Abstract
Synthetic analogues of 1,25-dihydroxyvitamin D 3 (1,25(OH) 2D 3) were examined for their biological activities in four assay systems: (a) inhibition of proliferation and stimulation of terminal differentiation in cultured normal human keratinocytes, (b) intestinal calcium absorption and bone calcium mobilization in vitamin D-deficient rats, (c) competitive binding to the rat intestinal 1,25(OH) 2D 3 receptor, and (d) induction of differentiation of human HL-60 leukemia cells. Six analogues were found to have minimal activity in enhancing intestinal calcium absorption and bone calcium mobilization while retaining at least the same activity as 1,25(OH) 2D 3 in inhibiting proliferation and inducing terminal differentiation of cultured keratinocytes. Evidence suggests that it may be possible to dissociate antiproliferative activity from differentiation-inducing activity and calcium metabolism by specific modifications of the 1,25(OH) 2D 3 molecule. The uncoupling of these activities could potentially create an ideal analogue to treat psoriasis that should have potent antiproliferative activity with minimum effects on differentiation and on calcium metabolism.
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