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

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

doi:10.1038/srep30038

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

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

National Cancer Institute United States

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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.

Original language	English
Article number	30038
Pages (from-to)	1-10
Number of pages	10
Journal	Scientific Reports
Volume	6
DOIs	https://doi.org/10.1038/srep30038
Publication status	Published - 22 Jul 2016

Bibliographical note

Acknowledgements
The authors would like to thank Maria Kisakyamaria and Scott McMenemy for preliminary experimental data. This work was supported by a Wellcome Trust-NIH PhD Studentship awarded to SB, WDF and NV (Grant number 098252/Z/12/Z). This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U.S. Government.

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Shared mechanism of teratogenicity of anti-angiogenic drugs identified in the chicken embryo model
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Neil Vargesson
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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. Weconfirmed 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 theembryo. We conclude that angiogenesis inhibitors, regardless of the moleculartarget, are teratogenic when exposed to chicken embryos.",

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N2 - 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. Weconfirmed 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 theembryo. We conclude that angiogenesis inhibitors, regardless of the moleculartarget, are teratogenic when exposed to chicken embryos.

AB - 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. Weconfirmed 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 theembryo. We conclude that angiogenesis inhibitors, regardless of the moleculartarget, are teratogenic when exposed to chicken embryos.

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

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