ANTIPROLIFERATIVE ACTIVITY AND TARGET-CELL CATABOLISM OF THE VITAMIN-D ANALOG 1-ALPHA,24(S)-(OH)(2)D-2 IN NORMAL AND IMMORTALIZED HUMAN EPIDERMAL-CELLS

Vitamin D analogs represent valuable new agents for the suppression of proliferation of a variety of cell types, including those of the skin . One such analog is the vitamin D-2 metabolite, 1 alpha,24(S)dihydrox yvitamin D-2, which binds strongly to the vitamin D receptor and induc es vitamin D-dependent gene expression in vitro. In the work described here, we studied the anti-proliferative activity and target cell meta bolism of 1 alpha,24(S)-dihydroxyvitamin D-2 in cells of human epiderm al origin. We found this analog to be equally potent in its anti-proli ferative effect to the hormone 1 alpha,25-dihydroxyvitamin D-3. Furthe rmore, la,24(S)dihydroxyvitamin D-2 was metabolized by the human kerat inocyte cell line HPK1A-ras at a slower rate than either 1 alpha,25 di hydroxyvitamin D-3 or calcipotriol, a drug used effectively in the tre atment of psoriasis. We characterized the metabolic products of 1 alph a,24(S)-dihydroxyvitamin D-2 as a mixture of side-chain truncated and hydroxylated products. The main product was identified by CC-MS and NM R techniques as 1 alpha,24(S),26-trihydroxyvitamin D-2. The biological activity of this main product was determined in a vitamin D-dependent , growth-hormone reporter gene expression system to be lower than that of the parent molecule. We conclude from these data that 1 alpha,24(S )-dihydroxyvitamin D-2 is a valuable new anti-proliferative agent with a slower rate of catabolism by cells of epidermal origin. Preliminary evidence suggests that the parent molecule, and not its products, is responsible for this biological activity in vitro.