School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom.
Proc Natl Acad Sci U S A. 2013 Jul 30;110(31):12703-8. doi: 10.1073/pnas.1307684110. Epub 2013 Jul 15.
Thalidomide and its analog, Lenalidomide, are in current use clinically for treatment of multiple myeloma, complications of leprosy and cancers. An additional analog, Pomalidomide, has recently been licensed for treatment of multiple myeloma, and is purported to be clinically more potent than either Thalidomide or Lenalidomide. Using a combination of zebrafish and chicken embryos together with in vitro assays we have determined the relative anti-inflammatory activity of each compound. We demonstrate that in vivo embryonic assays Pomalidomide is a significantly more potent anti-inflammatory agent than either Thalidomide or Lenalidomide. We tested the effect of Pomalidomide and Lenalidomide on angiogenesis, teratogenesis, and neurite outgrowth, known detrimental effects of Thalidomide. We found that Pomalidomide, displays a high degree of cell specificity, and has no detectable teratogenic, antiangiogenic or neurotoxic effects at potent anti-inflammatory concentrations. This is in marked contrast to Thalidomide and Lenalidomide, which had detrimental effects on blood vessels, nerves, and embryonic development at anti-inflammatory concentrations. This work has implications for Pomalidomide as a treatment for conditions Thalidomide and Lenalidomide treat currently.
沙利度胺及其类似物来那度胺目前临床上用于治疗多发性骨髓瘤、麻风病并发症和癌症。最近,另一种类似物泊马度胺已获得许可用于治疗多发性骨髓瘤,据称其临床疗效强于沙利度胺或来那度胺。我们使用斑马鱼和鸡胚胎以及体外测定法来确定每种化合物的相对抗炎活性。我们证明,体内胚胎测定法显示泊马度胺是一种比沙利度胺或来那度胺更有效的抗炎剂。我们测试了泊马度胺和来那度胺对血管生成、致畸和神经突生长的影响,这些是沙利度胺的已知有害作用。我们发现泊马度胺表现出高度的细胞特异性,在有效的抗炎浓度下没有可检测到的致畸、抗血管生成或神经毒性作用。这与沙利度胺和来那度胺形成鲜明对比,它们在抗炎浓度下对血管、神经和胚胎发育有不良影响。这项工作对泊马度胺作为沙利度胺和来那度胺目前治疗的疾病的治疗方法具有重要意义。