Page 335 - Vitamin D and Cancer

322 R. Vieth

14.3.1 Adaptation of Vitamin D Hydroxylases and Cancer Risk

What needs to be established is whether a slow rate of adaptation of the vitamin D
hydroxylases can be enough of a problem to affect cancer risk. It has recently been
shown that risk of pancreatic cancer in the US north increases with rising 25(OH)
D levels measured in summer, but in the US south, there is no such relationship
[33]. This would be expected based on the hypothesis proposed here. The present
hypothesis is also logically consistent with the evidence that some antineoplastic
drugs suppress expression of CYP24 [51].
Not all vitamin D-responsive tissues are likely to behave in the manner proposed here
for the prostate. Colon cancer has been well validated epidemiologically as being pro-
tected against by higher 25(OH)D concentrations [2, 7, 52]. However, the epidemiology
of prostate [6, 29] and pancreatic cancers [8, 33] suggests that these tissues are inefficient
at adapting to seasonal UV light and the seasonal cycles in serum 25(OH)D.
So long as serum 25(OH)D concentrations are in a phase of decline, there can
be no full achievement of tissue 1,25(OH) D to match its ideal set-point concentra-
2
tion. No matter how small the true increment below the set-point may prove to be,
it is by definition, a sub-optimal concentration. This may not be harmful as a single
event in an individual, but over many lifetimes, annual cycles of below set-point
phases in tissue 1,25(OH) D will have an adverse effect on the risk of promotion or
2
progression of certain types of cancer.

14.4 Vitamin D Hypothesis for Cancer Prevention

The hypothesis presented here integrates with the vitamin D hypothesis for cancer
prevention in a manner that accounts for the apparent contradictions outlined in
Table 14.1. This hypothesis is based on the unusual, first-order in vivo enzyme
kinetics of the vitamin D system. The key prediction based on this hypothesis was
published in 2004 was in relation to prostate cancer [30], and has been confirmed
subsequently at least once, in the context of cancer of the pancreas as shown in
Fig. 14.1 [33]. The hypothesis is testable in experimental models, such as the
TRAMP mouse model of prostate cancer, as well as with epidemiologic data. The
prediction is not tenable as a primary study outcome for human clinical trials,
because it predicts an increased risk of cancer of prostate and pancreas in individu-
als given large doses of vitamin D at dosing intervals of more than 2 months.

14.4.1 Implications of the Model

A major problem for clinical research is poor adherence to medication, which results
in negative findings [53, 54]. One way to improve adherence is to give vitamin D
less frequently, but at larger doses [55, 56]. A general guideline for a dosing interval