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An evaluation of 1,25-dihydroxyvitamin D3 analogues on the proliferation and differentiation of cultured human keratinocytes, calcium metabolism and the differentiation of human HL-60 cells

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Abstract

Synthetic analogues of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) 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)2D3 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)2D3 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)2D3 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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    This work was supported in part by grants 1-RO1-AR 36963 and 1-RO1-DK43690 from the National Institutes of Health.

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