The anti-proliferative and differentiation-inducing effects of vitamin D analogs are not determined by the binding affinity for the vitamin D receptor alone.
Calcipotriol, a synthetic analog of 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25[OH]2D3), is used in the treatment of psoriasis. In this investigation, the biological profile of calcipotriol and of two new vitamin D analogs, EB 1213 and GS 1500, has been studied and compared with the profile of 1 alpha,25(OH)2D3. Despite the fact that the affinity for the intracellular vitamin D receptor of the three analogs is comparable (EB 1213) or lower (GS 1500, calcipotriol) than that of 1 alpha,25(OH)2D3, they were all found to be more potent in inhibiting human skin cell proliferation in vitro. The anti-proliferative effect was accompanied by a change in the cytokeratin pattern of the skin cells, indicating a differentiation-inducing effect of the compounds similar to that of 1 alpha,25(OH)2D3. Further investigations including ligand-induced vitamin D receptor transcription studies in chloramphenicol acetyl transferase assays showed that EB 1213 and GS 1500 were more efficient than 1 alpha,25(OH)2D3 in inducing vitamin D receptor transcription. This strongly indicates that not only the binding affinity for the receptor, but more importantly, the ability of the compounds to induce vitamin D receptor transcription, is a determinant of the biological activity of the compounds.
Hansen
C M
CM
Department of Biochemistry, Leo Pharmaceutical Products, Ballerup, Denmark.
Mathiasen
I S
IS
Binderup
L
L
D001665:Binding Sites; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects; D018167:Receptors, Calcitriol / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects
D018167:Receptors, Calcitriol; C055085:calcipotriene; C103435:EB 1213; D002117:Calcitriol