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19-nor-Hexafluoride Analogue of Vitamin D₃: A Novel Class of Potent Inhibitors of Proliferation of Human Breast Cell Lines¹

Division of Hematology/Oncology, Cedars-Sinai Research Institute, UCLA School of Medicine, Los Angeles, California 90048 [M. K., E. E., M. J. C., H. A., H. P. K.]; Hoffmann LaRoche, Inc., Nutley, New Jersey 07110 [M. U.]; and Department of Hematology, Showa University School of Medicine, Tokyo, Japan [N. T.]

Breast cancer cells express vitamin D₃ receptors and 1,25-dihydroxyvitamin D₃ suppressed growth of these cells. We have synthesized six novel vitamin D₃ analogues to identify those with expanded capacity to inhibit the proliferative ability of breast cancer cells. These analogues incorporated many of the structural motifs shown previously to have antiproliferative activity in several cell types. Six breast cancer cell lines were used as targets. Dose-response studies showed that each of the analogues had antiproliferative activities, and LH [1,25-(OH)₂-16-ene-23-yne-26,27-F₆-19-nor D₃] was the most potent analogue, suppressing at 10^-11 M greater than 50% clonal proliferation (ED₅₀) of the MCF-7 and SK-BR-3 breast cancer cells, increasing the proportion of MCF-7 cells in the G₀-G₁ phase, and decreasing those in the S phase of the cell cycle. Pulse-exposure studies showed that a 3-day exposure to LH (10^-7 M) in liquid culture was adequate to achieve a 50% inhibition of MCF-7 clonal growth in soft agar in the absence of the analogue, suggesting that the growth inhibition mediated by LH is irreversible. The cyclin-dependent kinase inhibitor known as p27^Kip1 helps regulate the cell cycle and can mediate growth arrest in response to extracellular growth inhibitors. The analogue LH (10^-7 M) induced elevated expression of p27^Kip1 in MCF-7 and SK-BR-3 cells. Taken together, these results indicate that LH is an extremely potent vitamin D₃ analogue markedly inhibiting clonal growth of MCF-7 and SK-BR-3 cells with concomitant cell cycle arrest at G₀-G₁ and increased expression of p27^Kip1. Compound LH is worthy of in vivo analysis for possible future clinical trials.

¹ This study was supported by NIH Grants CA42377, CA42710, CA7067501-01, and CA26038; United States Army Grant DAMD17-961-6054; and grants from the Concern Foundation and Parker Hughes Trust.

² To whom requests for reprints should be addressed, at Cedars-Sinai Medical Center, UCLA School of Medicine, 8700 Beverly Boulevard, B208, Los Angeles, CA 90048. Phone: (310) 855-4609; Fax: (310) 659-9741.

Received 3/21/97. Accepted 8/15/97.

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