Effect of gefitinib on N-nitrosamine-4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induced lung tumorigenesis in A/J mice
Effect of gefitinib on N-nitrosamine-4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induced lung tumorigenesis in A/J mice
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DOI：
10.1016/j.lungcan.2008.11.021
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发表时间：
2009-09-01
期刊：
影响因子：
5.3
通讯作者：
Tanimoto, Mitsune
中科院分区：
文献类型：
--
作者：
Kishino, Daizo;Kiura, Katsuyuki;Tanimoto, Mitsune
吉非替尼是一种表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）。N-亚硝胺-4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK），烟草烟雾中发现的一种强致癌物，可诱导A/J小鼠肺肿瘤。NNK诱导细胞转化，导致EGFP的过表达。因此，EGFR可能是癌症预防的靶点。为探讨吉非替尼对NNK致瘤作用的影响及其致癌性，将180只4周龄雌性A/J小鼠随机分为6组：1组（对照组），给予去离子水; 2组（5 mg/kg p.o.吉非替尼;第3组，用50 mg/kg p.o.吉非替尼（以测试吉非替尼的致癌性）;组4（NNK处理的对照），用去离子水处理;组5，用5 mg/kg p.o.吉非替尼;和组6，用50 mg/kg p.o.吉非替尼，并在8周龄时注射NNK一次，以测试吉非替尼的化学预防活性。吉非替尼每天灌胃一次，每周5天，从4周龄开始，持续26周。所有小鼠在30周龄时处死。NNK诱导的肺肿瘤的多重性以剂量依赖性方式被显著抑制。吉非替尼在低剂量时对体重无影响。吉非替尼单独给药26周没有诱导肿瘤发生;相反，与其他抗癌药物相比，它显著抑制了小鼠自发性肿瘤的发生率。通过Azan-Mallory染色，与对照小鼠相比，吉非替尼未诱导肺纤维化。我们的研究结果表明，吉非替尼有一个弱的，但显着的化学预防作用，没有致癌性或肺毒性的A/J小鼠。(C)2008爱思唯尔爱尔兰有限公司保留所有权利。
Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). N-Nitrosamine-4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a potent carcinogen found in tobacco smoke, induces lung tumors in A/J mice. NNK induces cellular transformation resulting in the over-expression of EGFP. Accordingly, EGFR may be a target for cancer prevention. In this study, we investigated the effect of gefitinib on NNK-induced tumorigenesis and the carcinogenicity of gefitinib in A/J mice.A total of 180 four-week-old female A/J mice were randomly divided into six groups: group 1 (controls), treated with deionized water; group 2, treated with 5 mg/kg p.o. gefitinib; group 3, treated with 50 mg/kg p.o. gefitinib (to test the carcinogenicity of gefitinib); group 4 (controls for NNK treatment), treated with deionized water; group 5, treated with 5 mg/kg p.o. gefitinib; and group 6, treated with 50 mg/kg p.o. gefitinib and injected with NNK once at 8 weeks of age to test the chemopreventive activity of gefitinib. Gefitinib was given once a day, 5 days a week by gavage, beginning at 4 weeks of age and continuing for 26 weeks. All mice were sacrificed at 30 weeks of age. The multiplicities of the NNK-induced lung tumors were significantly suppressed in a dose-dependent manner. Gefitinib had no effect on body weight at a low dose. The administration of gefitinib alone for 26 weeks did not induce tumorigenesis; instead, it significantly suppressed the incidence of spontaneous tumors in the mice, in contrast with other anticancer agents. Gefitinib did not induce lung fibrosis when compared with control mice by Azan-Mallory staining. Our results suggest that gefitinib has a weak but significant chemopreventive effect with no carcinogenicity or pulmonary toxicity in A/J mice. (C) 2008 Elsevier Ireland Ltd. All rights reserved.