AZD2171 shows potent antitumor activity against gastric cancer over-expressing fibroblast growth factor receptor 2/keratinocyte growth factor receptor
AZD2171 shows potent antitumor activity against gastric cancer over-expressing fibroblast growth factor receptor 2/keratinocyte growth factor receptor
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DOI：
10.1158/1078-0432.ccr-06-2743
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发表时间：
2007-05-15
影响因子：
11.5
通讯作者：
Nishio, Kazuto
中科院分区：
文献类型：
--
作者：
Takeda, Masayuki;Arao, Tokuzo;Nishio, Kazuto
目的：AZD 2171是一种口服、高效、选择性血管内皮生长因子信号传导抑制剂，可抑制所有血管内皮生长因子受体酪氨酸激酶。本研究的目的是研究AZD 2171在胃癌中的活性。实验设计：我们在体外和体内检测AZD 2171对8种胃癌细胞系的抗肿瘤作用。AZD 2171对两种胃癌细胞株的生长有直接抑制作用（KATO-III和OATO 2 M），IC 50分别为0.15和0.37 μ mol/L，比表皮生长因子受体酪氨酸激酶抑制剂吉非替尼更有效。逆转录-PCR实验和免疫印迹显示，敏感的细胞系主要表达COOH末端截短的成纤维细胞生长因子受体2（FGFR 2）剪接变体，组成性磷酸化和自发二聚化。在敏感细胞系中，AZD 2171在比其他细胞系低10倍的浓度（0.1 μ mol/L）下可完全抑制FGFR 2和下游信号蛋白（FRS 2、AKT和丝裂原活化蛋白激酶）的磷酸化。体外激酶试验表明，AZD 2171抑制免疫沉淀FGFR 2的激酶活性，Ki值低于微摩尔（与0.05 μ mol/L相似）。最后，我们评估了AZD 2171在小鼠人胃肿瘤异种移植模型中的抗肿瘤活性。AZD 2171（1.5或6 mg/kg/d）经口给药可显著抑制KATO-III和OATO 2 M肿瘤异种移植小鼠的肿瘤生长，且呈剂量依赖性。结论：AZD 2171对过表达FGFR 2的胃癌异种移植瘤具有强效抗肿瘤活性。这些临床前研究的结果表明，AZD 2171可能为某些类型的胃癌患者提供临床获益。
Purpose: AZD2171 is an oral, highly potent, and selective vascular endothelial growth factor signaling inhibitor that inhibits all vascular endothelial growth factor receptor tyrosine kinases. The purpose of this study was to investigate the activity of AZD2171 in gastric cancer.Experimental Design: We examined the antitumor effect of AZD2171 on the eight gastric cancer cell lines in vitro and in vivo.Results: AZD2171 directly inhibited the growth of two gastric cancer cell lines (KATO-III and OCUM2M), with an IC50 of 0.15 and 0.37 mu mol/L, respectively, more potently than the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib. Reverse transcription-PCR experiments and immunoblotting revealed that sensitive cell lines dominantly expressed COOH terminus truncated fibroblast growth factor receptor 2 (FGFR2) splicing variants that were constitutively phosphorylated and spontaneously dimerized. AZD2171 completely inhibited the phosphorylation of FGFR2 and downstream signaling proteins (FRS2, AKT, and mitogen-activated protein kinase) in sensitive cell lines at a 10-fold lower concentration (0.1 mu mol/L) than in the other cell lines. An in vitro kinase assay showed that AZD2171 inhibited kinase activity of immunoprecipitated FGFR2 with submicromolar K-i values (similar to 0.05 mu mol/L). Finally, we assessed the antitumor activity of AZD2171 in human gastric tumor xenograft models in mice. Oral administration of AZD2171 (1.5 or 6 mg/kg/d) significantly and dose-dependently inhibited tumor growth in mice bearing KATO-III and OCUM2M tumor xenografts.Conclusions: AZD2171 exerted potent antitumor activity against gastric cancer xenografts overexpressing FGFR2. The results of these preclinical studies indicate that AZD2171 may provide clinical benefit in patients with certain types of gastric cancer.