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The in Vitro Evaluation of 25-Hydroxyvitamin D₃ and 19-nor-1,25-Dihydroxyvitamin D₂ as Therapeutic Agents for Prostate Cancer¹

Vitamin D, Skin and Bone Research Laboratory and Endocrine Section, Boston University Medical Center, Boston, Massachusetts 02118 [T. C. C., M. F. H.]; Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest University, Winston-Salem, North Carolina 27157 [G. G. S.]; Department of Molecular and Cellular Pharmacology[K. L. B.]; and Department of Urology, University of Miami School of Medicine, Miami, Florida 33101[B. L. L.]

Prostate cancer cells contain specific receptors [vitamin D receptors (VDRs)] for 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), which is known to inhibit the proliferation and invasiveness of these cells. These findings support the use of 1,25(OH)₂D₃ for prostate cancer therapy. However, because 1,25(OH)₂D₃ can cause hypercalcemia, analogues of 1,25(OH)₂D₃ that are less calcemic but that exhibit potent antiproliferative activity would be attractive as therapeutic agents. We investigated the effects of two different types of less calcemic vitamin D compounds, 25-hydroxyvitamin D₃ [25(OH)D₃] and 19-nor-1,25-dihydroxyvitamin D₂ [19-nor-1,25(OH)₂D₂], and compared their activity to 1,25(OH)₂D₃ on (a) the proliferation of primary cultures and cell lines of human prostate cancer cells; and (b) the transactivation of the VDRs in the androgen-insensitive PC-3 cancer cell line stably transfected with VDR (PC-3/VDR). 19-nor-1,25(OH)₂D₂, an analogue of 1,25(OH)₂D₃ that was originally developed for the treatment of parathyroid disease, has been shown to be less calcemic than 1,25(OH)₂D₃ in clinical trials. Additionally, we recently showed that human prostate cells in primary culture possess 25(OH)D₃-1-hydroxylase, an enzyme that hydroxylates the inactive prohormone, 25(OH)D₃, to the active hormone, 1,25(OH)₂D₃, intracellularly. We reasoned that the hormone that is formed intracellularly would inhibit prostate cell proliferation in an autocrine fashion. We found that 1,25(OH)₂D₃ and 19-nor-1,25(OH)₂D₂ caused similar dose-dependent inhibition in the cell lines and primary cultures in the [³H]thymidine incorporation assay and that both compounds were significantly more active in the primary cultures than in LNCaP cells. Likewise, 25(OH)D₃ had inhibitory effects comparable to those of 1,25(OH)₂D₃ in the primary cultures. In the chloramphenicol acetyltransferase (CAT) reporter gene transactivation assay in PC-3/VDR cells, 1,25(OH)₂D₃ and 19-nor-1,25(OH)₂D₂ caused similar increases in CAT activity between 10^-11 and 10^-9 M. Incubation of PC-3/VDR cells with 5 x 10^-8 M 25(OH)D₃ induced a 29-fold increase in CAT activity, similar to that induced by 10^-8 M 1,25(OH)₂D₃. In conclusion, our data indicate that 25(OH)D₃ and 19-nor-1,25(OH)₂D₂ represent two different solutions to the problem of hypercalcemia associated with vitamin D-based therapies: 25(OH)D₃ requires the presence of 1-hydroxylase, whereas 19-nor-1,25(OH)₂D₂ does not. Both drugs are approved for human use and may be good candidates for human clinical trials in prostate cancer.

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