Li Jing, Li Yan, Feng Zhi-Qiang, Chen Xiao-Guang
Institute of Material Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Xian Nong Tan Street, Beijing 100050, PR China.
Cancer Lett. 2009 Jul 8;279(2):213-20. doi: 10.1016/j.canlet.2009.01.042. Epub 2009 Mar 18.
Epidermal growth factor receptor (EGFR) is highly expressed in many human tumors including non-small cell lung cancer (NSCLC). Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has led to dramatic clinical improvement in selected patients with NSCLC. However, intrinsic and acquired resistance to EGFR-TKI remains a common phenomenon. Novel EGFR-TKI, structurally different with erlotinib or gefitinib might be beneficial for patients with NSCLC. In this study, we examined the anti-tumor effect of a newly synthesized novel EGFR tyrosine kinase inhibitor N-(3-chloro-4-fluorophenyl)-N-(7-methoxy-6-(3-morpholinopropoxy) quinazolin-4-yl)-3,3-dimethylbutanamide (F90). In vitro studies in a panel of three different human NSCLC cell lines revealed that F90 inhibited cell proliferation with high potency and induced G0/G1 arrest of cell cycle and apoptosis. F90 markedly reduced phosphorylation of EGFR and inhibited activation of MAPK and Akt. Oral administration of F90 (80mg/kg/day) to BALB/c nude mice bearing NSCLC cell lines xenografts significantly retarded tumor growth. In conclusion, F90 has potent anti-tumor activity on human lung cancer in vitro and in vivo.
表皮生长因子受体（EGFR）在包括非小细胞肺癌（NSCLC）在内的许多人类肿瘤中高表达。用表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）治疗已使部分NSCLC患者的临床症状得到显著改善。然而，对EGFR-TKI的内在和获得性耐药仍然是一种常见现象。结构上与厄洛替尼或吉非替尼不同的新型EGFR-TKI可能对NSCLC患者有益。在本研究中，我们检测了新合成的新型EGFR酪氨酸激酶抑制剂N-(3-氯-4-氟苯基)-N-(7-甲氧基-6-(3-吗啉丙氧基)喹唑啉-4-基)-3,3-二甲基丁酰胺（F90）的抗肿瘤作用。在三种不同的人NSCLC细胞系中的体外研究表明，F90高效抑制细胞增殖，诱导细胞周期的G0/G1期阻滞和凋亡。F90显著降低EGFR的磷酸化水平，并抑制MAPK和Akt的激活。对携带NSCLC细胞系异种移植瘤的BALB/c裸鼠口服给予F90（80mg/kg/天）可显著延缓肿瘤生长。总之，F90在体外和体内对人肺癌均具有强大的抗肿瘤活性。
