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Two Novel 14-Epi-Analogues of 1,25-Dihydroxyvitamin D₃ Inhibit the Growth of Human Breast Cancer Cells in Vitro and in Vivo¹

Laboratorium voor Experimentele Geneeskunde en Endocrinologie, Katholieke Universiteit Leuven, 3000 Leuven [L. V., A. V., M. V. C., S. M., R. B.], and Vakgroep voor Organische Chemie, Universiteit Gent, 9000 Ghent [K. S., X-Y. Z., P. D. C., M. V.], Belgium

The biological activity of two novel 14-epi-analogues of 1,25(OH)₂D₃, 19-nor-14-epi-23-yne-1,25(OH)₂D₃ (TX 522) and 19-nor-14,20-bisepi-23-yne-1,25(OH)₂D₃ (TX 527), is described. Both analogues were at least 10 times more potent than 1,25(OH)₂D₃ in inhibiting in vitro cell proliferation and had much lower in vivo calcemic effects than 1,25(OH)₂D₃. Treatment with 1,25(OH)₂D₃, TX 522, or TX 527 in vitro was accompanied by an accumulation of cells in the G₁ phase of the cell cycle. Protein levels of cyclin C and cyclin D1 in in vitro cultures of MCF-7 cells were down-regulated to 50 and 30%, respectively, of control levels at 72 and 120 h after stimulation. Protein levels of p21 and p27 at 72 h were significantly enhanced by 1,25(OH)₂D₃ and TX 522 but surprisingly not by TX 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 retinoblastoma protein after treatment with 1,25(OH)₂D₃, TX 522, or TX 527 may ultimately contribute to the growth inhibition caused by these compounds. According to the data presented, the induction of apoptosis seemed not to be a major mechanism responsible for the growth-inhibitory effect of 1,25(OH)₂D₃ and analogues. Both 14-epi-analogues significantly retarded tumor progression (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 analogues have the eligible profile to be tested as therapeutic agents for the treatment of hyperproliferative diseases such as breast cancer.

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