Page 193 - Vitamin D and Cancer

180 S.A. Mazzilli et al.

at inhibiting tumor growth and may have been too low to be effective. So while this
study does not demonstrate a chemopreventive effect of the vitamin D analog, there
are several factors that may contribute to the lack of response.
The studies in the Nkx3.1;Pten model indicate that vitamin D may elicit differ-
ent responses when administered in early versus late stage disease, with the pre-
ventive benefits being greatest when 1,25(OH) D is administered prior to
2 3
established disease. Elevated 1,25(OH) D levels prevented/reduced disease pro-
2 3
gression when administered early, while 1,25(OH) D had an antiproliferative
2 3
effect on established disease. This study supports the use of vitamin D for the
prevention of early stage prostate cancer. The studies using the Gg/T-15 model did
not demonstrate a preventive effect of the vitamin D analog, but did demonstrate
an antiproliferative response for the primary tumor and the metastatic lesions. The
lack of a preventive effect in the Gg/T-15 model compared to Nkx3.1;Pten model
could be due to several compounding factors. The target cells may not be able to
respond to VDR as suggested by the lack of VDR; the dose of vitamin D used at
the early stage disease was much lower than that used in the Nkx3.1;Pten model
and was a dose that was not sufficient to reduce proliferation in the model; and the
phenotype of the disease was different. The Nkx3.1;Pten model develops adeno-
carcinoma which retains androgen responsiveness while the Gg/T-15 model devel-
ops prostate cancer from the basal cells that is hormone refractory and has a more
neuroendocrine phenotype. These studies suggest that vitamin D may be more
effective as a chemopreventive agent against adenocarcinoma and less effective
against hormone refractory disease. However, both studies support a role for vita-
min D to prevent/limit the growth of prostate cancer at both early and late stage
disease.

8.2.3 Breast Cancer

To examine the chemopreventive effects of vitamin D in breast cancer similar meth-
ods seen in the examination of colorectal cancer were employed. Jacobson et al.
used a carcinogen-induced rat model of breast cancer to examine the effects of a
high fat combined with low vitamin D and low calcium diet on formation of tumors
compared to a low fat and calcium and vitamin D sufficient diet [23]. The rat model
utilized in this study was a female Sprague-Dawley rat treated with dimethylbenz(a)
anthracene (DMBA). At 43 days of age the rats received a starter diet consisting of
7% sunflower seed oil (SF)/kcal, 1.5 mg calcium (Ca)/kcal, and 0.5 IU vitamin D
3
(D)/kcal. Subsequently, the rats were treated with 2.5 mg DMBA via gastric gavage
and maintained on the starter diet for a second week. The rats were then split into
six cohorts receiving: (I) 38.5% SF/kcal, 1.5 mg Ca/kcal and 0.5 IU D/kcal per diet;
(II) 38.5% SF/kcal, 0.25 mg Ca/kcal and 0.05 IU D/kcal per diet; (III) 38.5%
SF/kcal, 0.1 mg Ca/kcal & 0.05 IU D/kcal per diet; (IV) 7% SF/kcal, 1.5 mg Ca/kcal
and 0.5 IU D/kcal per diet; (V) 7% SF/kcal, 0.25 mg Ca/kcal and 0.05 IU D/kcal
per diet; and (VI) 7% SF/kcal, 0.1 mg Ca/kcal and 0.05 IU D/kcal per diet. The rats