. Hayashizaki;K. Hiyama;M. Nishiyama

Yoshida, K.: "Future prospects of personalized chemotherapy in gastric cancer patients : results of a prospective randomized pilot study. : 82-9, 2003 Mar."Gastric Cancer. 6 Suppl 1. 82-89 (2003)

Yoshida, K.：“胃癌患者个性化化疗的未来前景：一项前瞻性随机试点研究的结果。：2003 年 3 月 82-9 日。”胃癌。

Activator protein accelerates dihydropyrimidine dehydrogenase gene transcription in cancer cells.

激活蛋白加速癌细胞中二氢嘧啶脱氢酶基因的转录。

• 发表时间: 2005
• 期刊: Cancer Res. 65(3)
• 作者: Ukon;K.
• 通讯作者: K.

Towards Molecular Medicine : Cancer Pharmacogenomics, Personalized Medicine, and Our Recent Approaches.

迈向分子医学：癌症药物基因组学、个性化医疗和我们最近的方法。

• 发表时间: 2003
• 期刊: Annals of Cancer Research and Therapy 11
• 作者: Kuwai T. et al.;Kuwai T. et al.;Yoshiga K. et al.;Tanimoto K. et al.;Pereira T. et al.;Tanimoto K. et al.
• 通讯作者: Tanimoto K. et al.

Hypoxia-inducible factor-1α polymorphisms associated with enhanced transactivation capacity, implying clinical significance

• DOI: 10.1093/carcin/bgg132
• 发表时间: 2003-11-01
• 期刊: CARCINOGENESIS
• 影响因子: 4.7
• 作者: Tanimoto, K;Yoshiga, K;Nishiyama, M
• 通讯作者: Nishiyama, M