Knobloch J, Jungck D, Koch A
Medical Clinic III, Bergmannsheil University Hospital, Bürkle-de-la-Camp-Platz 1, 44789 Bochum. Germany.
Department for Internal Medicine II, Pneumology, Allergology and Respiratory Medicine, Bethel Teaching Hospital, Berlin. Germany.
Curr Mol Med. 2017;17(2):108-117. doi: 10.2174/1566524017666170331162315.
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.
沙利度胺是一种致畸剂，会影响多个器官，但主要会导致肢体截断，如海豹肢畸形。啮齿动物对沙利度胺具有抗性。在20世纪50年代，这导致了对动物试验的错误解读，并产生了致命的假设，即该药物对孕妇使用以缓解孕吐是安全的。结果是医学史上最大的丑闻之一：欧洲有10000多名婴儿患有出生缺陷。尽管如此，沙利度胺在现代医学中仍有一席之地，因为它具有强大的治疗潜力：它已被美国食品药品监督管理局批准用于治疗多发性骨髓瘤和麻风结节性红斑，并且其抗炎、免疫调节和抗血管生成活性在许多其他难治性疾病中也受到关注。目标是开发出无致畸性但保留治疗潜力的衍生物。这需要对潜在的分子机制有详细的了解。在过去十年中，在破译致畸机制方面已经取得了很大进展。在这里，我们总结这些机制，解释啮齿动物对沙利度胺的抗性，并讨论可能解释该药物为何主要靶向胚胎发育中的肢体的机制。我们还总结了最重要的治疗机制。最后，我们讨论哪些治疗机制和致畸机制重叠以及哪些不重叠，以及是否有机会开发出具有治疗潜力的无致畸性沙利度胺衍生物。
