What is the mechanism of action of thalidomide?
First established as agents with antiangiogenic properties, thalidomide and IMiDs inhibit the production of interleukin (IL)-6, which is a growth factor for the proliferation of myeloma cells. In addition, they activate apoptotic pathways through caspase 8-mediated cell death.
How does thalidomide cause teratogenesis?
Our data suggest that thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting its ubiquitin ligase activity.
What process does thalidomide affect?
The mechanisms behind birth defects induced by thalidomide involve its teratogenic ability to bypass an intrinsically important embryonic defense system that is responsible for preventing toxic substances from entering embryonic cells as well as escorting tagged toxicants out of the cell.
What is effect of thalidomide teratogenicity?
Teratogenicity is the most severe and well-known adverse effect associated with thalidomide. Babies born with malformations such as amelia, phocomelia, bone hypoplasia and absence of bones resulted from the thalidomide tragedy.
What is the thalidomide tragedy?
In November 1961, thalidomide was taken off the market due to massive pressure from the press and public. Experts estimate that thalidomide led to the death of approximately 2,000 children and serious birth defects in more than 10,000 children, about 5,000 of them in West Germany.
How does thalidomide affect limb development?
Our data clearly demonstrate that the primary cause of thalidomide-induced limb malformations is the loss of the forming limb vasculature. As a consequence, changes in cell death and loss of gene signaling pathways then result.
How does thalidomide cause Phocomelia?
Phocomelia remains the most striking limb deformity caused by thalidomide, and remains the stereotypical image of thalidomide embryopathy. Phocomelia occurs through a severe shortening of the limb/s, due to proximal elements (long bones) being reduced or missing and leaving distal elements (handplate) in place.
How does thalidomide affect prenatal development?
Thalidomide can cause severe, life-threatening birth defects or death of a baby if the mother or the father is taking this medicine at the time of conception or during pregnancy. Even one dose of thalidomide can cause major birth defects of the baby’s arms and legs, bones, ears, eyes, face, and heart.
How does thalidomide affect fetal development?
The degradation of SALL4 interferes with limb development and other aspects of fetal growth. The result is the spectrum of complications indelibly linked to thalidomide: the deformed limbs and defective organs in children whose mothers took thalidomide during pregnancy as a treatment for morning sickness.
What is Revlimid and how does it compare to thalidomide?
Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties that inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells, including MM, mantle cell lymphoma, and del (5q) MDS.
Much is known about thalidomide’s mechanism of action underlying its anti‐inflammatory and anti‐myeloma activities in human adults, than its teratogenic activities. Thalidomide inhibits TNF‐α expression rapidly, vital for the inflammatory response.
How does thalidomide intercalate into DNA?
One of the proposed mechanisms of the teratogenic action of thalidomide is that thalidomide intercalates into DNA [36]. Jönsson [36] proposed that a stacked complex is formed between the flat double phthalimide rings of thalidomide and deoxyguanosine.
What is the PMCID for thalidomide‐induced teratogenesis?
PMCID: PMC4737249 PMID: 26043938 Thalidomide‐induced teratogenesis: History and mechanisms Neil Vargesson1 Neil Vargesson 1School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom Find articles by Neil Vargesson
Why are thalidomide analogs not teratogenic while retaining TNF-alpha activity?
Intercalation into G-rich promoter regions of DNA may explain why certain thalidomide analogs are not teratogenic while retaining their anti-tumor necrosis factor-alpha (TNF-alpha) activity, and suggests that we look elsewhere to explain the action of thalidomide on TNF-alpha.