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

胃癌肝转移HER2高表达细胞株GLm-1、GLm-2、GLm-4和NIC-N87对吉非替尼的IC50值分别为0.028、0.32、0.078和0.091μM，而对其他胃癌细胞株的IC50值仅为10μM。Gefitinib在体内对GLm-1异种移植瘤也有显著的抗增殖作用。吉非替尼1μ可诱导HER2高表达细胞凋亡，PI3K通路阻断剂LY294002也可诱导细胞凋亡，而U016则无此作用，HER2高表达细胞的增殖可能主要通过PI3K途径实现。在GLm-1细胞中，Erkl/2的磷酸化被配体刺激诱导，但吉非替尼可阻止这种磷酸化。在所有细胞系中都观察到AKT的结构性磷酸化而没有配体刺激，但只有在HER2过表达的细胞系中这种自磷酸化被吉非替尼阻断。GLm-1R，GLm-1Li…的GLm-1R抗性克隆更多的是由于接触低剂量的吉非替尼而产生的。GLm-1R的IC50值为1.82μM，是亲本GLm-1的65倍。在没有配体刺激的GLm-1R中观察到Akt的结构性磷酸化，其程度与亲代细胞系中观察到的程度相同，但Shc和Erkl/2的磷酸化在耐药克隆中更为显著，这表明通过MAPK通路的信号转导补偿了吉非替尼对PI3K通路的阻断，从而增加了耐药性。在三个被发现为敏感的标本中，三个都没有EGFR染色，而两个标本HER2染色很强。此外，在四名肝转移患者中，两名HER2染色阳性，对吉非替尼敏感。因此，确实存在表达HER2、有肝转移倾向且易受吉非替尼治疗的特定亚群胃癌。较少

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