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中国临床药理学与治疗学 ›› 2005, Vol. 10 ›› Issue (4): 456-461.

• 研究原著 • 上一篇    下一篇

表皮生长因子受体酪氨酸激酶抑制剂 BPI-2009的抗肿瘤作用及其机制的研究

邬楠1, 王爱平1, 王印祥1,2   

  1. 1中国医学科学院中国协和医科大学新药安全评价研究中心, 北京 100050;
    2贝达(浙江) 药业有限公司北京新药研发中心, 北京 100176
  • 收稿日期:2004-12-08 修回日期:2005-01-15 出版日期:2005-04-26 发布日期:2020-11-19
  • 通讯作者: 王印祥,男, 博士, 教授, 研究方向:肿瘤药理学。Tel:010-67869691 E-mail:yinxiang.wang@betapharma.com
  • 作者简介:邬楠, 女, 硕士生, 研究方向:药理学。Tel:010-63165210 E-mail:nan7111@hotmail.com

Effects and mechanisms of epidermal growth factor receptor of tyrosine kinase on cancer

WU Nan1, WANG Ai-ping1, WANG Yin-xiang1,2   

  1. 1New DrugsSafety Evaluation Center, Chinese Academic of Medical Science and Peking Union Medical College, Beijing100050, China;
    2NewDrug Research Center in Beijing, Beta (Zhejiang) Pharma Inc. , Beijing100176, China
  • Received:2004-12-08 Revised:2005-01-15 Online:2005-04-26 Published:2020-11-19

摘要: 目的: 探讨一种口服的表皮生长因子受体(epidermal growth factor receptor, EGFR) 酪氨酸激酶抑制剂(BPI-2009) 的抗肿瘤作用及其机制。方法: Western blot 方法检测 BPI-2009 对 酪氨酸激酶和EGFR自动磷酸化的抑制作用, MTT 法检测 BPI-2009对多种肿瘤细胞的生长抑制作用, 使用A431 肿瘤模型的荷瘤裸鼠进行体内的肿瘤抑制试验。结果: 通过对 EGFR激酶抑制剂化学文库的筛选, 发现 BPI-2009是一个有效的 EGFR 激酶抑制剂。BPI-2009 对EGFR 激酶的半数抑制浓度(IC50) 为 5 nmol°L-1, 当其浓度达到 62.5 nmol°L-1 的时候可以完全抑制EGFR激酶的活性, 但在 100 nmol°L-1 时对 Abl 、Abl相关基因(Abl-related genes, Arg) 以及 c-Src 酪氨酸激酶都没有明显的抑 制作用。 BPI-2009 可以 阻断EGFR介导的细胞内蛋白酪氨酸的磷酸化, IC 50 为45 nmol°L-1。在肿瘤细胞生长抑制试验中, BPI-2009 对于肿瘤细胞的生长抑制作用与 EGFR在细胞中的表达密切相关。人类肿瘤细胞 A431 移植瘤抑制试验的研究表明 BPI-2009 经口给药每天 1 次在100 mg°kg-1, 肿瘤抑制率达 64%, 有明显的剂量效应关系, 并没有发现明显的病态和体重下降。结论: BPI-2009 是一种有效的高选择性的以 EGFR 酪氨酸激酶为靶点的抗肿瘤药物。

关键词: 酪氨酸激酶, 表皮生长因子受体(EGFR), 自动磷酸化, 细胞生长抑制, 抗肿瘤作用

Abstract: AIM: To investigate the effects and mechanisms of BPI-2009, an orally active inhibitor of EGFR (Epidermal Growth Factor Receptor) tyrosine ki-nase on cancer therapy, and evaluate BPI-2009 as an an-ti-cancer drug targeting EGFR.METHODS: The tyro-sine kinase inhibition and the EGFR autophosphorylation inhibition of BPI-2009 were detected by Western Blot analysis.Cell growth inhibition was determined by MTT assays.In vitro tumor xenografts studies were tested in nude mice carried with A431 epidermoid tumor xenografts.RESULTS: BPI-2009, a leading com-pounds, was a potent inhibitor of EGFR kinase with an IC 50 of 5 nmol°L-1 (completed inhibitory concentration at 62.5 nmol°L-1), and it had no inhibitory activities a-gainst Abl, Abl-related gene (Arg) and c-Src tyrosine ki-nases at 100 nmol°L-1. BPI-2009 blocked EGFR-medi-ated intracellular tyrosine phosphorylation (IC50 45nmol°L-1) in the human epidermoidA431 carcinoma cell line.In cell proliferation assays, tumor cell growth was inhibited by BPI-2009 in the presence of FCS.In studies of nude mice which carried human-derived tumor, BPI-2009 produced significant and dose-dependent anti-tumor effects (human epidermoid A431 carcinoma). When oral-ly administered 100 mg°kg-1 BPI-2009 once a day, total 24 days in mice, there was no mortality or obviously body weight loss during the treatment. CONCLUSION: BPI-2009 isan selective anti-cancer drug targeting EGFR tyro-sine kinase.

Key words: tyrosine kinase, epidermal growth factor receptor (EFGR), autophosphorylation, cell growth inhi-bition, anti-cancer effect

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