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

对于从胃癌肝转移中建立的HER 2过表达细胞系GLM-1、GLM-2、GLM-4和NIC-N87，吉非替尼的IC 50值分别为0.028、0.32、0.078和0.091 μ M，而在其他胃癌细胞系中，这些值均>10 μ M。吉非替尼在体内对GLM-1异种移植物也表现出显著的抗增殖作用。吉非替尼在1 μ M剂量下诱导HER 2过表达细胞凋亡。PI 3 K通路阻断剂LY 294002也诱导细胞凋亡，而U 016不诱导，并且认为HER 2过表达细胞的增殖主要通过PI 3 K通路介导。在GLM-1中，Erkl/2的磷酸化由配体刺激诱导，但发现吉非替尼阻止这种磷酸化。在所有细胞系中观察到Akt在没有配体刺激的情况下的组成性磷酸化，但是这种自磷酸化仅在HER 2过表达细胞系中被吉非替尼阻断。 关于我们 neage是通过暴露于低剂量吉非替尼而产生的。GLM-1 R的IC 50值为1.82μ M，是亲本GLM-1的65倍。在GLM-1 R中在不存在配体刺激的情况下观察到Akt的组成性磷酸化达到在亲本细胞系中观察到的程度，但Shc和Erkl/2的磷酸化在抗性克隆中更突出，表明通过MAPK途径的信号转导补偿了吉非替尼对PI 3 K途径的阻断，用30个新鲜手术切除的标本进行胶原凝胶液滴化学敏感性试验，以测试对吉非替尼的敏感性。在发现敏感的三份标本中，所有三份均未对EGFR进行染色，而两份对HER 2进行了强染色。此外，在4例肝转移患者中，2例HER 2染色阳性，对吉非替尼敏感。因此，确实存在表达HER 2、具有肝转移倾向且易受吉非替尼治疗影响的特定胃癌亚组。少

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