Raloxifene (LY156758) produces antimetastatic responses and extends survival in the paiii rat prostatic adenocarcinoma model

Abstract

The benzothiophene antiestrogen, raloxifene (LY156758), has selective estrogen pharmacological antagonist activity in rats. The PAIII rat prostatic adenocarcinoma model was used to evaluate the effects of this agent on the lymphatic and pulmonary metastasis and survival in tumor-bearing male Lobund-Wistar (LW) rats. Raloxifene was inactive against colony formation of PAIII cells in vitro. Similarly, following subcutaneous (s.c.) implantation of 10(6) PAIII cells in the tail, s.c. administration of raloxifene (2.0, 10.0, or 20.0 mg/kg/day) for 30 days failed to demonstrate cytoreductive activity against primary tumor growth in the tail. However, in these same animals, raloxifene administration produced significant (P < 0.05) inhibition of PAIII metastasis from the primary tumor in the tail to the gluteal and iliac lymph nodes (maximal responses = 89% and 81% from control values, respectively). PAIII metastasis to the lungs was significantly inhibited by raloxifene treatment. Numbers of pulmonary foci in PAIII-bearing rats were significantly (P < 0.05) reduced by raloxifene administration in a dose-related manner (maximal reduction = 97% from control values). In these animals, maximal regression of 20% for ventral prostate and 21% for seminal vesicle were also seen after raloxifene administration (P < 0.05 for both). Coadministration of E2B and raloxifene had no consistent antagonistic effect upon the antitumor responses produced by raloxifene. Raloxifene (40.0 mg/kg/day for 28 days) produced marked decreases in PAIII metastasis in the lymphatic and pulmonary components. Continued administration of the compound produced significant (P < 0.05) extension of survival of PAIII-bearing rats. Further studies are needed to define the maximal antitumor efficacy and the mechanism of action of raloxifene in urogenital solid tumor animal models. These data support the contention that raloxifene represents a class of active antimetastatic agents with potential efficacy in the treatment of hormone-insensitive human prostatic cancer.

Role of estrogens in development of prostate cancer

“…Both decreased the metastatic speading of PAIII prostatic rat adenocarcinoma from primary tumors in Lobund-Wistar rats and increased the survival of the animals [89,90]. Raloxifene was also shown to induce apoptosis of both androgen dependent and independent prostate cancer cell lines in vitro [91].…”

Estrogen action and prostate cancer

“…Some anti-estrogen SERMs have been evaluated for prostatic responses in animal and cell culture models and as a few clinical trials and were recently summarized in a review by Bonkhoff and Berges [130]. Briefly, the antiestrogens tamoxifen, raloxifene, trioxifene, ICI and toremifene inhibited cancer cell growth and/or induced cancer cell apoptosis in vitro or in vivo [172–178]. One recent study of particular note demonstrated that ER-selective agonists exhibited differential regulation of the oncogenic TMPRSS2–ERG fusion gene in prostate cells, with ERα agonists stimulating expression and ERβ agonists inhibiting the oncogene expression [179].…”

Molecular, Cellular, and Developmental Biology of Breast Cancer

“…39,40 Studies in Drosophila species have also identified genetic connections between taiman, the homologue of the estrogen coactivator amplified in breast cancer (AIB1), cadherin expression, and cell migration. [45][46][47] Thus, evidence is accumulating that estrogens, ER, and estrogen coactivators function to regulate cell morphology and migration in addition to proliferation. Each of these factors likely functions in the continual remodeling that is required of normal breast throughout the mammary cycle, but when dysregulated, each promotes invasion and metastasis, which lie at the root of breast cancer mortality.…”