Eelen Guy, Verlinden Lieve, Laureys Jos, Marcelis Suzanne, De Clercq Pierre, Mathieu Chantal, Bouillon Roger, Verstuyf Annemieke
Laboratory for Experimental Medicine and Endocrinology (LEGENDO), Katholieke Universiteit Leuven, Leuven, Belgium.
Anticancer Res. 2009 Sep;29(9):3579-84.
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.
Proliferation/differentiation/transactivation assays as well as mouse models were used to determine the activity of CY10012 in vitro and in vivo.
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.
Analog CY10012 has greater antiproliferative action but also two-fold higher calcemic effects which depended entirely on VDR-mediated signalling pathways.
1,25 - 二羟基维生素D3 [1,25(OH)2D3] 具有强大的抗增殖作用，但高钙血症效应阻碍了其在治疗增殖性疾病中的应用。因此，设计了1,25-(OH)2D3的类似物，使其两种效应明显分离。本文讨论反式十氢化萘CD环类似物CY10012的生物学活性。
采用增殖/分化/反式激活测定以及小鼠模型来确定CY10012在体外和体内的活性。
CY10012的抗增殖作用比1,25(OH)2D3高10倍，但高钙血症效应也是其两倍。为了确定维生素D受体（VDR）在介导CY10012高钙血症作用中的作用，每天给VDRwt和VDRko小鼠施用该类似物。这种治疗导致VDRwt小鼠体重急剧下降并死亡，但VDRko小鼠未出现这种情况。
类似物CY10012具有更强的抗增殖作用，但高钙血症效应也高两倍，这完全依赖于VDR介导的信号通路。
