Effects of vitamin D derivatives on soft tissue calcification in neonatal and calcium mobilization in adult rats.

The activity of 18 vitamin D analogs on soft tissue calcification and growth impairment in neonatal rats and their effect on bone calcium mobilization, intestinal calcium absorption and binding to intestinal 1,25-dihydroxyvitamin D3 receptors in adult rats were compared. Depending on the chemical modification of the vitamin D parent compounds, they could be separated into active and inactive analogs. Cholecalciferol and ergocalciferol were similarly active, but epimerization of ergocalciferol at carbon 23 caused loss of activity. Hexafluorination at carbon 26 and 27 and the introduction of a double bond at carbon 22 or 23 had no or little effect on the activity. The loss of activity was caused by the introduction of a triple bond at carbon 23 and by hydroxylation at carbon 23, 26 or 28. The differentiation of human promyelocytic leukemia cells (HL-60) induced by these derivatives was used as a parameter for antitumour activity. All six analogs, which markedly affected calcium metabolism, were highly active in HL-60 cells. However, at least three derivatives were highly active in the antitumour test but failed to induce hypercalcemia. Thus, these results indicate that it could be possible to develop medically useful vitamin D derivatives devoid of hypercalcemic side-effects.