• Weiguo Jian, Jonathan M Levitt, Seth P Lerner, and Guru Sonpavde.
• Department of Urology, Baylor College of Medicine, Houston, TX, U.S.A.
• Anticancer Res. 2014 Jul 1;34(7):3377-82.

BackgroundAngiopoietin/Tyrosine Kinase-2 (ANG/TIE2), Fibroblast Growth Factor-1 (FGFR1) and Vascular Endothelial Growth Factor Receptors (VEGFRs) promote growth of urothelial carcinoma (UC). We examined the pre-clinical activity of CEP-11981, a tyrosine kinase inhibitor of TIE2, FGFR1 and VEGFR-1-3, in UC.Materials And MethodsThe in vitro activity of CEP-11981 was evaluated in four human UC cell lines. The effect of daily oral CEP-11981 was examined in RT4 xenografts, which also underwent immunohistochemistry (IHC) for cleaved caspase-3, Cluster of Differentiation (CD)-31, VEGFR2 and TIE2.ResultsIn vitro activity was not detected. Preliminary in vivo experiments suggested that CEP-11981 at both 5 mg/kg and 10 mg/kg induced similar regression of xenografts, greater than those at 2.5 mg/kg daily. Given the lower toxicity at 5 mg/kg, we performed a confirmatory experiment with 5 mg/kg, which significantly inhibited xenografts compared to controls (p<0.05). IHC of xenografts demonstrated no differences in CD31, cleaved caspase-3 or VEGFR2, but TIE2 was significantly down-regulated (p=0.008) by CEP-11981.ConclusionCEP-11981 demonstrated a significant pre-clinical activity against human UC xenografts, which was attributable primarily to effects on TIE2 receptor.Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

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