Antiproliferative and calcemic actions of trans-decalin CD-ring analogs of 1,25-dihydroxyvitamin D3.
Antiproliferative and calcemic actions of trans-decalin CD-ring analogs of 1,25-dihydroxyvitamin D3.
复制标题
1,25-二羟基维生素 D3 的反式十氢化萘 CD 环类似物的抗增殖和钙血作用。
作者：
G. Eelen;L. Verlinden;J. Laureys;S. Marcelis;P. D. De Clercq;C. Mathieu;R. Bouillon;A. Verstuyf
背景
1，25-二羟基维生素D3 [1，25（OH）2D 3]具有有效的抗增殖作用，但钙离子效应阻碍了其在治疗过度增殖性疾病中的应用。因此，1，25-（OH）2D 3的类似物被设计为在两种效应之间具有明显的分离。本文讨论了反式十氢萘CD环类似物CY 10012的生物活性。
材料和方法
使用增殖/分化/反式激活测定以及小鼠模型来确定CY 10012的体外和体内活性。
结果
CY 10012具有比1，25（OH）2D 3高10倍的抗增殖作用，但也是钙离子的两倍。为了确定维生素D受体（VDR）在介导CY 10012的钙调作用中的作用，每天向VDRwt和VDRko小鼠施用类似物。这种处理在VDRwt小鼠中引起剧烈的体重减轻和死亡，但在VDRko小鼠中没有。
结论
类似物CY 10012具有更大的抗增殖作用，但也具有两倍高的钙离子效应，其完全依赖于VDR介导的信号传导途径。
BACKGROUND
1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] has potent antiproliferative actions but calcemic effects obstruct its application in the treatment of hyperproliferative disorders. Therefore, analogs of 1,25-(OH)2D3 are designed with a clear dissociation between both effects. Here the biological activity of the trans-decalin CD-ring analog CY10012 is discussed.
MATERIALS AND METHODS
Proliferation/differentiation/transactivation assays as well as mouse models were used to determine the activity of CY10012 in vitro and in vivo.
RESULTS
CY10012, has ten-fold higher antiproliferative actions than 1,25(OH)2D3 but is also twice as calcemic. To determine the role of the Vitamin D Receptor (VDR) in mediating the calcemic actions of CY10012, the analog was daily administered to VDRwt and VDRko mice. This treatment caused drastic weight loss and death in VDRwt mice but not in VDRko mice.
CONCLUSION
Analog CY10012 has greater antiproliferative action but also two-fold higher calcemic effects which depended entirely on VDR-mediated signalling pathways.