Hexafluoro-1,25-dihydroxyvitamin D3 has markedly increased potency in inhibiting proliferation of cultured human keratinocytes compared with 1,25-dihydroxyvitamin D3.

Abstract

Although topical 1,25-dihydroxyvitamin D3 (calcitriol, 1, 25(OH)2D3) and its analogues, calcipotriol and tacalcitol, are effective for patients with psoriasis, some patients show little or no response. There is a need to develop more potent analogues of 1, 25(OH)2D3. Hexafluoro-1,25(OH)2D3 (F6-1,25(OH)2D3) is at least 10 times more potent than 1,25(OH)2D3 on calcium metabolism. We were interested in whether F6-1,25(OH)2D3 was also more potent than 1,25(OH)2D3 in inhibiting normal human and psoriatic keratinocyte proliferation. The antiproliferative activity of F6-1,25(OH)2D3 and 1,25(OH)2D3 was determined by 3H-thymidine incorporation into keratinocyte DNA and by counting basal cells. F6-1,25(OH)2D3 was approximately 10-fold more active and had a longer lasting antiproliferative effect than 1,25(OH)2D3 on normal human keratinocytes, and was about 100-fold more potent than 1, 25(OH)2D3 on human psoriatic keratinocytes as determined by 3H-thymidine incorporation. F6-1,25(OH)2D3 also caused a dose-dependent decrease in the number of basal cells and was 100-fold more active than 1,25(OH)2D3. The increased potency and the long-lasting effects of F6-1,25(OH)2D3 suggest that F6-1,25(OH)2D3 may be a potent candidate agent for treating psoriasis.