权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Nobel therapeutic strategy based on deficient expression of DNA repair gene in gastrointestinal cancers.

基于胃肠癌DNA修复基因表达缺陷的诺贝尔治疗策略。

基本信息

批准号：
15390400
负责人：
MIYAZAKI Kohji
金额：
$ 9.15万
依托单位：
Saga University (2004-2005)佐賀医科大学 (2003)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

Expression of O^6 methylguanine DNA methyltransferase (MGMT) and mismatch repair gene hMLH1 was frequently lost in gastrointestinal cancer including biliary tract, hepatocellular, gastric and colorectal cancers. We previously reported significant correlation between deficient expression of MGMT, hMLH1 gene and poor outcome in biliary tract, hepatocellular and gastric cancer patients. MGMT is known as repair enzyme against alkylating modifications of cellular DNA. Recent reports using MGMT/hMLH1 knockout mice demonstrated that mice with MGMT(-) /hMLH1(+) was highly sensitive to alkylating agent MNU, leading to death by severe myelosuppression. We hypothesized that drug sensitivity to alkylating anticancer drug might depend on expression status of MGMT and hMLH1 in cancer cells. In this research project, we attempted to build a novel therapeutic strategy using alkylating agents, in which the drug sensitivity is predictable by MGMT/hMLH1 gene expression before chemotherapeutic treatment.1 … More (2003) Using 6 biliary tract acncer cell lines, we correlated expression pattern of MGMT/hMLH1 gene with drug sensitivity to alkylating agent MNU. As a result, 2 cell lines with MGMT(-)/hMLH1(+) was the most highly sensitive to MNU, compared with resultant cells with MGMT(+)/hMLH1(+) or MGMT(-)/hMLH1(-). This association was also found in xenograft tumor on nude mice. These results suggested that expression status of MGMT/hMLH1 is a marker for predicting drug sensitivity to alkylating agents. Furthermore, we found MGMT expression was suppressed under cisplatin with low dose concentration. This result indicated a novel biochemical modulation therapy using alkylating agents, where MGMT positive cancer cellscould be altered to MGMT deficient type by cisplatin treatment.2 (2004) It was recently reported that loss of MGMT and hMLH1 expressions in cancer were mainly caused by epigenetic gene methylation. Thus we analyzed methylation status of MGMT, hMLH1 in biliary tract cancer tissues. We demonstrated a significant correlation between MGMT methylation and reduced expression of MGMT protein. This result suggested MGMT methylation in cancer cells, which leading to the reduced protein expression, is molecular marker predicting drug sensitivity to alkylating agents.3 (2005) We found significant correlation between hMLH1 (-) status and high sensitivity to topoisomerase 1 inhibitor CPT-11 in biliary trac cancer cells. We confirmed the association by hMLH1 siRNA transfection to cancer cells with hMLH1 (+). Besides, we found DPD deficient cell line among 6 biliary tract cancer cells. We elucidated epigenetic modification of DPD gene occured in this cell line. DPD is known as an important enzyme determinating sensitivity to 5-FU. Thus we indicated deficient DPD expression in gastrointestinal cancer might be molecular marker predicting drug sensitivity to 5-FU. In gastric cancer cell lines and tissues, we observed significant correlation of CHFR gene methylation with high sensitivity to mictotubule inhibitor, Taxan. These results contributed to enriching molecular marker for selecting various anticancer drugs. We are willing to develop this research project and apply to our protocol for clinical cancer treatment. Less

O^6甲基鸟嘌呤DNA甲基转移酶（MGMT）和错配修复基因hMLH 1在包括胆道癌、肝细胞癌、胃癌和结直肠癌在内的胃肠道肿瘤中的表达经常丢失。我们先前报道了MGMT、hMLH 1基因表达缺陷与胆道癌、肝细胞癌和胃癌患者预后不良之间的显著相关性。MGMT被称为针对细胞DNA的烷基化修饰的修复酶。最近使用MGMT/hMLH 1敲除小鼠的报告表明，MGMT（-）/hMLH 1（+）小鼠对烷化剂MNU高度敏感，导致严重骨髓抑制而死亡。我们推测，对烷化剂的药物敏感性可能取决于癌细胞中MGMT和hMLH 1的表达状态。在本研究项目中，我们尝试使用烷化剂建立一种新的治疗策略，其中药物敏感性可通过化疗治疗前MGMT/hMLH 1基因表达预测。 ...更多信息（2003）我们使用6种胆道癌细胞系，将MGMT/hMLH 1基因表达模式与对烷化剂MNU的药物敏感性相关联。结果表明，与MGMT（+）/hMLH 1（+）或MGMT（-）/hMLH 1（-）的细胞相比，MGMT（-）/hMLH 1（+）的2种细胞系对MNU最敏感。在裸鼠的异种移植瘤中也发现了这种关联。提示MGMT/hMLH 1的表达状态可作为预测烷化剂敏感性的指标。此外，我们发现MGMT表达在低剂量浓度的顺铂下受到抑制。这一结果表明使用烷化剂的新型生化调节疗法，其中MGMT阳性癌细胞可以通过顺铂治疗改变为MGMT缺陷型。2（2004）最近报道，癌症中MGMT和hMLH 1表达的丧失主要由表观遗传基因甲基化引起。因此，我们分析了胆道癌组织中MGMT、hMLH 1的甲基化状态。我们证明了MGMT甲基化和MGMT蛋白表达减少之间的显著相关性。这一结果表明，癌细胞中MGMT甲基化导致蛋白表达降低，是预测对烷化剂药物敏感性的分子标志物。3（2005）我们发现胆管癌细胞中hMLH 1（-）状态与对拓扑异构酶1抑制剂CPT-11的高敏感性之间存在显著相关性。我们通过hMLH 1 siRNA转染到具有hMLH 1（+）的癌细胞中证实了这种关联。此外，我们还在6个胆管癌细胞中发现了DPD缺陷细胞株。初步阐明了该细胞系中DPD基因的表观遗传修饰。DPD被认为是决定5-FU敏感性的重要酶。因此，我们认为DPD表达缺陷可能是预测胃肠道肿瘤对5-FU药物敏感性的分子标志。在胃癌细胞系和组织中，我们观察到CHFR基因甲基化与对微管抑制剂Taxan的高敏感性显著相关。这些结果有助于丰富抗肿瘤药物筛选的分子标记。我们愿意发展这项研究项目，并将其应用于我们的临床癌症治疗方案。少

项目成果

期刊论文数量（28）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Deficient MGMT and proficient hMLH1 expression renders gallbladder carcinoma cells sensitive to alkylating agents through G2-M cell cycle arrest.

MGMT 缺陷和 hMLH1 表达丰富使胆囊癌细胞通过 G2-M 细胞周期停滞对烷化剂敏感。

DOI：
发表时间：
2005
期刊：
International Journal of Oncology 26
影响因子：
0
作者：
K.Sato et al.;Y Koga;K.Sato et al.;K.Sato et al.
通讯作者：
K.Sato et al.

D E.Hansel: "Identification of Novel Cellular Targets in Biliary Tract Cancers using Global Gene Expression Technology."Am J Pathol. 163(1). 217-229 (2003)

D E.Hansel：“利用全球基因表达技术鉴定胆道癌的新细胞靶标。”Am J Pathol。

DOI：
发表时间：
期刊：
影响因子：
0
作者：
通讯作者：

Cisplatin represses transcriptional activity from the minimal promoter of MGMT gene and increases sensitivity of human gallblandder cancer cells.

顺铂抑制 MGMT 基因最小启动子的转录活性，并增加人胆囊癌细胞的敏感性。

DOI：
发表时间：
2005
期刊：
Oncology Reports 13
影响因子：
0
作者：
K.Sato et al.;Y Koga;K.Sato et al.
通讯作者：
K.Sato et al.

Tumor progression through epigenetic gene silencing of MGMT in Human billiard tract cancers

人台球道癌中 MGMT 表观遗传基因沉默导致的肿瘤进展

DOI：
发表时间：
期刊：
Ann Surgical Oncol (In press)
影响因子：
0
作者：
K.Sato et al.;Y Koga;K.Sato et al.;K.Sato et al.;K.Sato et al.;Y Koga et al.;K.Sato et al.;K.Sato;A Miyoshi et al.;K.Sato et al.;A.Miyoshi et al.;K Sato et al.;Y Koga et al.;K Sato et al.;K Sato et al.;K Sato et al.;Y Koga et al.;K.Sato et al.;Y.Koga et al.
通讯作者：
Y.Koga et al.

The significance of aberrant CHFR methylation for clinical response to microtubule inhibitors in gastric cancer