| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Departments of Cancer Biology [A. M. B., G. G. S., S. D. C.], Urology [S. D. C.] and Pathology [R. W.], Wake Forest University School of Medicine, Winston-Salem, North Carolina 27105
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
,25-dihydroxyvitamin
D3 [1,25(OH)2D3] is known to
inhibit the proliferation of prostatic epithelial cells. This has
stimulated interest in vitamin D compounds as therapeutic agents for
prostate cancer. However, the therapeutic use of
1,25(OH)2D3 is limited because elevations in
serum 1,25(OH)2D3 can cause dangerous
elevations in serum calcium levels. We wondered whether the prohormone
of 1,25(OH)2D3, 25-hydroxyvitamin
D3 (25-OH-D3), which is much less calcemic,
could also achieve antiproliferative effects in prostatic cells.
25-OH-D3 is converted to
1,25(OH)2D3 by the mitochondrial enzyme
1--hydroxylase. We have recently shown that human prostatic
cells also possess significant 1--hydroxylase activity (Schwartz
et al., Cancer Epidemiol. Biomark. Prev.,
7: 391–395, 1998). We studied 1--hydroxylase
gene expression in four strains of primary human prostatic
epithelial cells by reverse transcription PCR amplification (RT-PCR) of
1--hydroxylase. Human prostatic stromal cells were negative for
1--hydroxylase by RT-PCR. This led us to hypothesize that
25-OH-D3 would inhibit the proliferation of prostatic
epithelial cells because 25-OH-D3 would be converted to
1,25(OH)2D3 intracellularly. We studied the
effects of 25-OH-D3 and 1,25(OH)2D3
on the proliferation of prostatic epithelial cells using high density
growth and clonal growth assays on two different primary cell strains
derived from normal human prostatic peripheral zone.
25-OH-D3 and 1,25(OH)2D3 each
inhibited growth in a dose- and time-dependent manner. Growth
inhibition was evident at 1 nM, and maximal inhibition was
observed at 100 nM within 10–12 days of exposure. The
potencies of 25-OH-D3 and
1,25(OH)2D3 were not significantly different.
These data demonstrate that 25-OH-D3, which previously was
thought to have little biological activity, can become a potent
antiproliferative hormone for prostatic cells that express
1--hydroxylase. Because 25-OH-D3 exhibits similar
potency to 1,25(OH)2D3 but is less calcemic,
25-OH-D3 may offer a safer option than
1,25(OH)2D3 for prostate cancer therapy.
Moreover, because 25-OH-D3 is produced endogenously from
vitamin D, these findings support a potential role for vitamin D in the
chemoprevention of prostate cancer. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
"Vitamin" D is a hormone that is produced from 7-dehydrocholesterol
by a series of reactions that culminates in the most active metabolite
of vitamin D,
1,25(OH)2D3,2
also known as calcitriol (for a recent review, see Ref.
6
). When the skin is exposed to sunlight, UV rays convert
7-dehydrocholesterol in the skin to vitamin D3
(cholecalciferol). Vitamin D can also be obtained from the diet, either
as cholecalciferol or ergocalciferol (vitamin
D2). Cholecalciferol is transported to the liver,
where the enzyme 25-hydroxylase converts it to
25-OH-D3, also known as calcifidiol and
calcidiol. This relatively inactive compound is the major circulating
metabolite of vitamin D. From the liver, 25-OH-D3
is transported to the kidneys, where 1--hydroxylase converts
25-OH-D3 to
1,25(OH)2D3, the active
hormonal metabolite of vitamin D. In vitamin D-target tissues such as
the intestine, 1,25(OH)2D3
exerts most of its biological activity through binding to the VDR.
1,25(OH)2D3 has
approximately 500-1000 times the affinity for the nuclear VDR than does
25-OH-D3 (7)
.
1,25(OH)2D3 plays a major
role in mineral homeostasis by regulating serum calcium and phosphorus
levels. In addition to its role in mineral homeostasis, it is now
apparent that 1,25(OH)2D3
exhibits potent antiproliferative and differentiating properties in a
variety of cell types, including prostatic cells
(8, 9, 10, 11)
.
In 1990, Schwartz and Hulka (3) proposed the vitamin D hypothesis for prostate cancer. On the basis of epidemiological data, they proposed that vitamin D maintains the normal phenotype of prostatic cells and that decreased vitamin D exposure increased the risk for clinical prostate cancer. Since the proposal of that hypothesis, several groups have demonstrated antiproliferative and prodifferentiatng effects of 1,25(OH)2D3 on human prostatic cells (8, 9, 10, 11) . These data have led to the investigation of 1,25(OH)2D3 as a therapeutic agent for prostate cancer. The first clinical trial with 1,25(OH)2D3 as a treatment for prostate cancer was performed by Osborn et al. (12) . Osborn et al. assessed the effects of 1,25(OH)2D3 on patients with hormone-refractory (androgen-insensitive) metastatic prostate cancer. No partial responses (defined as a sustained 50% decrease in serum PSA) were observed, although two men showed substantial decreases in serum PSA (25% and 45% declines). Hypercalcemia was the major dose-limiting toxicity. More recently, Gross et al. (13) assessed the effects of 1,25(OH)2D3 in patients with biochemical recurrence of localized prostate cancer after definitive therapy. They demonstrated that 0.5–2.5 µg of 1,25(OH)2D3 given daily decreased the PSA doubling time by 50% every 3.3 month. However, several of these patients developed hypercalciuria, which resulted in a halt to the dose escalation during this trial. Thus, the calcemic effects associated with 1,25(OH)2D3 therapy limit the utility of this hormone for prostate cancer therapy.
The rate-limiting step in the synthesis of systemic
1,25(OH)2D3 is the
conversion of 25-OH-D3 to
1,25(OH)2D3 by renal
1--hydroxylase. Local production of
1,25(OH)2D3 by nonrenal
tissues that express 1--hydroxylase has emerged as a new aspect of
the vitamin D endocrine system. 1--hydroxylase activity has been
identified in a number of extrarenal sites in humans, including
decidua, keratinocytes, macrophages, spleen cells, osteoblasts, and
colon carcinoma cells (reviewed in Ref. 14
). In
keratinocytes, endogenously produced
1,25(OH)2D3 is involved in
the control of keratinocyte growth and differentiation (15
, 16)
. Recently, Schwartz et al. showed that prostate
cancer cell lines and normal and benign prostatic hyperplasia primary
cultures have 1--hydroxylase activity and synthesize
1,25(OH)2D3 from
25-OH-D3 (17)
. The 1--hydroxylase
activity of the primary human prostatic epithelial cells was comparable
to that of primary renal proximal tubular cells.
The intracellular production of
1,25(OH)2D3 by the prostate
suggested to us that 25-OH-D3 might regulate the
growth and differentiation of prostatic cells. To date, no study has
reported on the antiproliferative effects of
25-OH-D3 on human prostatic cells that express
1--hydroxylase. In this report, we demonstrate that
25-OH-D3 can inhibit primary prostatic epithelial
cell growth in a time- and dose-dependent manner and that its effects
are similar in magnitude to those of
1,25(OH)2D3.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Cell Culture.
Primary human epithelial cell cultures from histologically normal
prostate peripheral zones were obtained from radical prostatectomies
performed at Wake Forest University School of Medicine and were
maintained as described previously (18
, 19)
. Briefly, a
small piece of tissue from each specimen was removed and minced. The
tissue was digested with collagenase overnight. To remove the
collagenase and the majority of the stromal cells, the tissue was
rinsed and centrifuged. The tissue was inoculated into a 60-mm tissue
culture dish coated with collagen type I (Collagen Corporation, Palo
Alto, CA) and grown in medium PFMR-4A supplemented with growth factors
and hormones (19)
. Previous studies have demonstrated that
prostatic stromal cells do not grow in the serum-free conditions used
in this study, yet these conditions maintain the growth and
differentiation of prostatic epithelial cells (19)
.
Morphological characteristics of the cultures used in the present study
were consistent with the growth of epithelial cells. The cells that
grew out from the tissue were aliquoted and stored in liquid nitrogen.
The histology of each specimen was verified by inking and fixing the
prostate after dissection and serially sectioning the marked area. The
histology of sections immediately adjacent to the area of the
dissection was reviewed. The frozen aliquots were thawed to produce
secondary cultures, which were grown in medium MCDB 105 (Sigma, St.
Louis, MO) supplemented with growth factors and hormones
(19)
. Nomenclature for epithelial cell strains is "E"
followed by the histology of origin (peripheral zone) and then the
strain number (e.g., E-PZ-1).
Stromal cell cultures were established by inoculating collagenase-digested tissues into medium MCDB 105 with 10% fetal bovine serum and 100 µg/ml gentamicin in 60-mm tissue culture dishes (20) . Although epithelial cells attach in this medium, they do not grow well and are lost after the first passage. Passaged cultures were aliquoted and stored frozen in liquid nitrogen until use. Stromal cell cultures do not express keratin but express vimentin and fibronectin (20) . Nomenclature for stromal cell strains is "F" followed by the histology of origin (peripheral zone) and then the strain number (e.g., F-PZ-1). Strain numbers for stromal cells do not necessarily correlate with strain numbers for epithelial cells.
Experimental Media.
Complete medium for the primary prostatic epithelial cells is defined
as MCDB 105 supplemented with cholera toxin (10 ng/ml),
epidermal growth factor (10 ng/ml), bovine pituitary extract (10
µg/ml), phosphoethanolamine (0.1 mM), hydrocortisone (1
µg/ml), selenium (3 x 10-8
M), gentamicin (100 µg/ml), retinoic acid (0.01 ng/ml),
insulin (4 µg/ml), and vitamin E (2.3 x
10-6 M). Experimental medium is
defined as MCDB-105 with the aforementioned supplements, 20
µM DPPD [an antioxidant used to prevent the generic
conversion of 25-OH-D3 to
1,25(OH)2D3], and
increasing dosages of either 25-OH-D3 or
1,25(OH)2D3.
High-Density Dose Response and Time Course.
Prostatic epithelial cells (5 x 103) from
thawed secondary cultures were inoculated into 35-mm tissue culture
dishes coated with type I collagen and containing complete MCDB 105
medium. After 48 h of growth at 37°C in a humidified incubator
with 5% CO2, the media were replaced and cells
were treated with vehicle (0.1% ethanol and 20 µM DPPD)
or with media containing 0.1–100 nM
25-OH-D3 or
1,25(OH)2D3. The media were
changed every 3 days. For the dose response, cells were grown for 11
more days and then trypsinized and counted with a hemocytometer. Each
dose was tested on triplicate plates. For the time course, three plates
were trypsinized and counted as T0 on the first
day the experimental medium was added. Cell counts were done in
triplicate on days 1, 2, 4, 6, 8, and 10 for each experimental medium.
Results are expressed as the mean cell number per plate ± SE.
Clonal Growth Assay.
Clonal growth assays were performed as described previously (10
, 18)
. Six hundred cells from thawed primary cultures were
inoculated into 60-mm tissue culture dishes coated with type I collagen
containing experimental medium. Cells were grown at 37°C in a
humidified incubator with 5% CO2 for 13–14
days, at the end of which, cells were fixed with 10% formalin and
stained with 0.1% crystal violet. The number and size of stained
colonies were then determined on each plate.
1--Hydroxylase mRNA Expression.
Total RNA was isolated from cultured cells by the
guanidinium-phenol-chloroform extraction method (21)
.
Oligo dT-primed RT with 1 µg of total RNA was performed using the
GeneAmp RNA PCR kit (Perkin-Elmer, Branchburg, NJ) according to the
manufacturer’s protocol. The RT reaction [6 µl (1/3)] was
used for subsequent PCR amplification of the 3' untranslated region of
the 1--hydroxylase cDNA from base 1853 to 2150 of the sequence
reported by Monkawa et al.
(22)
.3
The reaction was performed with 150 nM 5' primer
(5'-TGGTCTCTCTGCTTGCTTGG-3'), 150 nM 3' primer
(5'-GACACCTAGTCAGAGACAGG-3'), 1x PCR buffer (Promega, Madison, WI),
150 µM each dNTP, and 2
mM MgCl2 in a final
reaction volume of 100 µl. All of the thermal reactions were
performed in a Perkin Elmer Applied Biosystems GenAmp 2400
(South San Francisco, CA). Samples were incubated for 5 min at 94°C
followed by 5 min at 80°C, during which 2.5 units of Taq DNA
polymerase (Promega) were added. Samples were subjected to 30 cycles of
1 min at 94°C, 1 min at 52°C, and 1 min at 72°C, followed by a
7-min final extension at 72°C. RT-PCR reactions were fractionated on
2% agarose gels and visualized by ethidium bromide staining using an
IS-500 digital imaging system (Alpha Innotech, San Leandro, CA) and
processed with the software provided by the manufacturer. 
X174
genomic DNA, digested with HaeIII restriction enzyme
(Promega), was fractionated in a parallel lane as a size marker. For a
positive control of RT, the GAPDH mRNA was amplified using human GAPDH
primers purchased from Stratagene (La Jolla, CA) according to the
manufacturer’s protocol.
For sequence analysis of RT-PCR product, a sample was fractionated on a
2% agarose gel, and the 298-bp fragment was sliced out of the gel and
extracted from the agarose using the GeneClean DNA purification kit
(Bio 101, Vista, CA). The nucleotide sequence of the purified PCR
product was determined by automated fluorescent nucleotide sequencing
with an ABI Prism 377 DNA Sequencer by the DNA sequencing facility of
the Comprehensive Cancer Center of Wake Forest University. Sequence
comparison with the published 1--hydroxylase was determined
using the Blast software at the National Center for Biotechnology
Information Web
site.4
Statistics.
Statistical analyses were performed using the SAS statistical package
release 6.12 TS Level 0020 Windows version 4.0.950, (SAS Institute
Inc., Cary, NC). Multiple ANOVA controlling for dose or time and
vitamin D compound [ethanol (the control),
25-OH-D3, or
1,25(OH)2D3] was used to
detect differences between vitamin D treatment groups. ANOVA followed
by Tukey-Kramer Multiple Comparison Test was used to evaluate
significant differences within each treatment group (i.e.,
different doses of 25-OH-D3).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-hydroxylase in
epithelial cells grown under the conditions used in this study. Four
epithelial strains and two stromal strains derived from human
prostatectomy specimens were evaluated for 1--hydroxylase gene
expression. Fig. 1
shows that all of the four epithelial cell strains expressed detectable
1--hydroxylase transcripts. Sequence analysis of the PCR product
verified the 1--hydroxylase sequence. Neither of the stromal cell
strains expressed any detectable 1--hydroxylase transcript.
|
shows the results of a representative experiment showing high-density
growth inhibition by 25-OH-D3 and
1,25(OH)2D3 of strain
E-PZ-1. Both 25-OH-D3 and
1,25(OH)2D3 inhibited
growth in a dose-dependent manner. The dose-response curves for the two
compounds were parallel, with the effects of both compounds apparent at
10 nM. The two curves were not statistically different.
However, we observed a trend for a higher potency of
1,25(OH)2D3
versus 25-OH-D3, with
1,25(OH)2D3 approximately
10-fold more potent than 25-OH-D3. ANOVA
performed on the individual dose-response curves demonstrated that
significant growth inhibition occurred at 10 nM
1,25(OH)2D3, but that 100
nM 25-OH-D3 was required
for this effect. These results were repeated once with this strain
(E-PZ-1) and twice with an additional strain (E-PZ-2; data not shown).
|
shows a time course of the effects of both
25-OH-D3 and
1,25(OH)2D3 on the primary
prostatic epithelial cell strain E-PZ-1. Three different concentrations
of each of the compounds were studied [1 nM (Fig. 3A
), 10 nM (Fig. 3B
), and
100 nM (Fig. 3C
)]. Both
25-OH-D3 and
1,25(OH)2D3 inhibited
growth in a time-dependent manner at all of the three concentrations
tested, although this effect was not statistically significant at 1
nM. The difference in growth between control- and
vitamin D-treated cultures is significant by 10 days with 100
nM, whereas it took 12 days for this effect to be
significant with 10 nM. As with the dose
response, the effects of 25-OH-D3 and
1,25(OH)2D3 were not
statistically different. These results were repeated once with this
strain and twice with strain E-PZ-2 (data not shown).
|
shows representative clonogenic growth plates from strain E-PZ-1
treated with various concentrations of 25-OH-D3
or 1,25(OH)2D3 and stained
with crystal violet after 14 days of growth. The results were
essentially identical to the results from high-density growth with
1,25(OH)2D3. The assay was
performed three times with strain E-PZ-1 and three times with strain
E-PZ-2. All of the experiments gave similar results.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-hydroxylase in human prostatic
cells by Schwartz et al. (17)
suggested that
intracellular production of
1,25(OH)2D3 may be an
important modulator of prostatic growth. In this report we describe the
growth inhibitory properties of 25-OH-D3 on
primary human prostatic epithelial cells. Maximal growth inhibition
(essentially no growth) was observed at 100 nM
25-OH-D3 by 6–8 days. The concentrations
of 25-OH-D3 used in this study are within the
normal physiological range in humans (35–100 nM;
Ref. 7
) and may play a role in the normal modulation of
prostatic growth and differentiation. However, in vivo
studies will be required to validate this hypothesis. Interestingly,
the concentrations of
1,25(OH)2D3 needed to
inhibit prostatic growth range from 1 to 100 nM,
but the physiological range of serum
1,25(OH)2D3 in normal
healthy adults is in the pM range. Therefore,
systemic 1,25(OH)2D3 levels
are less likely to play a normal role in prostatic growth and
differentiation. Concentrations of
1,25(OH)2D3 above the
normal physiological range, which are needed to inhibit prostatic
growth, are known to cause hypercalciuria and/or hypercalcemia
(12
, 13)
. A noncalcemic form of vitamin D that inhibits
prostatic growth, therefore, would be very useful for the treatment of
prostate cancer. One way to circumvent the problem of hypercalcemia is via the use of synthetic, relatively noncalcemic forms of 1,25(OH)2D3, such as EB 1089 (24) , which is presently in human clinical trials for prostate cancer. We propose that the prohormone 25-OH-D3 may be another way to circumvent this problem. 25-OH-D3 appears to be an ideal candidate for a therapeutic vitamin D compound for several reasons: (a) it is effective in inhibiting prostatic growth at concentrations within its normal physiological range; (b) it is safe at levels far exceeding its physiological range (7) ; (c) oral dosing of 50 µg per day has been used in long-term studies for other diseases with no adverse side-effects (25) ; and (d) oral formulations of 25-OH-D3 have long been available (e.g., for the treatment of vitamin D insufficiency), and their safety has long been established.
The relative affinity of 25-OH-D3 for the VDR is
approximately 500- to 1000-fold lower than the affinity of
1,25(OH)2D3 for the VDR
(7)
. On the basis of these affinities, one would expect a
500- to 1000-fold difference in biological activities between
25-OH-D3 and
1,25(OH)2D3 if both
compounds were acting by directly binding to the VDR. We found no
significant difference between 25-OH-D3 and
1,25(OH)2D3 in their
ability to inhibit prostatic growth. Our data (and those of others)
strongly suggest that the growth inhibition by
25-OH-D3 is due to prostatic conversion of
25-OH-D3 to
1,25(OH)2D3. In support of
this interpretation, the human prostatic cell line LNCaP expresses VDR
but not 1--hydroxylase. One hundred nM
1,25(OH)2D3 will cause
maximal growth inhibition of LNCaP cells; however, 100 nM
25-OH-D3 has no effect on the proliferation of
these cells (26)
. To further validate this interpretation,
we examined the expression of 1--hydroxylase in our primary culture
system. All of the four epithelial strains were positive for
1-hydroxylase, including the strain E-PZ-2 used in this study.
Although some variation in 1--hydroxylase expression was evident,
the assay that we used was not quantitative and should not be used to
interpret differences in level of expression. It is interesting to note
that the two prostatic stromal cultures were essentially negative for
1--hydroxylase expression, indicating little or no 1--hydroxylase
expression in prostatic stromal cultures. To our knowledge, this is the
first evidence that 1--hydroxylase expression is specific to the
epithelial cells of the prostate.
In addition to the potential use of 25-OH-D3 for
prostate cancer therapy, our findings have implications for the
molecular epidemiology of prostate cancer. For example, little is known
about the relative expression of prostatic 1--hydroxylase
between individuals. Variations of 1--hydroxylase have been observed
between primary prostatic epithelial cells and three commonly used
prostatic cell lines (PC3, DU-145, and LNCaP; Ref. 17
).
Expression of 1--hydroxylase in the primary prostatic cultures is
approximately 10 to 40 times that in the cell lines. Because
1--hydroxylase governs the synthesis of a key autocrine hormone in
the prostate, heterogeneity in the expression of this enzyme may have
important physiological consequences. Our data with primary prostatic
cultures that show complete growth inhibition with 100 nM
25-OH-D3, in conjunction with data showing no
growth inhibition of LNCaP cells with 100 nM
25-OH-D3, further reinforce the significance of
1--hydroxylase expression in the prostate-vitamin D endocrine
system.
In summary, we report that primary human prostatic epithelial cells are
growth-inhibited by physiological concentrations of
25-OH-D3 in a dose- and time-dependent manner
that did not differ significantly from the effects of
1,25(OH)2D3. These data
imply that the normal prostate-vitamin D endocrine system involves the
conversion of 25-OH-D3 to
1,25(OH)2D3 by prostatic
1--hydroxylase. These findings support the use of
25-OH-D3 as a chemotherapeutic agent in the
treatment of prostate cancer. A preclinical trial of
25-OH-D3 in mice xenografted with human prostatic
tumors is presently underway in our laboratory. Finally, because
25-OH-D3 is produced endogenously from exposure
to vitamin D, our data raise the exciting possibility that vitamin D
(i.e., cholecalciferol or ergocalciferol), which is
inexpensive and relatively nontoxic, may be useful as a chemopreventive
agent to reduce the risk of prostate cancer (3)
.
|
Footnotes |
|---|
1 To whom requests for reprints should be
addressed, at Department of Cancer Biology, Wake Forest University
School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157
Phone: (336) 716-9330; Fax: (336) 716-0255; E-mail: scramer{at}wfubmc.edu 
2 The abbreviations used are:
25-OH-D3, 25-hydroxyvitamin D3;
1,25(OH)2D3, 1,25-dihydroxyvitamin
D3; VDR, vitamin D receptor; RT, reverse transcription;
PSA, prostate-specific antigen; DPPD, 1,2 dianilinoethane; GAPDH,
glyceraldehyde-3-phosphate dehydrogenase.
3 GenBank Accession No. AB005038.
4 Internet address:
http://www.ncbi.nlm.nih.gov/BLAST/
Received 7/19/99; revised 11/22/99; accepted 12/ 8/99.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
,25-dihydroxyvitamin D3 and platinum drugs act synergistically to inhibit the growth of prostate cancer cell lines. Clin. Cancer Res., 5: 695-703, 1999., 25-dihydroxyvitamin D2/D3. J. Clin. Investig., 58: 61-70, 1976.
,25-dihydroxyvitamin D3. Cancer Res., 52: 515-520, 1992.-hydroxylase. Biochem. Biophys. Res. Commun., 239: 527-533, 1997.[Medline]
-hydroxylase. Biochemistry, 25: 6821-6826, 1986.[Medline]
This article has been cited by other articles:
|
|
 |
|
  J. M. Faupel-Badger, L. Diaw, D. Albanes, J. Virtamo, K. Woodson, and J. A. Tangrea Lack of Association between Serum Levels of 25-Hydroxyvitamin D and the Subsequent Risk of Prostate Cancer in Finnish Men Cancer Epidemiol. Biomarkers Prev., December 1, 2007; 16(12): 2784 - 2786. [Full Text] [PDF]
|
|
|
|
|
|
C. N. Holick, J. L. Stanford, E. M. Kwon, E. A. Ostrander, S. Nejentsev, and U. Peters Comprehensive Association Analysis of the Vitamin D Pathway Genes, VDR, CYP27B1, and CYP24A1, in Prostate Cancer Cancer Epidemiol. Biomarkers Prev., October 1, 2007; 16(10): 1990 - 1999. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Urushino, S. Nakabayashi, M. A. Arai, A. Kittaka, T. C. Chen, K. Yamamoto, K. Hayashi, S. Kato, M. Ohta, M. Kamakura, et al. Kinetic Studies of 25-Hydroxy-19-nor-vitamin D3 and 1{alpha},25-Dihydroxy-19-nor-vitamin D3 Hydroxylation by CYP27B1 and CYP24A1 Drug Metab. Dispos., September 1, 2007; 35(9): 1482 - 1488. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Cicek, X. Liu, F. R. Schumacher, G. Casey, and J. S. Witte Vitamin D Receptor Genotypes/Haplotypes and Prostate Cancer Risk Cancer Epidemiol. Biomarkers Prev., December 1, 2006; 15(12): 2549 - 2552. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. Dusso, A. J. Brown, and E. Slatopolsky Vitamin D Am J Physiol Renal Physiol, July 1, 2005; 289(1): F8 - F28. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. John, G. G. Schwartz, J. Koo, D. Van Den Berg, and S. A. Ingles Sun Exposure, Vitamin D Receptor Gene Polymorphisms, and Risk of Advanced Prostate Cancer Cancer Res., June 15, 2005; 65(12): 5470 - 5479. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Townsend, C. M. Banwell, M. Guy, K. W. Colston, J. L. Mansi, P. M. Stewart, M. J. Campbell, and M. Hewison Autocrine Metabolism of Vitamin D in Normal and Malignant Breast Tissue Clin. Cancer Res., May 1, 2005; 11(9): 3579 - 3586. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. W. Barclay, R. D. Woodruff, M. C. Hall, and S. D. Cramer A System for Studying Epithelial-Stromal Interactions Reveals Distinct Inductive Abilities of Stromal Cells from Benign Prostatic Hyperplasia and Prostate Cancer Endocrinology, January 1, 2005; 146(1): 13 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. McCarty Targeting Multiple Signaling Pathways as a Strategy for Managing Prostate Cancer: Multifocal Signal Modulation Therapy Integr Cancer Ther, December 1, 2004; 3(4): 349 - 380. [Abstract] [PDF]
|
|
|
|
 |
|
 G. M. Zinser and J. Welsh Accelerated Mammary Gland Development during Pregnancy and Delayed Postlactational Involution in Vitamin D3 Receptor Null Mice Mol. Endocrinol., September 1, 2004; 18(9): 2208 - 2223. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. V. Young, G. G. Schwartz, L. Wang, D. P. Jamieson, L. W. Whitlatch, J. N. Flanagan, B. L. Lokeshwar, M. F. Holick, and T. C. Chen The prostate 25-hydroxyvitamin D-1{alpha}-hydroxylase is not influenced by parathyroid hormone and calcium: implications for prostate cancer chemoprevention by vitamin D Carcinogenesis, June 1, 2004; 25(6): 967 - 971. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. G. Schwartz, D. Eads, A. Rao, S. D. Cramer, M. C. Willingham, T. C. Chen, D. P. Jamieson, L. Wang, K. L. Burnstein, M. F. Holick, et al. Pancreatic cancer cells express 25-hydroxyvitamin D-1{alpha}-hydroxylase and their proliferation is inhibited by the prohormone 25-hydroxyvitamin D3 Carcinogenesis, June 1, 2004; 25(6): 1015 - 1026. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. V. Stewart and N. L. Weigel Vitamin D and Prostate Cancer Experimental Biology and Medicine, April 1, 2004; 229(4): 277 - 284. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. V. Grau, J. A. Baron, R. S. Sandler, R. W. Haile, M. L. Beach, T. R. Church, and D. Heber Vitamin D, Calcium Supplementation, and Colorectal Adenomas: Results of a Randomized Trial J Natl Cancer Inst, December 3, 2003; 95(23): 1765 - 1771. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Rodriguez, M. L. McCullough, A. M. Mondul, E. J. Jacobs, D. Fakhrabadi-Shokoohi, E. L. Giovannucci, M. J. Thun, and E. E. Calle Calcium, Dairy Products, and Risk of Prostate Cancer in a Prospective Cohort of United States Men Cancer Epidemiol. Biomarkers Prev., July 1, 2003; 12(7): 597 - 603. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Rao, R. D. Woodruff, W. N. Wade, T. E. Kute, and S. D. Cramer Genistein and Vitamin D Synergistically Inhibit Human Prostatic Epithelial Cell Growth J. Nutr., October 1, 2002; 132(10): 3191 - 3194. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Vieth Dairy products, calcium, and prostate cancer risk in the Physicians' Health Study Am. J. Clinical Nutrition, August 1, 2002; 76(2): 490 - 491. [Full Text]
|
|
|
|
|
|
U. Peters, K. A. McGlynn, N. Chatterjee, E. Gunter, M. Garcia-Closas, N. Rothman, and R. Sinha Vitamin D, Calcium, and Vitamin D Receptor Polymorphism in Colorectal Adenomas Cancer Epidemiol. Biomarkers Prev., December 1, 2001; 10(12): 1267 - 1274. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Y. Hsu, D. Feldman, J. E. McNeal, and D. M. Peehl Reduced 1{{alpha}}-hydroxylase Activity in Human Prostate Cancer Cells Correlates with Decreased Susceptibility to 25-Hydroxyvitamin D3-induced Growth Inhibition Cancer Res., April 1, 2001; 61(7): 2852 - 2856. [Abstract] [Full Text]
|
|
|
|
|
|
E. A. Platz, E. B. Rimm, W. C. Willett, P. W. Kantoff, and E. Giovannucci Racial Variation in Prostate Cancer Incidence and in Hormonal System Markers Among Male Health Professionals J Natl Cancer Inst, December 20, 2000; 92(24): 2009 - 2017. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research |
, 25-OH-D3-treated cultures; •,
1,25(OH)2D3-treated cultures; *,
significantly different from control, P = 0.05.
,
1,25(OH)2D3-treated cultures. Each
point, the mean ± SE of triplicate dishes; *,
significantly different from control, P = 0.05.