Transgenic mouse models of
prostate cancer provide unique opportunities to understand the molecular events in prostate
carcinogenesis and for the preclinical testing of new
therapies. We studied the G gamma T-15 transgenic mouse line, which contains the human fetal
globin promoter linked to SV40
T antigen (Tag) and which develops
androgen-independent
prostate cancer. Using the immunohistochemistry of normal mouse prostates before
tumor formation, we showed that the target cells of
carcinogenesis in G gamma T-15 mice are located in the basal epithelial layer. We tested the efficacy of the
1,25(OH)(2)D(3) analogue,
EB 1089, to chemoprevent
prostate cancer in these transgenic mice. Compared with treatment with placebo, treatment with
EB 1089 at three different time points before the onset of prostate
tumors in mice did not prevent or delay
tumor onset. However,
EB 1089 significantly inhibited prostate
tumor growth. At the highest dose,
EB 1089 inhibited prostate
tumor growth by 60% (P = 0.0003) and the growth in the number of
metastases, although this dose also caused significant
hypercalcemia and
weight loss. We conducted several in vitro experiments to explore why
EB 1089 did not prevent the occurrence of the primary
tumors.
EB 1089 significantly inhibited the growth of a Tag-expressing human prostate epithelial cell line, BPH-1, and an
androgen-insensitive subline of LNCaP cells [which was not inhibited by
1,25(OH)(2)D(3)]. Thus, neither Tag expression nor
androgen insensitivity explain the absence of chemopreventive effect. Conversely, neither
1,25(OH)(2)D(3) nor
EB 1089 inhibited the growth of the normal rat prostate basal epithelial cell line NRP-152. It is likely that
EB 1089 was not effective in delaying the growth of the primary
tumor in G gamma T-15 transgenic mice because the target cells of
carcinogenesis in these mice are located in the basal epithelial layer. We conclude that G gamma T-15 transgenic mice are a useful model for testing
vitamin D-based
therapies in
androgen-insensitive
prostate cancer but are not suitable for studies of
vitamin D-based
chemoprevention. The superiority of
EB 1089 over
1,25(OH)(2)D(3) in the growth suppression of
androgen-insensitive
prostate cancer cells supports the use of
EB 1089 in
androgen-insensitive
prostate cancer.