Vertebrate embryos as tools for anti-angiogenic drug screening and function

Abstract

The development of new angiogenic inhibitors highlights a need for robust screening assays that adequately capture the complexity of vessel formation, and allow for the quantitative evaluation of the teratogenicity of new anti-angiogenic agents. This review discusses the use of screening assays in vertebrate embryos, specifically focusing upon chicken and zebrafish embryos, for the detection of anti-angiogenic agents.

“The legacy of thalidomide” ‐ A multidisciplinary meeting held at the University of York, United Kingdom, on September 30, 2016

“…Indeed, he described how the drug's actions on blood vessels can result in a range of limb damage (Vargesson, , ; Vargesson and Hootnick, ). He also described the advances his team has made in finding a “safe” form of the drug, retaining the clinical benefits but without the side‐effect of embryonic damage (Beedie et al, ). This is extremely relevant today as sadly new generations of thalidomide children have been born in recent decades in Brazil as the original drug is used to treat a form of Leprosy (Schuler‐Faccini et al, ; Vianna et al, ; Vargesson, ).…”

The Primodos components Norethisterone acetate and Ethinyl estradiol induce developmental abnormalities in zebrafish embryos

“…Previously we have shown that drugs such as thalidomide and some of its analogs 35 , 37 – 39 as well as antiangiogenic agents such as Sunitinib 29 , 34 cause damage to a range of tissues including the fins, otic vesicle and eyes through disrupting blood vessel formation. To investigate if blood vessel loss or patterning defects occur in zebrafish embryos following NA/EE-mixture exposure we used the transgenic fli1 :EGFP reporter line of zebrafish embryos 40 .…”

“…The zebrafish embryo has become increasingly popular in drug screening assays due to its rapid development, optical transparency and the ability to visualise and follow development live and in vivo 29 . Indeed, many drugs have actions in zebrafish embryos that are similar to actions in mammalian species including humans.…”

“…For example, thalidomide exposure causes damage in zebrafish embryos in similar or equivalent tissues damaged in humans following thalidomide exposure 30 – 33 . Furthermore, zebrafish embryos are becoming increasingly popular to screen compounds to identify lead compounds that could be used for further analysis in mammalian species and/or to determine if compounds may have harmful effects 29 , 30 , 34 – 37 .…”

The teratogenic effects of thalidomide on limbs

“…We also know that thalidomide survivors themselves exhibit a wide range of cardiovascular changes, including heart defects, some of which might actually contribute to the differences seen in thalidomide survivors (Tajima et al, 2016; see also Vargesson and Hootnick, 2017). In further support of this mechanism, multiple anti-angiogenic drugs used as anti-cancer agents, for example sunitinib and sorafenib (Beedie et al, 2016a), which induce cell death, have a wide range of molecular targets and all of these can cause limb damage (Beedie et al, 2016a(Beedie et al, , 2017. This indicates that vessel inhibition is a key element underlying druginduced limb defects.…”