Thalidomide is a teratogen that affects many organs but primarily induces limb
truncations like phocomelia. Rodents are thalidomide resistant. In the 1950s, this has led
to misinterpretations of animal tests and to the fatal assumption that the drug was safe
for pregnant women to use against morning sickness. The result was one of the biggest
scandals in medical history: 10.000 and more infants with birth defects in Europe.
Nonetheless, thalidomide still has its place in modern medicine as it has strong
therapeutic potential: it has been approved by the FDA for multiple myeloma and
erythema nodosum leprosum, and its anti-inflammatory, immunomodulatory and antiangiogenic
activities are considered in many other refractory diseases. The aim is to
develop derivatives that are not teratogenic but maintain the therapeutic potential. This
requires detailed knowledge about the underlying molecular mechanisms. Much
progress has been made in deciphering the teratogenic mechanisms in the last decade.
Here, we summarize these mechanisms, explain thalidomide resistance of rodents, and
discuss possible mechanisms that could explain why the drug primarily targets the
developing limb in the embryo. We also summarize the most important therapeutic
mechanisms. Finally, we discuss which therapeutic and teratogenic mechanisms do and
do not overlap, and if there is a chance for the development of non-teratogenic
thalidomide derivatives with therapeutic potential.
Keywords: Teratogen, limb truncations, oxidative stress, angiogenesis, CRBN, TNFα, inflammation, anti-cancer
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