Page 192 - Vitamin D and Cancer

8 Vitamin D and Cancer Chemoprevention 179

8.2.2 Prostate Cancer

In a study by Banach-Petrosky et al. the chemopreventive activity of 1,25(OH) D
2
3
was investigated in the Nkx3.1;Pten mutant model of prostate cancer [18]. This
model has a loss of function of Nkx3.1 and the tumor suppressor Pten. With time,
Nkx3.1;Pten mutant mice develop progressive prostate cancer with histopathology
ranging from intraepithelial neoplasia (PIN) to adenocarcinoma. In this study, wild-
type litter mates (Nkx3.1+/+;Pten+/+) were compared with mutant mice
(Nkx3.1−/−;Pten+/−). An osmotic pump was used to give a continuous dose of
1,25(OH) D to the animals at a rate of 0.25 mL/h for a dose of 46 ng/kg/day.
2
3
Treatment was initiated prior to the formation of cancerous lesions or after cancer
had been established. Disease status was evaluated by histological evaluation.
Treatment with 1,25(OH) D had no effect on the wild-type litter mates. However,
2
3
mutant mice displayed a reduction in high-grade PIN lesions when treatment was
administered prior to the onset of cancer. In the precancerous cohort treated with
vehicle alone 0/8 animals had low-grade PIN and 8/8 had high-grade PIN with inva-
sion compared with the 1,25(OH) D treatment cohort that had 10/12 with low-
3
2
grade PIN and 2/12 with high-grade PIN. In contrast when 1,25(OH) D was
3
2
administered to animals with established disease no preventive effect was observed.
This study demonstrated a clear preventive effect of 1,25(OH) D when treatment
2
3
was administered in the precancerous stage.
Perez-Stable et al. used the Gg/T-15 model of prostate cancer to examine the
chemopreventive activity of the 1,25(OH)2D analog EB1089 [22]. The Gg/T-15
3
model is a transgenic mouse model that uses the human fetal the globin promoter
to express SV40 T antigen. These mice rapidly develop prostate cancer with
expression of the transgene detectable by 11 weeks of age and tumors present by
16 weeks of age. The transgene is expressed in the cells in the basal layer of the
prostate. The tumors that develop are refractory to androgens and have a more
neuroendocrine phenotype. Mice were administered EB1089 by IP injection three
times a week at 0.5, 2, 3, 5, or 10 mg/kg starting at 14 weeks of age, 0.5, 2, 3, or
4 mg/kg at 12 weeks of age and 2 mg/kg at 9 weeks of age. Animals were palpated
for tumors 3× week and tissues collected 21 days post detection of a palpable tumor
or at 24 weeks of age. Prostatic tissues were collected and evaluated for the pres-
ence of tumors. In this model, no difference in the tumor incidence was observed
at any treatment dose or timing of initiation of treatment. However, tumor size was
decreased in animals treated with higher doses of EB1089 (>4 mg/kg) and the num-
ber of metastatic lesions was decreased in animals receiving the 10 mg/kg dose. The
authors demonstrate that EB1089 inhibits growth in BPH-1 cells expressing SV40
T antigen. Thus, the expression of the transgene does not render the cells unrespon-
sive to EB1089. The authors contend that the target cells in the model may be
insensitive to vitamin D. This is supported by the low level of VDR expression in
target cells that undergo carcinogenesis in this model. It should be noted that the
most effective doses at inhibiting tumor size were not administered at the early time
point (9 weeks of age). The doses given at the earliest time point were not effective