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.