Thalidomide Embryopathy: An Enigmatic Challenge

Vargesson, Neil

doi:10.1155/2013/241016

Cited by 53 publications

(113 citation statements)

References 180 publications

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“…Moreover, anti-angiogenic analogs of thalidomide cause teratogenic effects by inhibiting the growth of newly forming vessels (2, 3, 5). fli 1:EGFP zebrafish, which are known to be sensitive to teratogens (5, 27, 28), were used to assess the ability of Gu compounds to affect the development of the forming vasculature.…”

Section: Resultsmentioning

confidence: 99%

“…Thalidomide exhibits anti-inflammatory actions (1-3) and its analog, lenalidomide, is known to be clinically effective in the treatment of multiple myeloma via its anti-inflammatory properties (35, 36). We therefore tested the Gu compounds to determine if they have an effect on the inflammatory response.…”

Section: Resultsmentioning

confidence: 99%

“…The chicken embryo is a well-established system to study teratogenesis and the effects of drugs upon development (2, 3, 5, 28, 33). Gu998 and Gu992 were shown to be teratogenic, causing limb, spinal and head defects as well as causing a high death rate.…”

Section: Discussionmentioning

confidence: 99%

“…Shortly thereafter, it was found that thalidomide had adverse effects upon fetal development, leading to multiple severe deformities in newborns, including phocomelia (shortening of the long bones of the limbs), as well as causing miscarriages (1-3). The mechanism for these teratogenic effects has since been linked to thalidomide having anti-angiogenic characteristics (4, 5).…”

Section: Introductionmentioning

confidence: 99%

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Anticancer Properties of a Novel Class of Tetrafluorinated Thalidomide Analogues

Beedie

Peer

Pisle

et al. 2015

Molecular Cancer Therapeutics

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Thalidomide has demonstrated clinical activity in various malignancies affecting immunomodulatory and angiogenesis pathways. The development of novel thalidomide analogs with improved efficacy and decreased toxicity is an ongoing research effort. We recently designed and synthesized a new class of compounds, consisting of both tetrafluorinated thalidomide analogs (Gu973 and Gu998) and tetrafluorobenzamides (Gu1029 and Gu992). In this study, we demonstrate the anti-angiogenic properties of these newly synthesized compounds. We examined the specific anti-angiogenic characteristics in vitro using rat aortic rings with carboxyamidotriazole as a positive control. Additionally, further in vitro efficacy was evaluated using HUVECs and PC3 cells treated with 5μM and 10μM doses of each compound. All compounds were seen to reduce microvessel outgrowth in rat aortic rings as well as inhibit HUVECs to a greater extent, at lower concentrations than previously tested thalidomide analogs. The anti-angiogenic properties of the compounds was also examined in vivo in fli1:EGFP zebrafish embryos, where all compounds were seen to inhibit the extent of outgrowth of newly developing blood vessels. In addition, Gu1029 and Gu973 reduced the anti-inflammatory response in mpo:GFP zebrafish embryos, while Gu998 and Gu992 showed no difference. The compounds anti-tumor effects were also explored in vivo using the human prostate cancer PC3 xenograft model. All four compounds were also screened in vivo in chicken embryos to investigate their teratogenic potential. This study establishes these novel thalidomide analogs as a promising immunomodulatory class with anti-cancer effects that warrant further development to characterize their mechanisms of action.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Anticancer Properties of a Novel Class of Tetrafluorinated Thalidomide Analogues

Beedie

Peer

Pisle

et al. 2015

Molecular Cancer Therapeutics

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“…Perhaps surprisingly, thalidomide has little effect on rodent embryos, so research on its actions has necessarily been carried out on other organisms (Vargesson, 2013). Initial studies indicated that thalidomide is harmful to early chick embryos and injection into the yolk caused facial and spinal anomalies and shortening and stunting of the legs (Boylen et al, 1963).…”

Section: Studies In the Chick On Limb Deficiencies Produced By Thalidmentioning

confidence: 99%

The chick limb: embryology, genetics and teratology

Davey¹,

Towers²,

Vargesson³

et al. 2018

Int. J. Dev. Biol.

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The chick embryo has a long history in investigations of vertebrate limb development because of the ease with which its limbs can be experimentally manipulated. Early studies elucidated the fundamental embryology of the limb and identified the key signalling regions that govern its development. The chick limb became a leading model for exploring the concept of positional information and understanding how patterns of differentiated cells and tissues develop in vertebrate embryos. When developmentally important molecules began to be identified, experiments in chick limbs were crucial for bridging embryology and molecular biology. The embryological mechanisms and molecular basis of limb development are largely conserved in mammals, including humans, and uncovering these molecular networks provides links to clinical genetics. We emphasise the important contributions of naturally occurring chick mutants to elucidating limb embryology and identifying novel developmentally important genes. In addition, we consider how the chick limb has been used to study mechanisms involved in teratogenesis with a focus on thalidomide. These studies on chick embryos have given insights into how limb defects can be caused by both genetic changes and chemical insults and therefore are of great medical significance.

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Molecular Genetics of Human Congenital Limb Malformations

Pickering

Towers

2014

Encyclopedia of Life Sciences

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Congenital limb malformations are observed in approximately 1 in 500 people making them one of the most frequent birth defects. Increasing numbers of genes are being identified that when functionally perturbed result in human limb abnormalities. The functions of many of these genes have been investigated in the two main models of limb development – the chick and the mouse. Limb defects are often part of complex syndromes that affect other structures in the body. This reflects the multiple roles that many genes play during embryonic development. Recently, an emerging theme is that the disruption of cis ‐regulatory enhancers controlling expression of important developmental genes can lead to limb‐specific birth defects. Future research focusing on how the human limb develops will increase our understanding of the molecular and genetic basis of congenital defects. Key Concepts: Chick and mouse embryology has contributed to our knowledge of limb development and the basis of human limb defects. Many key patterning genes found in mouse and chick research cause human limb defects when mutated. Limb defects are often part of complex syndromes. Defects which affect only the limb are often caused by disruption of cis ‐regulatory enhancers. Future work on how the human limb develops will further our understanding of congenital defects.

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Thalidomide Embryopathy: An Enigmatic Challenge

Cited by 53 publications

References 180 publications

Anticancer Properties of a Novel Class of Tetrafluorinated Thalidomide Analogues

Anticancer Properties of a Novel Class of Tetrafluorinated Thalidomide Analogues

The chick limb: embryology, genetics and teratology

Molecular Genetics of Human Congenital Limb Malformations

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