Establishment of tailor-made treatment strategy with gefitinib against peritoneal metastasis from gastric carcinoma.

建立吉非替尼针对胃癌腹膜转移的个体化治疗策略。

• 批准号: 17591388
• 负责人: KODERA Yasuhiro
• 金额: $ 2.24万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591388/
• 关键词: gastric cancer; molecular targeting; gefitinib; chemosensitivity test; PI3K pathway; MAPK pathway; apoptosis; drug resistance; 耐性株; 抗腫瘍効果

The IC50 values against gefitinib was 0.028, 0.32, 0.078, and 0.091 μ M respectively for HER2 over-expressing cell lines GLM-1, GLM-2, GLM-4, and NIC-N87 established from gastric cancer liver metastases whereas they were >10 μ M in other gastric cancer cell lines. Gefitinib also exhibited eminent antiproliferative effect against GLM-1 xenografts in vivo. Gefitinib induced apoptosis in HER2 over-expressing cells at a dose of 1 μ M. LY294002, a blocker of the PI3K pathway, also induced apoptosis whereas U016 did not, and proliferation of HER2 over-expressing cells are considered to be mediated mainly through the PI3K pathway. In GLM-1, the phosphorylation of Erkl/2 was induced by ligand stimulation, but gefitinib was found to prevent this phosphorylation. Constitutive phosphorylation of Akt without ligand stimulation was observed in all cell lines, but this autophosphorylation was blocked by gefitinib only in HER2 over-expressing cell lines.GLM-1R, a gefitinib resistant clone of GLM-1 li … More neage, was created by exposure to low dose gefitinib. The IC50 value of GLM-1R was 1.82μ M and was 65-fold that of parental GLM-1. Constitutive phosphorylation of Akt was observed in the absence of ligand stimulation in GLM-1R to the extent observed in the parental cell line, but phosphorylation of Shc and Erkl/2 was more prominent in the resistant clone, suggesting that signal transduction through the MAPK pathway compensates for the blockage of PI3K pathway by gefitinib, thus conferring drug resistance.Collagen gel droplet chemosensitivity test was performed with 30 fresh surgically resected specimens to test for sensitivity against gefitinib. Of three specimens found sensitive, all three were not stained for EGFR whereas two were strongly stained for HER2. In addition, of four patients with hepatic metastases, two stained positive for HER2 and were sensitive against gefitinib. Thus, a specific subgroup of gastric cancer that expresses HER2, has propensity towards liver metastasis, and is vulnerable to a treatment with gefitinib does exist. Less

针对Gefitinib的IC50值分别为0.028、0.32、0.078和0.091μm，用于HER2过表达的细胞系GLM-1，GLM-1，GLM-4和NIC-N87，由胃癌肝脏转移酶建立，而在其他胃癌癌症细胞系中>10μm，而在其他胃癌癌细胞系中则>10μm。吉非替尼还暴露了针对体内GLM-1 Xenographtics的显着抗增生作用。吉非替尼以1μm的剂量诱导HER​​2过表达细胞的凋亡。 LY294002是PI3K途径的阻滞剂，也诱导了凋亡，而U016则没有，而HER2过表达细胞的增殖被认为主要是通过PI3K途径介导的。在GLM-1中，通过配体刺激诱导ERKL/2的磷酸化，但发现吉非替尼可防止这种磷酸化。在所有细胞系中都观察到AKT的本构磷酸化，但是仅在HER2过表达的细胞系中，这种自磷酸化仅被Gefitinib封闭。GLM-1R.GLM-1R，GLM-1 LI的GEFITINIB抗性克隆GLM-1 LI…更多的NEAGE…更多的NEAGE，通过暴露于低剂量的Gefitiitib创建了更多的NEAGE。 GLM-1R的IC50值为1.82μm，是父母GLM-1的65倍。在GLM-1R中没有配体刺激的情况下观察到AKT的组成型磷酸化在父母细胞系中观察到的程度，但是SHC和ERKL/2的磷酸化在耐药克隆中更为突出，这表明通过MAPK途径通过MAPK途径进行信号过量弥补了PI3KARG的阻止。使用30个新鲜的手术切除标本进行化学敏度试验，以测试对吉非替尼的敏感性。在发现敏感的三个标本中，所有三个标本均未染色EGFR，而HER2的两个标本对HER2进行了强烈染色。此外，在四名患有肝脏转移的患者中，两名对HER2染色阳性，对Gefitinib敏感。这是一种表达HER2的特定胃癌亚组，有望对肝转移，并且很容易接受吉非替尼治疗。较少的