Pomalidomide is nonteratogenic in chicken and zebrafish embryos and nonneurotoxic in vitro
Pomalidomide is nonteratogenic in chicken and zebrafish embryos and nonneurotoxic in vitro
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DOI：
10.1073/pnas.1307684110
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发表时间：
2013-07-30
影响因子：
11.1
通讯作者：
Vargesson, Neil
中科院分区：
文献类型：
--
作者：
Mahony, Chris;Erskine, Lynda;Vargesson, Neil
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。另一种类似物泊马度胺最近已被批准用于治疗多发性骨髓瘤，据称在临床上比沙利度胺或来那度胺更有效。使用斑马鱼和鸡胚结合体外实验，我们已经确定了每个化合物的相对抗炎活性。我们证明，在体内胚胎试验中，泊马度胺是一种比沙利度胺或来那度胺更有效的抗炎药。我们测试了泊马度胺和来那度胺对血管生成、畸形形成和轴突生长的影响，已知的沙利度胺的不利影响。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，后者在抗炎浓度下对血管、神经和胚胎发育有不利影响。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具有指导意义。
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.