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Development of molecular target medicine using ZD1839 in esophageal cancer

ZD1839食管癌分子靶向药物的开发

基本信息

批准号：
16591346
负责人：
IKEDA Kenichiro
金额：
$ 2.05万
依托单位：
Iwate Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591346/
关键词：
hTERT telomere esophageal cancer MAPK ZD1839 glioblastoma molecular target medicine telomerase 食道癌悪性膠芽腫瘍

项目摘要

The selective epidermal growth factor receptor-tyrosine kinase-(EGFR, TK)-inhibitor, gefitinib, blocks several signal transduction pathways involved in tumor cell proliferation, anti-apoptosis and angiogenesis. We demonstrate for the first time that human telomerase reverse transcriptase (hTERT) is a molecular target of gefitinib through repression of the classical mitogen-activated protein kinase (MAPK)-Ets pathway. We used four human esophageal cancer cell lines (TE-1, TE-3, TE-4, and TE-5) that strongly express EGFR to evaluate the effects of gefitinib treatment on the phosphorylation status of EGFR/mitogen-activated protein kinase (MAPK), hTERT mRNA/protein expression, transcriptional activation of the hTERT gene promoter, and telomerase activity. Phosphorylation of EGFR tyrosine residues PY1086 and PY1173, and of ERK 1/2, as well as hTERT mRNA/protein expression were markedly repressed by gefitinib treatment. A reporter assay demonstrated that exposure to gefitinib markedly down-r … More egulated the transcriptional activity (0.28-to 0.45-fold decrease) of the Ets site of the hTERT core promoter. Telomerase activity was down-regulated by gefitinib treatment in a dose-dependent manner. The concentration necessary for 50% inhibition of telomerase activity (0.12-0.71 μM) was lower than that necessary for inhibition of growth (6.35-18.54 μM). Long-term and relatively low-dose exposure to gefitinib significantly (P< 0.01) increased the proportion of cells positive for β-galactosidase in 3 cell lines (TE-1, TE-4, and TE-5), but not in TE-3. The mean TRF lengths of the 3 susceptible cell lines, but not of TE-3, were reduced in comparison with those of no-treatment controls. These results suggest that gefitinib targets telomerase activity as an anti-cancer effect through inhibition of direct EGF-induced transcriptional activation of the hTERT gene. The ability of gefitinib to inhibit telomerase at low doses may provide an approach to avoid severe adverse effects such as pulmonary fibrosis. Less

选择性表皮生长因子受体酪氨酸激酶（EGFR， TK）抑制剂吉非替尼阻断肿瘤细胞增殖、抗凋亡和血管生成的信号转导途径。我们首次证明人类端粒酶逆转录酶（hTERT）是吉非替尼通过抑制经典的丝裂原活化蛋白激酶(MAPK)-Ets途径的分子靶点。我们使用四种强烈表达EGFR的人食管癌细胞系（TE-1、TE-3、TE-4和TE-5）来评估吉非替尼治疗对EGFR/丝裂原活化蛋白激酶（MAPK）磷酸化状态、hTERT mRNA/蛋白表达、hTERT基因启动子转录激活和端粒酶活性的影响。吉非替尼显著抑制EGFR酪氨酸残基PY1086和PY1173的磷酸化，以及ERK 1/2和hTERT mRNA/蛋白的表达。报告分析表明，暴露于吉非替尼可显著降低hTERT核心启动子Ets位点的转录活性（降低0.28- 0.45倍）。吉非替尼治疗后端粒酶活性呈剂量依赖性下调。抑制端粒酶活性50%所需的浓度（0.12 ~ 0.71 μM）低于抑制生长所需的浓度（6.35 ~ 18.54 μM）。长期和相对低剂量暴露于吉非替尼显著（P< 0.01）增加了3种细胞系（TE-1、TE-4和TE-5）中β-半乳糖苷酶阳性细胞的比例，但在TE-3中没有。与未处理的对照组相比，3个易感细胞系的平均TRF长度减少，但TE-3没有。这些结果表明，吉非替尼通过抑制egf直接诱导的hTERT基因转录激活来靶向端粒酶活性，从而起到抗癌作用。吉非替尼在低剂量下抑制端粒酶的能力可能提供一种避免严重不良反应的方法，如肺纤维化。少