Two novel 14-epi-analogues of 1,25-dihydroxyvitamin D-3 inhibit the growthof human breast cancer cells in vitro and in vivo

The biological activity of two novel 14-epi-analogues of 1,25(OH)(2)D-3, 19 -nor-14-epi-23-yne-1,25(OH)(2)D-3 (TX 522) and 19-nor-14,20-bisepi-23-yne-1 ,25(OH)(2)D-3 (TX 527), is described. Both analogues were at least 10 times more potent than 1,25(OH)(2)D-3 in inhibiting in vitro cell proliferation and had much loner in vivo calcemic effects than 1,25(OH)(2)D-3. Treatment with 1,25(OH)(2)D-3, TX 522, or TX 527 in vitro was accompanied by an accum ulation of cells in the G(1) phase of the cell cycle. Protein levels of cyc lin C and cyclin D1 in in vitro cultures of MCF-7 cells were downregulated to 50 and 30%, respectively, of control levels at 72 and 120 h after stimul ation. Protein levels of p21 and p27 at 72 h were significantly enhanced by 1,25(OH)(2)D-3 and TX 522 but surprisingly not by TS 527, The inability of TX 527 to up-regulate p21 seemed to be cell type specific because p21 was induced in other cell types. Diminished phosphorylation of the retinoblasto ma protein after treatment with 1,25(OH)(2)D-3, TX 522, or TX 527 may ultim ately contribute to the growth inhibition caused by these compounds. Accord ing to the data presented, the induction of apoptosis seemed not to be a ma jor mechanism responsible for the growth-inhibitory effect of 1,25(OH)(2)D- 3 and analogues. Both 14-epi-analogues significantly retarded tumor progres sion (40% reduced compared with control mice) in an in vivo model of MCF-7 breast cancer cells established in nude mice. In conclusion, these novel an alogues have the eligible profile to be tested as therapeutic agents for th e treatment of hyperproliferative diseases such as breast cancer.