Journal
BLOOD
Volume 114, Issue 5, Pages 1110-1122Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-03-211771
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Funding
- Roche Research Foundation
- National Institutes of Health [CA69184]
- Swiss National Science Foundation [3100A0108207, 3100A0-114102]
- Austrian Science Foundation [S9408-B11]
- Cancer League Zurich
- European Community [LSHC-CT2005-518178, LSHG-CT-2004-005085]
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Angiogenesis and lymphangiogenesis are essential for organogenesis but also play important roles in tissue regeneration, chronic inflammation, and tumor progression. Here we applied in vivo forward chemical genetics to identify novel compounds and biologic mechanisms involved in (lymph) angiogenesis in Xenopus tadpoles. A novel 2-step screening strategy involving a simple phenotypic read-out (edema formation or larvallethality) followed by semiautomated in situ hybridization was devised and used to screen an annotated chemical library of 1280 bioactive compounds. We identified 32 active compounds interfering with blood vascular and/or lymphatic development in Xenopus. Selected compounds were also tested for activities in a variety of endothelial in vitro assays. Finally, in a proof-of-principle study, the adenosine A1 receptor antagonist 7-chloro-4-hydroxy-2-phenyl-1,8-naphthyridine, an inhibitor of blood vascular and lymphatic development in Xenopus, was shown to act also as a potent antagonist of VEGFA-induced adult neovascularization in mice. Taken together, the present chemical library screening strategy in Xenopus tadpoles represents a rapid and highly efficient approach to identify novel pathways involved in ( lymph) angiogenesis. In addition, the recovered compounds represent a rich resource for in-depth analysis, and their drug-like features will facilitate further evaluation in preclinical models of inflammation and cancer metastasis. (Blood. 2009; 114:1110-1122)
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