Antiproliferative and calcemic actions of trans-decalin CD-ring analogs of 1,25-dihydroxyvitamin D3.

Guy Eelen, Lieve Verlinden, Jos Laureys, Suzanne Marcelis, Pierre De Clercq, Chantal Mathieu, Roger Bouillon, Annemieke Verstuyf

Index: Anticancer Res. 29(9) , 3579-84, (2009)

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Abstract

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.