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hMLH1的表达在胃肠道癌（包括胆道癌、肝细胞癌、胃癌和结直肠癌）中经常丢失，我们之前报道了MGMT、hMLH1基因的表达缺陷与不良预后之间存在显着相关性。胆道癌、肝细胞癌和胃癌患者中的 MGMT 被称为针对细胞 DNA 烷基化修饰的修复酶。最近使用 MGMT/hMLH1 敲除小鼠的报告表明，具有 MGMT(-) /hMLH1(+) 的小鼠对烷化剂 MNU 高度敏感，导致严重骨髓抑制导致死亡。我们热衷于对烷化抗癌药物的药物敏感性可能取决于表达状态。在这个研究项目中，我们尝试建立一种使用烷化剂的新型治疗策略，其中药物敏感性可通过以下方式预测。化疗前的 MGMT/hMLH1 基因表达。1 … More (2003) 使用 6 个胆道癌细胞系，我们将 MGMT/hMLH1 基因的表达模式与烷化剂 MNU 的药物敏感性相关联，结果，2 个细胞系与 MGMT 相关。 -)/hMLH1(+) 与使用 MNU 生成的细胞相比对 MNU 最敏感MGMT(+)/hMLH1(+)或MGMT(-)/hMLH1(-)在裸鼠的异种移植肿瘤中也发现了这种关联，这些结果表明MGMT/hMLH1的表达状态是预测药物敏感性的标志物。此外，我们发现低剂量浓度的顺铂可抑制 MGMT 表达，这一结果表明使用烷化剂的新型生化调节疗法，其中 MGMT 阳性癌症。顺铂治疗可将细胞转变为MGMT缺陷型。2 (2004) 最近报道，癌症中MGMT和hMLH1表达的丧失主要是由表观遗传基因甲基化引起的，因此我们分析了胆道癌组织中MGMT、hMLH1的甲基化状态。我们证明了 MGMT 甲基化与 MGMT 蛋白表达减少之间存在显着相关性，这一结果表明 MGMT 甲基化会导致癌细胞。减少的蛋白质表达是预测药物对烷化剂敏感性的分子标记。3 (2005) 我们发现胆道癌细胞中 hMLH1 (-) 状态与拓扑异构酶 1 抑制剂 CPT-11 的高敏感性之间存在显着相关性。 hMLH1 siRNA 转染 hMLH1 (+) 此外，我们在 6 个胆道癌细胞中发现了 DPD 缺陷细胞系。该细胞系中发生的 DPD 基因的表观遗传修饰被认为是决定对 5-FU 敏感性的重要酶，因此我们表明胃肠癌中 DPD 表达缺陷可能是预测胃癌细胞对 5-FU 药物敏感性的分子标记。我们观察到CHFR基因甲基化与微管抑制剂紫杉烷的高敏感性存在显着相关性，这些结果有助于丰富选择各种抗癌药物的分子标记。并适用于我们的临床癌症治疗方案。

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