Page 244 - Vitamin D and Cancer

10 Vitamin D and Prostate Cancer 231

There were important differences between the four positive studies. Two of the
positive studies showed that higher 1,25-OH vitamin D levels were associated with
2
a protective effect against prostate cancer [90, 91]. Corder et al. had a large number
of vitamin D deficient subjects (approximately 50%). In Li, et al. the protective
effect of the higher 1,25-OH vitamin D levels was a reduction in the risk of aggres-
2
sive prostate cancers. Two other studies showed a link between low 25-OH vitamin
D levels and increased risk of prostate cancer [89, 92]. Tuohimaa et al. showed an
increased risk of prostate cancer with extreme 25-OH vitamin D deficiency
(<7.6 ng/mL) but also showed an increased risk of prostate cancer with highest
25-OH vitamin D levels suggesting a U-shaped relationship between vitamin D
status and prostate cancer risk [92].
This suggestion of an increased risk of prostate cancer at higher 25-OH vitamin
D levels was reproduced in one recent study [93]. Ahn et al. found a statistically
significant increase in risk of aggressive prostate cancers (Gleason > 7) with higher
25-OH vitamin D levels. This possible increased risk at higher vitamin D levels has
not been fully explained and requires further investigation.
In the aforementioned 2007 study by Li et al., there was an increased risk of
aggressive prostate cancer when both 1,25-OH vitamin D and 25-OH vitamin D
2
levels were low, but not solely with low 25-OH levels. This additive effect of low
levels of both forms of vitamin D was also shown by Corder et al. Three of the
studies that had positive results, demonstrating increased risk of aggressive pros-
tate cancer, but not necessarily an increased risk of lower grade cancers [89, 91,
93]. Of the studies that had null results, two did not analyze risk based on aggres-
siveness [94, 99] and three had relatively small numbers of aggressive cases [95,
96, 98]. This may support a hypothesis that vitamin D deficient states will
increase the risk of aggressive prostate cancers, rather than all grades of prostate
cancers.
Thus, epidemiologic evidence is mixed, but generally consistent with the hypoth-
esis that circulating 1,25-OH vitamin D levels, and factors that influence them (i.e.,
2
oral calcium intake, severe vitamin D deficiency) play a role in prostate cancer
development and its course [100]. There are multiple preclinical observations
involving vitamin D and prostate cancer risk and mortality that still need further
investigation with humans. In addition to the ongoing trials with vitamin D analogs
in treating prostate cancer, the observation that 1-alpha-hydroxylase is reduced or
lost in prostate cancer tissue needs further confirmation and study in humans.

10.6 Therapeutic Applications of Vitamin D

10.6.1 Vitamin D in Combination with Other Antineoplastic
Agents in Preclinical Models

Experiments in preclinical models suggest that VDR ligands enhance the activity
of a broad range of antineoplastic agents.