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

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。

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

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.