title: Shared mechanism of teratogenicity of anti-angiogenic drugs identified in the chicken embryo model.
abstract: Angiogenesis, the formation of new blood vessels, is essential for tumor growth, stabilization and progression. Angiogenesis inhibitors are now widely used in the clinic; however, there are relatively few published studies on the mechanism of their presumed teratogenic effects. To address this issue, we screened a variety of angiogenesis inhibitors in developing zebrafish and chicken embryo models to assess for developmental defects and potential teratogenic effects. We confirmed previous reports that sunitinib, sorafenib and TNP-470 are teratogenic and demonstrate that axitinib, pazopanib, vandetanib, and everolimus are also teratogens in these models. A dose response study identified the drugs inhibit HUVEC cell proliferation in vitro, and also target the developing blood vessels of embryos in vivo. This provides further evidence for the potential risk of fetal toxicity when using these drugs in a clinical setting, and emphasizes the importance of the development and maintenance of the vasculature in the embryo. We conclude that angiogenesis inhibitors, regardless of the molecular target, are teratogenic when exposed to chicken embryos.
authors.affiliation: School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK.|Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Shaunna L
authors.initials: SL
authors.lastname: Beedie
authors.affiliation: School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Mahony
authors.affiliation: School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Walker
authors.affiliation: Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Cindy H
authors.initials: CH
authors.lastname: Chau
authors.affiliation: Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.affiliation: School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Vargesson
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects*; D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D006801:Humans; D064793:Teratogenesis; D013723:Teratogens / Q000494:pharmacology*; D015027:Zebrafish / Q000196:embryology
chemical_list: D020533:Angiogenesis Inhibitors; D013723:Teratogens