Flk-1 as a target for tumor growth inhibition

Laurie M. Strawn, Gerald McMahon, Harald App, Randall Schreck, William R. Kuchler, Michael P. Longhi, Terence H. Hui, Cho Tang, Alexander Levitzki, Aviv Gazit, Irit Chen, Gyorgy Keri, Laszlo Orfi, Werner Risau, Ingo Flamme, Axel Ullrich, K. Peter Hirth, Laura K. Shawver

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Abstract

A number of growth factor receptor tyrosine kinases have been implicated in angiogenesis, including epidermal growth factor receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor, Flk-1/KDR, Flt-1, Tie-1, and Tek/Tie-2. Flk-1/KDR, a receptor for vascular endothelial growth factor (VEGF), is expressed exclusively in endothelial cells. Using dominant-negative methods, Flk-1 was shown to play a role in angiogenesis and the growth of a variety of tumor types. Because of this, a drug discovery effort was established to identify Flk-1 kinase inhibitors. For initial screening, an ELISA in a 96-well format was used to measure VEGF-induced Flk- 1 tyrosine phosphorylation in whole cells. Compounds that inhibited ligand- induced receptor autophosphorylation were confirmed by antiphosphotyrosine immunoblotting. Inhibition of VEGF-stimulated DNA synthesis in human endothelial cells was also assessed. Inhibitors were further evaluated for their effects on vessel formation using the chorioallantoic membrane assay. Using these methods, antiangiogenesis compounds that inhibit Flk-1 tyrosine kinase activity, endothelial cell mitogenesis, and blood vessel formation in the chorioallantoic membrane assay have been found.

Original languageEnglish
Pages (from-to)3540-3545
Number of pages6
JournalCancer Research
Volume56
Issue number15
Publication statusPublished - Aug 1 1996

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Strawn, L. M., McMahon, G., App, H., Schreck, R., Kuchler, W. R., Longhi, M. P., Hui, T. H., Tang, C., Levitzki, A., Gazit, A., Chen, I., Keri, G., Orfi, L., Risau, W., Flamme, I., Ullrich, A., Hirth, K. P., & Shawver, L. K. (1996). Flk-1 as a target for tumor growth inhibition. Cancer Research, 56(15), 3540-3545.