Page 191 - Vitamin D and Cancer

178 S.A. Mazzilli et al.

MC-26 tumor bearing mice were used to examine the chemopreventive effects of
dietary vitamin D through the administration 0 IU (vitamin D deficient cohort) or
3
50,000 IU of vitamin D (vitamin D sufficient cohort) in the diet. When mice on
3 3
the vitamin D deficient diet had a mean serum 25(OH)D level of £ 5 ng/mL, all mice
3 3
in both cohorts received 10,000 MC-26 cells subcutaneously. The vitamin D suffi-
cient cohort maintained a mean 25(OH)D serum level of 26 ng/mL. This study also
3
demonstrated that a diet deficient in vitamin D results in larger tumor volumes as
compared to a vitamin D sufficient diet.
In addition to examining the effects of dietary intake of vitamin D , studies have
3
been performed to examine the chemopreventive effects of the active metabolite of
vitamin D, 1,25(OH) D on the formation and the progression of colorectal cancers.
2 3
Fichera et al. examined the chemopreventive effect of a 1,25(OH) D analog
2 3
(1a,25-dihydroxy-16,23(Z)-diene-26,27-hexafluoro-19-nor-cholecalciferol)
(Ro26–2198) on colon carcinogenesis in A/J mice treated with the carcinogens
azoxymethane (AOM) and Dextran sulfate sodium (DSS) [20]. The AOM/DSS
carcinogen-induced mouse model recapitulates many aspects of human colon can-
cer via the induction of colitis that progresses into carcinoma. The AOM/DSS mice
received Ro26–2198 (0.01 mg/kg body weight/day × 28 days) or vehicle by mini-
osmotic pump 1 week prior to treatment with carcinogen. Subsequently, AOM/SDS
mice are treated with a single dose of 5 mg/kg AOM and receive 3% DSS in their
water for 7 days at the beginning of week 3. Mice receiving Ro26–2198 treatment
had a delayed onset of colitis and those not treated with Ro26–2198 had several
dysplastic foci. These results support a chemopreventive effect of vitamin D in
colorectal cancer.
To further support that vitamin D has chemopreventive properties, Kallay et al.
compared hyperproliferation and oxidative damage in mice with wild-type vita-
min D receptor (VDR) (VDR ), heterozygote VDR (VDR ) and knock out of
+/+
+/−
−/−
the VDR (VDR ) mice [21]. An inverse relationship was found between VDR
expression and proliferation in the colon, with the VDR mice having a higher
−/−
rate of proliferation. These studies demonstrate a significant role for vitamin D in
modulating proliferation. Additionally it was demonstrated that there was an
increase in the expression of 8-hydroxy-20-deoxyguanosine (8-OHdG), a marker
−/−
−/−
of oxidative stress in the VDR mice resulting in the VDR mice having a
higher amount of oxidative damage. Over all this study demonstrated that the
genomic action of 1,25(OH) D that is modulated by VDR expression is required
2 3
to protect against the nutritional linked hyperproliferation and oxidative
damage.
By and large, the preclinical studies examining the effect of vitamin D in the
3
diet and/or administration of the active metabolite or its analogs support the notion
that there is chemopreventive potential for vitamin D in colorectal cancers. The
rationale that vitamin D has chemopreventive potential is further reinforced by the
demonstration that there is a relationship between VDR status and proliferation.
More studies may be required to further elucidate the impact of dose and timing for
clinical studies; however, it is plausible that vitamin D can alter the course of pro-
gression of colorectal cancers.