Drug Polymorphic triple nucleotide alterations in cell cycle transactivator E2F-4 and sensitivity to the anlicancer agents

细胞周期反式激活因子 E2F-4 中的药物多态性三核苷酸改变和对抗癌药物的敏感性

• 批准号: 12671227
• 负责人: MATSUBARA Nagahide
• 金额: $ 2.3万
• 依托单位: Okayama University Hospital
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671227/
• 关键词: E2F-4; polymorphism; choemoterapy; drug sensitivitv; 小腸移植; 門脈内注入; 免疫抑制; 大腸癌; microsatellite instability; 化学療法

Deficiency of mismatch repair system has been shown to cause hereditary non-polyposis coloredal cancer as well as approximately 15% of the sporadic cobrectal cancer. In advancement of molecular oncology, several molecular mechanisms of the resistance against antineoplastic agents have bee elucidated. Besides its function of mismatch repair (MMR), the MMR system also recognizes certain DNA adducts or distortion caused by chemotherapeulic agents, which ultimately leads to cell cycle arrest or cell death. MMR deficient cells acquire resistance- to some alkylathig agents, such as platinum, and 5FU because the detected MMR system cannot recognize, the DNA damage caused by such agents. The MMR target genes such as TGFbRII, BAX, and E2F-4 also have the potential to modify the drug sensitivity because these genes are on the down stream pathway of MMR deficiency. Here we demonstrale that the E2F-4 aherations, which we jdentified for the first time, is apparently modified the sensitivity of chemotherapeulic agents such as, VP-16 and CBDCA by transfecting various wild type and mutant E2F-4s in NIH3T3 cells. The knowledge of the resistance to some chemotherapeutic agents caused by MMR deficiency or downstream genes should be considered in a clinical setting near future.

错配修复系统的缺陷已被证明是导致遗传性非息肉病性结直肠癌以及约15%的散发性结直肠癌的原因。随着分子肿瘤学的发展，肿瘤耐药的分子机制已被阐明。除了其错配修复（MMR）功能之外，MMR系统还识别由化疗剂引起的某些DNA加合物或畸变，其最终导致细胞周期停滞或细胞死亡。MMR缺陷型细胞获得对某些烷基化试剂（例如铂和5 FU）的抗性，因为检测到的MMR系统不能识别由这些试剂引起的DNA损伤。MMR靶基因如TGFbRII、BAX和E2 F-4也具有改变药物敏感性的潜力，因为这些基因位于MMR缺陷的下游通路上。本文通过在NIH 3 T3细胞中检测各种野生型和突变型E2 F-4，证明了我们首次鉴定的E2 F-4表达明显改变了化疗药物如VP-16和CBDCA的敏感性。对MMR缺陷或下游基因引起的某些化疗药物耐药的认识应在不久的将来被考虑用于临床。

项目成果

Matsubara N, et al.: "The farthest 3' distal end APC mutation identified attenuated in adenomatous polyposios coil with extracolonic manifestations"Diseases of Colon & Rectum. 43・5. 720-721 (2000)

Matsubara N 等人：“在具有结肠外表现的腺瘤性息肉病线圈中鉴定出最远的 3 远端 APC 突变”，《结肠和直肠疾病》43・5（2000 年）。

Takashima H, el al: "Effect of naturally occurring E2F-4 alterations on transcriplional aclivation and proliferation in transfected cells"Lab. Invest. 81. 1565-1573 (2001)

Takashima H 等人：“自然发生的 E2F-4 改变对转染细胞转录激活和增殖的影响”实验室。

馬場正三, 他: "21世紀の大腸癌診断治療戦略のために HNPCC in the year 200(hereeditary nonpolyposis colorectal cancer)"株式会社マイライフ社. 71 (2000)

Shozo Baba 等人：“200 年的 HNPCC（遗传性非息肉病性结直肠癌）”MyLife Inc. 71 (2000)

Mori Y, et al.: "Instabilotyping reveals unique mutational spectra in microsatellite-unstable gastric cancer"Cancer Res. 62. 3641-3645 (2002)

Mori Y 等人：“不稳定分型揭示了微卫星不稳定胃癌的独特突变谱”Cancer Res。

Takashima H, et al.: "Effect of naturally occurring E2F-4 alterations on transcriptional activation and proliferation in transfected cells"Lab. Invest. 81. 1565-1573 (2001)

Takashima H 等人：“自然发生的 E2F-4 改变对转染细胞转录激活和增殖的影响”实验室。