EFFECTS OF SYNTHETIC VITAMIN-D ANALOGS ON BREAST-CANCER CELL-PROLIFERATION INVIVO AND INVITRO

Calcipotriol (MC903) is a novel vitamin D analogue which effects cellular differentiation and proliferation in vitro and has reduced effects on calcium metabolism in vivo. In the present study its in vitro activity was evaluated using the MCF-7 breast cancer cell line, and its effects on calcium metabolism and mammary tumour growth were measured in vivo in adult female rats. Calcipotriol was compared to the natural metabolite of vitamin D3, 1-alpha,25-dihydroxycholecalciferol [1,25(OH)2D3] and its synthetic analogue 1-alpha-hydroxycholecalciferol [1-alpha(OH)D3]. Both calcipotriol and 1,25(OH)2D3 Produced significant inhibition of MCF-7 cell proliferation at a concentration of 5 x 10(-11) M. Intraperitoneal administration of calcipotriol to normal female rats showed that the analogue was 100-200 times less active than 1,25(OH)2D3 in raising serum calcium concentration and urinary calcium excretion. Anti-tumour activity of the vitamin D analogues was investigated in vivo using the nitrosomethylurea-induced rat mammary tumor model. Rats, maintained on a low calcium diet, were treated with 1-alpha(OH)D3 (0.25 and 1.25-mu-g/kg). Both doses produced a response rate of 25% but hypercalcaemia developed. Treatment with calcipotriol (50-mu-g/kg) of rats maintained on a normal laboratory diet caused inhibition of tumour progression (response rate 17%) without the development of severe hypercalcaemia. This study supports the concept that vitamin D derivatives may inhibit breast cancer cell proliferation in vivo.