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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。

基本信息

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

项目摘要

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

HER2过表达的胃癌肝转移细胞株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0.091 μ M，而对其他胃癌细胞株的IC50值为0.010 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。1 μ m剂量的吉非替尼诱导HER2过表达细胞凋亡，而PI3K通路阻断剂LY294002也诱导凋亡，而U016则没有，HER2过表达细胞的增殖被认为主要通过PI3K通路介导。在GLM-1中，Erkl/2的磷酸化是由配体刺激引起的，但吉非替尼可以阻止这种磷酸化。在没有配体刺激的情况下，所有细胞系都观察到Akt的组成性磷酸化，但这种自磷酸化仅在HER2过表达细胞系中被吉非替尼阻断。GLM-1R是GLM-1 li的耐吉非替尼克隆。GLM-1R的IC50值为1.82μ M，是亲本GLM-1的65倍。在没有配体刺激的情况下，GLM-1R中出现了与亲代细胞系相同程度的Akt组成性磷酸化，但在耐药克隆中，Shc和Erkl/2的磷酸化更为突出，这表明通过MAPK途径的信号转导补偿了吉非替尼阻断PI3K途径，从而产生了耐药性。采用30例新鲜手术切除标本进行胶原凝胶滴化学敏感性试验，检测对吉非替尼的敏感性。在发现敏感的三个标本中，三个都没有EGFR染色，而两个则强烈染色HER2。此外，在4例肝转移患者中，2例HER2染色阳性，对吉非替尼敏感。因此，确实存在一种表达HER2、有肝转移倾向、易受吉非替尼治疗的胃癌特异性亚群。少

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Gene expression of 5-fluorouracil metabolic enzymes in primary gastric cancer: Correlation with drug sensitivity against 5-fluorouracil

DOI：
10.1016/j.canlet.2007.01.006
发表时间：
2007-07-18
期刊：
CANCER LETTERS
影响因子：
9.7
作者：
Kodera, Yasuhiro;Ito, Seiji;Nakao, Akimasa
通讯作者：
Nakao, Akimasa

Molecular basis for sensitivity and acquired resistance to gefitinib in HER2-overexpressing human gastric cancer cell lines derived from liver metastasis.

在源自肝转移的HER2过表达的HER2过表达的人类胃癌细胞系中，敏感性并获得了对吉非尼的抗性的分子基础。

DOI：
10.1038/sj.bjc.6603459
发表时间：
2006-12-04
期刊：
BRITISH JOURNAL OF CANCER
影响因子：
8.8
作者：
Yokoyama, H;Ikehara, Y;Kodera, Y;Ikehara, S;Yatabe, Y;Mochizuki, Y;Koike, M;Fujiwara, M;Nakao, A;Tatematsu, M;Nakanishi, H
通讯作者：
Nakanishi, H

In vitro chemosensitivity test to predict chemosensitivity for paclitaxel, using human gastric carcinoma tissues.