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


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.


CONCLUSIONS
Analog CY10012 has greater antiproliferative action but also two-fold higher calcemic effects which depended entirely on VDR-mediated signalling pathways.
Eelen
Guy
G
Laboratory for Experimental Medicine and Endocrinology (LEGENDO), Katholieke Universiteit Leuven, Leuven, Belgium.
Verlinden
Lieve
L
Laureys
Jos
J
Marcelis
Suzanne
S
De Clercq
Pierre
P
Mathieu
Chantal
C
Bouillon
Roger
R
Verstuyf
Annemieke
A
D000818:Animals; D019556:COS Cells; D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002522:Chlorocebus aethiops; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009281:Naphthalenes / Q000737:chemistry*; D018167:Receptors, Calcitriol / Q000502:physiology
D009281:Naphthalenes; D018167:Receptors, Calcitriol; C007229:decalin; D002117:Calcitriol; D002118:Calcium