The chemopreventive efficacy of
toremifene, an
antiestrogen, was evaluated in the transgenic
adenocarcinoma of mouse prostate (TRAMP) model. TRAMP mice were segregated into three groups: (a) the low-dose
toremifene group (6.6 mg/kg/day); (b) the high-dose
toremifene group (33 mg/kg/day); and (c) the control placebo group. Efficacy of treatment was measured by the absence of palpable
tumor. To extend these studies using more sensitive techniques, TRAMP mice were then treated with placebo,
flutamide (an
antiandrogen; 33 mg/kg/day), or
toremifene (10 mg/kg/day). Animals from each treatment group were sacrificed at 7, 10, 15, 20, 25, and 30 weeks of age, and prostate tissues and seminal vesicles were harvested. Tissues from animals (n = 5) in each group were evaluated by wholemount dissections of genitourinary tracts, histology, immunohistochemistry, and Western blot analyses. Blood was pooled per group to measure
estradiol and
testosterone hormonal levels.
Tumors formed at week 17 in the placebo group (n = 10), at week 21 in the high-dose
toremifene group (n = 12), and at week 29 in the low-dose
toremifene group (n = 12). This represents an increased
tumor latency of up to 12 weeks. By 33 weeks, all animals in the placebo group had
tumors compared with only 35% of the animals treated with
toremifene. Although both
flutamide and
toremifene decreased
tumor incidence compared with the placebo,
toremifene was more effective than
flutamide. High-grade
prostatic intraepithelial neoplasia was observed in animals in the placebo group, but not in animals treated with
toremifene. Moreover,
toremifene-treated animals had prolonged survival compared with placebo-treated animals. By 33 weeks of age, 100% of the placebo-treated animals had developed palpable
tumors and died, whereas 60% of the
toremifene-treated animals were
tumor free.
T antigen levels in the prostate of
toremifene-treated animals were similar to those of placebo-treated, age-matched animals. Whereas serum
estradiol levels remained unchanged, the total and free
testosterone levels were elevated in the
toremifene-treated group.
Toremifene treatment did not affect
androgen receptor levels. Because
toremifene prevented
prostate cancer in a milieu of elevated blood free
testosterone levels with no change in prostate
androgen receptor expression, the mechanism of
toremifene's chemopreventive activity may be through nonandrogenic pathways, such as
estrogen receptor signaling.