Shared mechanism of teratogenicity of anti-angiogenic drugs identified in the chicken embryo model.

Shaunna L Beedie,Cindy H Chau,Neil Vargesson,Chris Mahony,William D Figg,Heather M Walker

doi:10.1038/srep30038

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.

Highlights

Angiogenesis, the formation of new blood vessels, is essential for tumor growth, stabilization and progression
We investigated a variety of angiogenesis inhibitors with different molecular targets including the small-molecule tyrosine kinase inhibitors sunitinib, vandetanib, pazopanib, axitinib, and sorafenib, the mammalian target of rapamycin inhibitor everolimus, the methionine aminopeptidase 2 inhibitor TNP-470 and CPS49
In order to confirm the inhibitory effect of the compounds on blood vessel formation and to establish an IC50 for the compounds in vitro we applied the compounds to an endothelial cell line, Human Umbilical Venous Endothelial Cells (HUVEC) (n = 9)

Summary

Introduction

Angiogenesis, the formation of new blood vessels, is essential for tumor growth, stabilization and progression. Given that the teratogenic drug thalidomide is thought to produce embryonic defects by inhibition of growth of naive, newly forming blood vessels, it is possible that anti-angiogenic drugs used during pregnancy could induce birth defects in a developing embryo[19,20,21,22,23]. Because of this possibility, the regulatory approvals state a contraindication of use during pregnancy within the packaging and safety information. Our study aims to determine if all the drugs tested target newly forming vessels to cause defect, and if the defects are comparable, regardless of the differing downstream molecular targets

Methods

Results

Conclusion