|
一项对酞谷酰亚胺（反应停）衍生物进行的研究结果提示，酞谷酰亚胺导致的声名狼藉的出生缺陷很可能源于它中止了新血管的生长。多年以来，酞谷酰亚胺被选择性地用作抗癌药物，这主要是由于它具有抑制新血管生长的能力，这让它可以有效地对抗肿瘤。但是酞谷酰亚胺在体内有许多分解产物，尚不清楚哪种产物起了作用——科学家也无法准确解释酞谷酰亚胺如何导致了出生缺陷。 Christina Therapontos及其同事证明了一种合成的酞谷酰亚胺类似体CPS49基本中止了正在发育的胚胎的新血管生长。这组作者在鸡和斑马鱼的胚胎、培养的小鼠心脏以及一个人类细胞系中进行了实验。看上去只有新血管受到了影响，特别是肢芽的新血管，而且它们早在被认为可能造成了出生缺陷的几个细胞事件出现之前就停止生长了。这些结果解释了酞谷酰亚胺引发的出生缺陷如何发生在如此短的时间窗口内。这组作者说，这项工作可能帮助科学家寻求理解酞谷酰亚胺在抗癌治疗中的作用。 推荐原始出处： PNAS May 11, 2009, doi: 10.1073/pnas.0901505106 Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation Christina Therapontosa,b, Lynda Erskineb, Erin R. Gardnerc, William D. Figgd and Neil Vargessona,b,1 Thalidomide is a potent teratogen that induces a range of birth defects, most commonly of the developing limbs. The mechanisms underpinning the teratogenic effects of thalidomide are unclear. Here we demonstrate that loss of immature blood vessels is the primary cause of thalidomide-induced teratogenesis and provide an explanation for its action at the cell biological level. Antiangiogenic but not antiinflammatory metabolites/analogues of thalidomide induce chick limb defects. Both in vitro and in vivo, outgrowth and remodeling of more mature blood vessels is blocked temporarily, whereas newly formed, rapidly developing, angiogenic vessels are lost. Such vessel loss occurs upstream of changes in limb morphogenesis and gene expression and, depending on the timing of drug application, results in either embryonic death or developmental defects. These results explain both the timing and relative tissue specificity of thalidomide embryopathy and have significant implications for its use as a therapeutic agent. (责任编辑：Doctor001) |
