Page 190 - Vitamin D and Cancer

8 Vitamin D and Cancer Chemoprevention 177

In addition to the large body of epidemiological evidence that supports the use
of vitamin D as a chemopreventive agent for cancer, in vitro tissue culture studies
have elucidated many of the mechanisms by which vitamin D and its active metab-
olites act to inhibit the growth of malignant cells [10–13]. These studies have set
the foundation for in vivo preclinical and clinical studies. As the epidemiological
and molecular mechanisms of vitamin D have previously been discussed, this chap-
ter will focus on the preclinical and clinical evidence that support the use of vitamin
D as a chemopreventive agent across different cancer subtypes.

8.2 Pre-clinical Studies

Pre-clinical studies evaluating the chemopreventive effects of vitamin D are essen-
tial for establishing the rational for designing clinical trials. Here we summarize the
pre-clinical studies that have been conducted in animal models of colon, prostate,
breast, and lung and briefly discuss other tumor subtypes that are currently under
investigation. These studies have examined not only differences in tumor growth
associated with changes in dietary vitamin D levels but also through administration
of the active metabolite of vitamin D (1,25(OH) D ) or vitamin D analogs. In vitro
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assays of 1,25(OH) D have demonstrated that 1,25(OH) D is responsible for the
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most potent anticancer effects as measured by proliferation, apoptosis, differentia-
tion and cell cycle arrest [10–13]. However, administration of 1,25(OH) D can
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cause hypercalcemia and associated toxicities; therefore analogs of 1,25(OH) D
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are also being examined in efforts to maintain anticancer responses while lowering
toxicity [14].
8.2.1 Colorectal Cancer
Studies by Lipkin et al. and Newmark et al. examined the effects of a diet high in
fat and low in vitamin D and calcium (Western-style diet) on the induction of neo-
plasms in the colons of C57Bl/6 mice with and without the adenomatous polyposis
coli (APC) gene mutations [15–17]. Comparisons are made between mice fed the
Western-style diet containing 20% fat (corn oil)/g, 0.5 mg calcium (Ca)/g and
0.11 IU vitamin D /g/diet and the AIN-76A diet containing 5% fat/g, 5 mg Ca/g
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and 1 IU vitamin D /g/diet for various amounts of time ranging from several weeks
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to 2 years. These studies demonstrated that the C57Bl/6 mice on a Western diet
developed hyperproliferative colon crypt hyperplasia while APC mice on a
Western diet had an increased incidence of carcinoma with more invasive disease.
However, mice that were fed diets high in vitamin D and calcium did not develop
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lesions.
Tangpricha et al. performed additional studies that further examined the effect
of low vitamin D and calcium in the diet [18, 19]. In these studies, two cohorts of
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