ENHANCEMENT OF ANTIPROLIFERATIVE ACTIVITY OF 1-ALPHA,25-DIHYDROXYVITAMIN D-3 (ANALOGS) BY CYTOCHROME-P450 ENZYME-INHIBITORS IS COMPOUND-SPECIFIC AND CELL-TYPE-SPECIFIC

Ketoconazole (keto) or liarozole (liaro), inhibitors of the cytochrome P450 enzymes that mediate vitamin D and A hydroxylations, could poten tiate the antiproliferative effects of 1 alpha,25-dihydroxyvitamin D-3 [1 alpha,25(OH)(2)D-3] and its analogs. Proliferation of MCF-7 and T4 7-D human breast cancer cells, MG-63 human osteosarcoma. cells and HL- 60 human promyeloid leukemia cells was concentration dependently inhib ited by 1 alpha,25(OH)(2)D-3. The vitamin D analogs KH 1060 [20-epi-22 -oxa-24,26,27-trihomo-1 alpha,25(OH)(2)D-3], RO 23-6010 [16-ene-23-yne -26-trifluoro-1,25(OH)(2)D-3], ZXY 835 [20-epi-23-yne-25,26-epoxy-1 al pha(OH)D-3], and CD 99 [11 alpha-methyl-1 alpha,25(OH)(2)D-3] were 150 -, 58-, 16- and 7-fold more potent than 1 alpha,25(OH)(2)D-3 in inhibi ting the proliferation of MCF-7 cells, respectively. A similar rank or der of potency was observed in other cell lines. The antiproliferative effects of the vitamin D hormone and analogs was enhanced in MCF-7 ce lls when coincubated with 1 mu M keto (7-, 10-, 5-, 25- and 1.3-fold m ore potent than in the absence of keto), respectively. The antiprolife rative effect was less enhanced when 1 alpha,25(OH)(2)D-3 or its analo gs KH 1060, ZXY 835 and RO 23-6010 were combined with liaro (3-, 7-, 2 - and 3-fold, respectively). Keto and liaro did not markedly potentiat e the activity of 1 alpha,25(OH)(2)D-3 or its analogs in MG-63 or HL-6 0 cells. These results suggest that differences in cellular metabolism can at least partially explain the different potency of vitamin D ana logs. Moreover, the metabolism of vitamin D analogs is cell-type speci fic. Copyright (C) 1996 Elsevier Science Ltd