摘要

Thalidomide and its derivatives, lenalidomide and pomalidomide, are clinically effective treatments for multiple myeloma and myelodysplastic syndrome with del(5q). These molecules lack activity in murine models, limiting investigation of their therapeutic activity or toxicity in vivo. Here, we report the development of a mouse model that is sensitive to thalidomide derivatives because of a single amino acid change in the direct target of thalidomide derivatives, cereblon (Crbn). In human cells, thalidomide and its analogs bind CRBN and recruit protein targets to the CRL4CRBN E3 ubiquitin ligase, resulting in their ubiquitination and subsequent degradation by the proteasome. We show that mice with a single I391V amino acid change in Crbn exhibit thalidomide-induced degradation of drug targets previously identified in human cells, including Ikaros (Ikzf1), Aiolos (Ikzf3), Zfp91, and casein kinase 1a1 (Ck1α), both in vitro and in vivo. We use the CrbnI391V model to demonstrate that the in vivo therapeutic activity of lenalidomide in del(5q) myelodysplastic syndrome can be explained by heterozygous expression of Ck1α in del(5q) cells. We found that lenalidomide acts on hematopoietic stem cells with heterozygous expression of Ck1α and inactivation of Trp53 causes lenalidomide resistance. We further demonstrate that CrbnI391V is sufficient to confer thalidomide-induced fetal loss in mice, capturing a major toxicity of this class of drugs. Further study of the CrbnI391V model will provide valuable insights into the in vivo efficacy and toxicity of this class of drugs.

译文

沙利度胺及其衍生物,来那度胺和波那度胺,是临床有效的治疗多发性骨髓瘤和骨髓增生异常综合征的 del (5q)。这些分子在小鼠模型中缺乏活性,限制了对其治疗活性或体内毒性的研究。在这里,我们报道了一种对沙利度胺衍生物敏感的小鼠模型的开发,因为沙利度胺衍生物的直接靶标 cereblon (Crbn) 中存在单个氨基酸的变化。在人类细胞中,沙利度胺及其类似物结合 CRBN 并将蛋白质靶招募到 CRL4CRBN E3 泛素连接酶,导致它们的泛素化并随后被蛋白酶体降解。我们表明,在 Crbn 中具有单一 I391V 氨基酸变化的小鼠表现出沙利度胺诱导的先前在人类细胞中鉴定的药物靶标降解,包括 Ikaros (Ikzf1) 、 Aiolos (Ikzf3) 、 Zfp91, 和酪蛋白激酶 1a1 (ck1 α),包括体外和体内。我们使用 CrbnI391V 模型证明来那度胺在 del (5q) 骨髓增生异常综合征中的体内治疗活性可以通过 del (5q) 细胞中 ck1 α 的杂合表达来解释。我们发现来那度胺作用于造血干细胞,ck1 α 杂合表达和 Trp53 失活导致来那度胺耐药。我们进一步证明了 CrbnI391V 足以赋予沙利度胺引起的小鼠胎儿丢失,捕捉到了这类药物的主要毒性。对 CrbnI391V 模型的进一步研究将为这类药物的体内功效和毒性提供有价值的见解。

thalidomide

免疫 沙利度胺 药物
概述  :  

沙利度胺最早在50年代推出,刚开始主要治疗妊娠引起的恶心、呕吐,但后来因服用沙利度胺的孕妇生下以往极其罕见的海豹肢畸形儿,沙利度胺曾被迫退出国际市场。近年来,随着各种临床研究的开展,科学家们发现沙利度胺在免疫、抗炎、抗血管生成方面具有良好的疗效。 药理作用 1.沙利度胺能抑制中枢神经系统,故有镇静、催眠、镇痛、止吐、抗焦虑、抗焦躁作用。许多恶性肿瘤患者在治疗过程常伴有失眠、疼痛、焦虑等负面情绪,而且在化疗中常出现恶心、呕吐现象,沙利度胺可

Thalidomide 英 /θəˈlɪdəmaɪd/ 美 /θəˈlɪdəmaɪd/

释义    n. 沙利度胺

例句    Objective: To observe the therapeutic effects and side-effects of thalidomide combined with arsenious oxide and retinoic acid for the treatment of low-risk myelodysplastic syndromes (MDS).目的:观察沙利度胺联合三氧化二砷和维甲酸治疗低危骨髓增生异常综合征(MDS)的疗效和不良反应。

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