Antiproliferative and Calcemic Actions of Trans-Decalin CD-Ring Analogs of 1,25-Dihydroxyvitamin D3

Background: 1,25-Dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] has potent antiproliferative actions but calcemic effects obstruct its application in the treatment of hyperproliferative disorders. Therefore, analogs of 1,25-(OH) 2 D 3 are designed with a clear dissociation between both effects. Here the bio...

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Bibliographic Details
Published in:Anticancer research 2009-09, Vol.29 (9), p.3579-3584
Main Authors: EELEN, Guy, VERLINDEN, Lieve, LAUREYS, Jos, MARCELIS, Suzanne, DE CLERCQ, Pierre, MATHIEU, Chantal, BOUILLON, Roger, VERSTUYF, Annemieke
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Calcitriol - analogs & derivatives
Calcitriol - pharmacology
Calcium - metabolism
Cell Line, Tumor
Cell Proliferation - drug effects
Cercopithecus aethiops
COS Cells
Homeostasis - drug effects
Humans
Medical sciences
Mice
Mice, Knockout
Naphthalenes - chemistry
Receptors, Calcitriol - physiology
Tumors
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Summary:Background: 1,25-Dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] has potent antiproliferative actions but calcemic effects obstruct its application in the treatment of hyperproliferative disorders. Therefore, analogs of 1,25-(OH) 2 D 3 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) 2 D 3 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 VDR wt and VDR ko mice. This treatment caused drastic weight loss and death in VDR wt mice but not in VDR ko mice. Conclusion: Analog CY10012 has greater antiproliferative action but also two-fold higher calcemic effects which depended entirely on VDR-mediated signalling pathways.
ISSN:0250-7005
1791-7530