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The
in vitro evaluation of 25-hydroxyvitamin D3 and
19-nor-1alpha,25-dihydroxyvitamin D2 as therapeutic agents for prostate cancer
Chen TC, Schwartz GG,
Burnstein KL, Lokeshwar BL, Holick MF
Vitamin
D, Skin and Bone Research Laboratory, Boston University Medical Center,
Massachusetts 02118, USA.
taichen@bu.edu
Prostate cancer cells contain specific receptors [vitamin D receptors (VDRs)]
for 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3), which is known to inhibit
the proliferation and invasiveness of these cells.
These findings support the use of 1alpha,25(OH)2D3 for prostate cancer
therapy.
However, because 1alpha,25(OH)2D3 can cause hypercalcemia, analogues of
1alpha,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-1alpha,25-dihydroxyvitamin
D2 [19-nor-1,25(OH)2D2], and compared their activity to 1alpha,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-1alpha,25(OH)2D2, an analogue of 1alpha,25(OH)2D3 that was originally
developed for the treatment of parathyroid disease, has been shown to be less
calcemic than 1alpha,25(OH)2D3 in clinical trials.
Additionally, we recently showed that human prostate cells in primary culture
possess 25(OH)D3-1alpha-hydroxylase, an enzyme that hydroxylates the inactive
prohormone, 25(OH)D3, to the active hormone, 1alpha,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 1alpha,25(OH)2D3 and 19-nor-1alpha,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
1alpha,25(OH)2D3 in the primary cultures.
In the chloramphenicol acetyltransferase (CAT) reporter gene transactivation
assay in PC-3/ VDR cells, 1alpha,25(OH)2D3 and 19-nor-1alpha,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
1alpha,25(OH)2D3.
In conclusion, our data indicate that 25(OH)D3 and 19-nor-1alpha,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
1alpha-hydroxylase, whereas 19-nor-1alpha,25(OH)2D2 does not.
Both drugs are approved for human use and may be good candidates for human
clinical trials in prostate cancer.
PMID: 10741714 [PubMed - indexed for MEDLINE]
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