Chemopreventive effects of gefitinib on nonsmoking-related lung tumorigenesis in activating epidermal growth factor receptor transgenic mice.
Chemopreventive effects of gefitinib on nonsmoking-related lung tumorigenesis in activating epidermal growth factor receptor transgenic mice.
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DOI：
10.1158/0008-5472.can-08-4205
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发表时间：
2009-09
期刊：
影响因子：
11.2
通讯作者：
K. Ohashi;N. Takigawa;Masahiro Osawa;E. Ichihara;Hiromasa Takeda;T. Kubo;Seiki Hirano;T. Yoshino;M. Takata;M. Tanimoto;K. Kiura
中科院分区：
文献类型：
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作者：
K. Ohashi;N. Takigawa;Masahiro Osawa;E. Ichihara;Hiromasa Takeda;T. Kubo;Seiki Hirano;T. Yoshino;M. Takata;M. Tanimoto;K. Kiura
25%的肺癌病例与吸烟无关。表皮生长因子受体（EGFR）突变，这涉及约50%的非吸烟者肺癌，与吉非替尼的反应性呈正相关，与吸烟史呈负相关。激活EGFR突变在非吸烟相关肺癌的发生中起关键作用。为了研究吉非替尼对非吸烟相关肺癌的化学预防作用，我们使用表面活性蛋白C启动子在II型肺细胞中组成性表达EGFR L 858 R的转基因小鼠。转基因小鼠在4周龄时无一例外地发生了非典型腺瘤性增生，在7周龄时发生了大小不等的多灶性腺癌。值得注意的是，磷酸化和总ErbB 2，ErbB 3和甲状腺转录因子-1的表达水平在转基因小鼠与野生型对照组相比，在3周龄时升高。在致癌前给予3周龄转基因小鼠吉非替尼1周，可将小鼠肺中磷酸化EGFR的量降低至基线水平。吉非替尼（5 mg/kg/d; n = 5、5和15）或赋形剂（n = 5、5和15）分别给予3 - 8、13和18周龄的转基因小鼠。对照组和吉非替尼治疗组的肺肿瘤数分别为1.75、5.8、10.2和0（P < 0.05）。两组均未发生致死性毒性事件，吉非替尼在该小鼠模型中完全抑制肿瘤发生。这些结果表明，对非吸烟相关的肺癌分子靶向化学预防的效用。
Twenty-five percent of all lung cancer cases are not attributable to smoking. Epidermal growth factor receptor (EGFR) mutations, which are involved in approximately 50% of nonsmoker lung cancer, are positively correlated with responsiveness to gefitinib, and inversely correlated with smoking history. Activating EGFR mutations play a critical role in the carcinogenesis of nonsmoking-related lung cancer. To investigate the chemopreventive effects of gefitinib on nonsmoking-related lung cancer, we generated transgenic mice expressing EGFR L858R in type II pneumocytes constitutively using the surfactant protein-C promoter. The transgenic mice invariably developed atypical adenomatous hyperplasia at age 4 weeks and multifocal adenocarcinoma of varying sizes at age 7 weeks. Notably, the expression levels of phosphorylated and total ErbB2, ErbB3, and thyroid transcription factor-1 were elevated in the transgenic mice compared with wild-type controls at age 3 weeks. Administration of gefitinib to 3-week-old transgenic mice for 1 week before carcinogenesis reduced the amount of phosphorylated EGFR in the lungs of the mice to the baseline level. Gefitinib (5 mg/kg/d; n = 5, 5, and 15) or vehicle (n = 5, 5, and 15) was administered to transgenic mice from age 3 to 8, 13, and 18 weeks, respectively. The numbers of lung tumors in the control and gefitinib-treated groups were 1.75, 5.8, 10.2, and 0 (P < 0.05), respectively. No fatal toxic events occurred in either group, and gefitinib inhibited tumorigenesis completely in this mouse model. These results suggest the utility of molecular targeted chemoprevention against nonsmoking-related lung cancer.