Trioxifene (LY133314) is a
selective estrogen receptor modulator (
SERM) with competitive binding activity against
estradiol for
estrogen receptor alpha (
ERalpha) and antagonistic activity against
ERalpha-mediated gene expression. The PAIII rat prostatic
adenocarcinoma (PCa) is an
androgen receptor-negative,
ERalpha- and
ERbeta-positive, spontaneously metastatic rodent tumor cell line. After s.c. implantation of 10(6) PAIII cells in the tail, s.c. administration of
trioxifene (2.0, 4.0, 20.0, or 40.0 mg/kg-day) for 30 days produced significant (P < 0.05) inhibition of PAIII
metastasis from the primary
tumor in the tail to the gluteal and iliac lymph nodes (maximum nodal weight decreases, 86% and 88% from control values, respectively). PAIII
metastasis to the lungs was significantly inhibited by
trioxifene treatment. Numbers of pulmonary foci in PAIII-bearing rats were significantly (P < 0.05) reduced by
trioxifene administration in a dose-related manner (maximal reduction, 98% from control values). Continual administration of the compound significantly (P < 0.05) extended survival of PAIII-bearing rats.
Trioxifene inhibited the proliferation of PAIII cells at micromolar levels in vitro but did not slow growth of the primary
tumor growth in the tail.
Trioxifene administration also produced regression of male accessory sex organs. In PAIII-
tumor-bearing animals,
trioxifene administration produced a maximal regression of 76% for ventral prostate and 64% for seminal vesicle (P < 0.05 for both).
SERMs may be preferable to
estrogens given their efficacy in experimental PCa models and relative lack of side effects observed in clinical trials. Our data support the contention that
trioxifene represents a
SERM with potential antimetastatic efficacy for the treatment of
androgen-independent, metastatic PCa.