Drug Discovery Research Laboratories, Fuji Research Park, Research Division, Kyowa Hakko Kirin Co., Ltd., Japan.
J Pharmacol Sci. 2014;124(2):201-7. doi: 10.1254/jphs.13162fp. Epub 2014 Jan 23.
The mouse embryonic stem cell test (mEST) is used to assess the embryotoxicity of drug candidates by evaluating the effects on the cardiac differentiation of stem cells. However, thalidomide embryotoxicity has not yet been reported using the mEST. To detect the effects of thalidomide, we used human induced pluripotent stem cells (hiPSCs) instead of mouse embryonic stem cells, and assessed three endpoints: the inhibition of cardiac differentiation, the cytotoxicity to hiPSCs, and the cytotoxicity to human dermal fibroblasts, according to the mEST. From these data (IC50 values), the embryotoxicity was classified into one of three different classes based on the mEST and our criteria. Valproate was used as a positive control and ascorbic acid was used as a negative control, and their effects were assessed. Similar to valproate, thalidomide was classified as a Class 2 agent, with weak embryotoxicity, by the mEST criteria, and was classified as Category 3 embryotoxic based on our criteria. Ascorbic acid was classified as a Class 1 / Category 1, non-embryotoxic agent, based on both criteria. Thalidomide embryotoxicity was detected in the embryonic stem cell test based on hiPSCs. This test system is thus considered to have a much greater predictive ability than the mEST.
小鼠胚胎干细胞试验（mEST）用于通过评估对干细胞心脏分化的影响来评估候选药物的胚胎毒性。然而，尚未使用 mEST 报告沙利度胺的胚胎毒性。为了检测沙利度胺的作用，我们用人诱导多能干细胞（hiPSC）代替小鼠胚胎干细胞，并根据 mEST 评估了三个终点：心脏分化抑制、hiPSC 的细胞毒性和人真皮成纤维细胞的细胞毒性。根据这些数据（IC50 值），根据 mEST 和我们的标准，将胚胎毒性分为三类中的一类。使用丙戊酸作为阳性对照，抗坏血酸作为阴性对照，并评估它们的作用。与丙戊酸类似，沙利度胺根据 mEST 标准被归类为 2 类药物，具有较弱的胚胎毒性，根据我们的标准被归类为 3 类胚胎毒性。抗坏血酸根据这两个标准均被归类为 1 类/1 类非胚胎毒性药物。在基于 hiPSC 的胚胎干细胞试验中检测到沙利度胺的胚胎毒性。因此，该试验系统被认为比 mEST 具有更大的预测能力。
