血小板源性生长因子受体
酪氨酸激酶抑制剂
酪氨酸激酶
化学
激酶插入结构域受体
药理学
受体酪氨酸激酶
磷酸化
酪氨酸磷酸化
激酶
癌症研究
分子生物学
生物
血管内皮生长因子
受体
生长因子
血管内皮生长因子A
生物化学
癌症
血管内皮生长因子受体
遗传学
作者
Sandra R. Brave,Kirsty Ratcliffe,Zena Wilson,Neil H. James,Susan Ashton,Anna Wainwright,Jane Kendrew,Phillippa Dudley,Nicola Broadbent,Graham Sproat,Sian Taylor,Claire H. Barnes,Jeffrey C. Silva,Charles L. Farnsworth,Laurent Hennequin,Donald Ogilvie,Juliane M. Jürgensmeier,Masabumi Shibuya,Stephen R. Wedge,Simon T. Barry
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2011-05-01
卷期号:10 (5): 861-873
被引量:79
标识
DOI:10.1158/1535-7163.mct-10-0976
摘要
Abstract Cediranib is a potent inhibitor of the VEGF receptor (VEGFR)-2 and VEGFR-3 tyrosine kinases. This study assessed the activity of cediranib against the VEGFR-1 tyrosine kinase and the platelet-derived growth factor receptor (PDGFR)-associated kinases c-Kit, PDGFR-α, and PDGFR-β. Cediranib inhibited VEGF-A–stimulated VEGFR-1 activation in AG1-G1-Flt1 cells (IC50 = 1.2 nmol/L). VEGF-A induced greatest phosphorylation of VEGFR-1 at tyrosine residues Y1048 and Y1053; this was reversed by cediranib. Potency against VEGFR-1 was comparable with that previously observed versus VEGFR-2 and VEGFR-3. Cediranib also showed significant activity against wild-type c-Kit in cellular phosphorylation assays (IC50 = 1–3 nmol/L) and in a stem cell factor–induced proliferation assay (IC50 = 13 nmol/L). Furthermore, phosphorylation of wild-type c-Kit in NCI-H526 tumor xenografts was reduced markedly following oral administration of cediranib (≥1.5 mg/kg/d) to tumor-bearing nude mice. The activity of cediranib against PDGFR-β and PDGFR-α was studied in tumor cell lines, vascular smooth muscle cells (VSMC), and a fibroblast line using PDGF-AA and PDGF-BB ligands. Both receptor phosphorylation (IC50 = 12–32 nmol/L) and PDGF-BB–stimulated cellular proliferation (IC50 = 32 nmol/L in human VSMCs; 64 nmol/L in osteosarcoma cells) were inhibited. In vivo, ligand-induced PDGFR-β phosphorylation in murine lung tissue was inhibited by 55% following treatment with cediranib at 6 mg/kg but not at 3 mg/kg or less. In contrast, in C6 rat glial tumor xenografts in mice, ligand-induced phosphorylation of both PDGFR-α and PDGFR-β was reduced by 46% to 61% with 0.75 mg/kg cediranib. Additional selectivity was showed versus Flt-3, CSF-1R, EGFR, FGFR1, and FGFR4. Collectively, these data indicate that cediranib is a potent pan-VEGFR kinase inhibitor with similar activity against c-Kit but is significantly less potent than PDGFR-α and PDGFR-β. Mol Cancer Ther; 10(5); 861–73. ©2011 AACR.
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