© 1997 by Oxford University Press
Journal Of The National Cancer Institute, Vol 89, 212-218, Copyright © 1997 by Oxford University Press
RG Mehta, RM Moriarty, RR Mehta, R Penmasta, G Lazzaro, A Constantinou and L Guo
BACKGROUND: The form of vitamin D (vitamin D3) in fortified milk and the
provitamin D produced by the body undergo metabolic activation to a
biologically active form, 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3].
This compound can induce cell differentiation and can prevent proliferation
of cancer cells. However, because 1alpha,25(OH)2D3 is hypercalcemic
(effective in increasing serum calcium level), it is not suitable for use
in cancer prevention or cancer therapy trials. PURPOSE: We synthesized a
vitamin D5 series analogue, 1alpha-hydroxy, 24-ethyl-cholecalciferol, or
1alpha- hydroxyvitamin D5 [1alpha(OH)D5], and evaluated its chemopreventive
activity in carcinogen-treated mammary glands in organ culture experiments.
METHODS: The analogue 1alpha(OH)D5 was synthesized from sitosterol acetate
and was characterized by nuclear magnetic resonance. Its purity was
evaluated by high-pressure liquid chromatography. The calcemic activities
of vitamin D3 and D5 analogues were determined in vitamin D-deficient
Sprague-Dawley rats. Mammary glands of BALB/c mice were placed in organ
culture and treated with the carcinogen 7,12- dimethylbenz[a]anthracene
(DMBA) to induce preneoplastic lesions. Vitamin D analogues were added to
the culture medium at four different concentrations, and formation of
mammary lesions was evaluated. The effects of 1alpha(OH)D5 and
1alpha,25(OH)2D3 on the expression of vitamin D receptors (VDRs) and
transforming growth factor-beta1 (TGF- beta1) were studied by
immunohistochemistry. Statistical significance was determined by the
chi-squared test. All reported P values were two- sided. RESULTS:
1alpha,25(OH)2D3 was fourfold more calcemic than 1alpha(OH)D5 at a dose of
0.042 microg/kg per day in rats. Both 1alpha,25(OH)2D3 and 1alpha(OH)D5
inhibited the development of DMBA- induced preneoplastic lesions in mouse
mammary glands compared with untreated glands. The effect of the vitamin D3
analogue was observed at a much lower concentration (0.01 microM).
Treatment with 1alpha(OH)D5 resulted in a dose-related (0.01-10.0 microM)
inhibition without any toxicity, whereas the vitamin D3 analogue was highly
potent but toxic at concentrations of 1.0 microM or higher. Normal mouse
mammary glands poorly express VDR and TGF-beta1; incubation with
1alpha(OH)D5 or 1alpha,25(OH)2D3 dramatically induced their expression.
CONCLUSIONS: This is the first report showing the possibility of
chemoprevention by a vitamin D5 series compound. We conclude that
1alpha(OH)D5 is less calcemic than 1alpha,25(OH)2D3. It is nontoxic at a
wide range of concentrations, but it is potent in inhibiting the
development of preneoplastic lesions in mammary glands in organ culture. In
addition, we show for the first time the induction of TGF-beta1 in normal
mammary tissues by a chemopreventive agent. IMPLICATIONS: 1alpha(OH)D5 is a
good candidate for in vivo chemoprevention studies. It may mediate its
action by inducing expression of VDR and of TGF-beta1, as is seen in other
systems.
ARTICLES
Prevention of preneoplastic mammary lesion development by a novel vitamin D analogue, 1alpha-hydroxyvitamin D5
Department of Surgical Oncology, College of Medicine, University of Illinois, Chicago 60612, USA.
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