成纤维细胞生长因子受体
血管生成
血管内皮生长因子
受体酪氨酸激酶
癌症研究
药理学
酪氨酸激酶
受体
血小板源性生长因子受体
酪氨酸激酶抑制剂
碱性成纤维细胞生长因子
成纤维细胞生长因子
医学
化学
生长因子
内科学
癌症
血管内皮生长因子受体
作者
Frank Hilberg,Gerald J. Roth,Martin Krššák,Susanna Kautschitsch,Wolfgang Sommergruber,Ulrike Tontsch-Grunt,Pilar Garin‐Chesa,Gerd Bader,Andreas Zoephel,Jens Quant,Armin Heckel,Wolfgang Rettig
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2008-06-15
卷期号:68 (12): 4774-4782
被引量:870
标识
DOI:10.1158/0008-5472.can-07-6307
摘要
Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a novel treatment modality in oncology. Preclinical findings suggest that long-term clinical outcomes may improve with blockade of additional proangiogenic receptor tyrosine kinases: platelet-derived growth factor receptors (PDGFR) and fibroblast growth factor receptors (FGFR). BIBF 1120 is an indolinone derivative potently blocking VEGF receptor (VEGFR), PDGFR and FGFR kinase activity in enzymatic assays (IC(50), 20-100 nmol/L). BIBF 1120 inhibits mitogen-activated protein kinase and Akt signaling pathways in three cell types contributing to angiogenesis, endothelial cells, pericytes, and smooth muscle cells, resulting in inhibition of cell proliferation (EC(50), 10-80 nmol/L) and apoptosis. In all tumor models tested thus far, including human tumor xenografts growing in nude mice and a syngeneic rat tumor model, BIBF 1120 is highly active at well-tolerated doses (25-100 mg/kg daily p.o.), as measured by magnetic resonance imaging of tumor perfusion after 3 days, reducing vessel density and vessel integrity after 5 days, and inducing profound growth inhibition. A distinct pharmacodynamic feature of BIBF 1120 in cell culture is sustained pathway inhibition (up to 32 hours after 1-hour treatment), suggesting slow receptor off-kinetics. Although BIBF 1120 is rapidly metabolized in vivo by methylester cleavage, resulting in a short mean residence time, once daily oral dosing is fully efficacious in xenograft models. These distinctive pharmacokinetic and pharmacodynamic properties may help explain clinical observations with BIBF 1120, currently entering phase III clinical development.
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