Page 319 - Vitamin D and Cancer

306 M. Fakih et al.

The importance of VDR activation in the prevention of colorectal carcinogenesis
has been demonstrated in several pre-clinical models. An inverse association
between cellular proliferation and VDR expression was demonstrated in mice colon
[75]. Furthermore, complete loss of VDR (knockout) was associated with an
increased proliferation and increased oxidative DNA stress, which may promote
carcinogenesis [75, 77]. Vitamin D antitumor activity was also documented in an
min
APC mouse model [78]. Vitamin D may also induce detoxification through
VDR-induced expression of cyp3A, a cytochrome P450 enzyme that detoxifies the
secondary bile acid, lithocolic acid [79].
An association between vitamin D levels and supplementation and intestinal
mucosal proliferation has also been proposed. Holt et al. have shown an inverse
association between colonic epithelial proliferation and increasing levels of 25-D
3
[80]. In a subsequent study of daily 400 IU of cholecalciferol and three-times daily
1,500 mg of calcium carbonate, the same investigator showed a decrease in prolif-
eration in both normal and polyp tissue after 6 months of replacement [81].

13.2.2 Clinical Studies with Vitamin D Supplementation

Only one large randomized study evaluated and reported on the effect of vita-
min D supplementation on the risk of colorectal cancer [45]. Participants on the
Women’s Health Initiative (WHI) study were randomized to receive daily vita-
min D (400 IU) and elemental calcium (1,000 mg) or placebo. Study partici-
pated were post-menopausal females with an age ranging between 50 and
79 years. Among WHI participants, 18,176 were randomized to receive vitamin
D plus calcium and 18,106 were randomized to the placebo arm. The study
population was followed for outcome after an average of 7 years of treatment.
The incidence of colorectal cancer did not differ significantly between the vita-
min D and placebo arms (168 cases in the vitamin D arm vs 154 in the placebo;
HR = 1.08 (95% CI: 0.86–1.34)) [45]. While the study shows no beneficial
effect of low dose vitamin D on the risk of colorectal cancer, several consider-
ations should be kept in mind regarding this study design and its limitations.
First, the dose of vitamin D used on this study was likely inadequate to test for
a protective role for vitamin D against colorectal cancer. Most epidemiological
studies suggest that if a benefit is derived with higher 25-D levels, this benefit
3
is typically limited to the highest quartile or quintiles of the population. This
suggests that to derive a benefit from vitamin D supplementation, we would
need to aim for 25-D concentration considerably in excess of 30 ng/mL. The
3
median 25-D levels from a nested case-control from the WHI study was noted
3
to be 17 ng/mL. Since, 400 IU/day of vitamin D is expected to raise 25-D lev-
3
els by only 3–4 ng/mL, it would be unlikely that the dose selected for this study
would have resulted in any significant shift in 25-D levels towards the favor-
3
able protective range. Second, the follow-up period on this study may have
been insufficient. The carcinogenesis process for colorectal cancer may span a