The Journal of Steroid Biochemistry and Molecular Biology
Ospemifene inhibits the growth of dimethylbenzanthracene-induced mammary tumors in Sencar mice
Introduction
Selective estrogen receptor modulators (SERMs) are a unique class of compounds that induce structural changes in the estrogen receptor (ER), which lead to either an estrogen agonistic response or an estrogen antagonistic response, depending both on the target tissue and the pharmacological activity of a particular SERM [1], [2], [3], [4]. The goal in SERM development, especially for prophylactic use in healthy women, is to design a compound with specific target tissue activity, which would optimize the beneficial effects of the drug and minimize the adverse effects. For example, the ideal SERM would have ER antagonistic effects on breast tissue while having estrogenic or agonistic effects on bone and the cardiovascular system, and neutral effects on the endometrium. The activity of SERMs is thought to be regulated through two ERs, ER-α and ER-β. The ligands, or SERMs, diffuse into the cell and bind to either ER-α or -β, causing a conformational change, which results in receptor dimerization. This promotes the interaction of the receptor with the promoter regions of the DNA, causing either a transcriptional activation or repression of estrogen target genes [5].
Tamoxifen, the first clinically useful SERM, is a triphenylethylene (Fig. 1) that has been used for the treatment of breast cancer for over 25 years [6], [7], [8], [9]. As a result of tamoxifen's clinical activity in breast cancer, the National Surgical Adjuvant Breast and Bowel Project's (NSABP) Breast Cancer Prevention Trial was initiated to evaluate tamoxifen as a chemopreventive agent. The trial showed tamoxifen reduced the risk of invasive breast cancer by 49% and noninvasive breast cancer by 50%, ultimately resulting in FDA approval of tamoxifen for reducing the risk of breast cancer in women at high risk of developing the disease [10], [11].
Raloxifene is a benzothiophene SERM (Fig. 1) that has been approved for the treatment and prevention of osteoporosis, and similar to tamoxifen, is associated with several adverse effects including hot flashes, leg cramps, influenza-like symptoms and thromboembolic events [12], [13]. However, unlike tamoxifen, it has not been associated with an increased risk of endometrial cancer, which is most likely a result of its clinically insignificant effects in the endometrium [12]. Though raloxifene is approved to treat osteoporosis, it is now being evaluated for chemopreventive effects on breast cancer as a result of its antiestrogenic activity in breast tissue [12].
Ospemifene, a triphenylethylene compound, is currently in phase III trials for the treatment of urogenital atrophy and secondarily for the prevention of osteoporosis (Fig. 1) [14], [15]. Phases I and II trials have demonstrated that ospemifene is well tolerated in healthy postmenopausal women [15], [16], [17], [18]. Though it has primarily been studied for its effects on improving bone mass and inhibiting bone loss, ospemifene has also been shown to have antiestrogenic effects on breast tissue [14]. Ospemifene appears to have few clinically significant side effects. Unlike tamoxifen which acts as an estrogen agonist in endometrial tissue, ospemifene has been shown to have neutral effects in the endometrium at clinically relevant doses [15], [16], [17]. Ospemifene treatment does not result in a high incidence of side effects commonly associated with tamoxifen and raloxifene, such as hot flashes, insomnia [15], [16], [17], nervousness, dizziness, melancholy, weakness, joint or muscle pain, headache, breast tenderness or skin itch [17]. Ospemifene also has a significant estrogenic effect in vaginal tissue [15], [17], and unlike other SERMs, does not cause vaginal dryness [15], [16]. Furthermore, to date, no thromboembolic complications have been reported [16], which is a common fear among patients receiving hormonal therapies. With the decline in hormone replacement therapy (HRT) use following the report from the Women's Health Initiative (WHI) study that HRT increases the incidence of breast cancer [19], ospemifene may also provide an alternative to postmenopausal women seeking hormonal therapies. Given the overall tolerability of ospemifene and its antiestrogenic effects in breast tissue, it is important to determine whether ospemifene may be a good candidate for breast cancer chemoprevention.
Section snippets
Chemicals
Tamoxifen was a gift from the Orion Corporation, Orion-Pharma (Espoo, Finland). Raloxifene was manufactured by Toronto Research Chemicals, Inc. (North York, Ont., Canada) and was donated by Hormos Medical Corporation (Turku, Finland). Ospemifene (Z-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol) was provided by the Orion Corporation, Orion-Fermion, (Espoo, Finland). OSP VI (4-hydroxyospemifene), OSP VIII (2-carboxy-4-hydroxyospemifene), OSP XIII (ospemifene monophenol) and OSP XVIII
Chemoprevention study
To evaluate the effects of ospemifene, tamoxifen and raloxifene on the incidence of mammary carcinomas in the DMBA-induced mammary carcinoma mouse model, four groups of mice were implanted with MPA pellets and were treated daily by oral gavage for 6 weeks with 20 μg DMBA, in combination with 50 mg/(kg day) ospemifene, tamoxifen or raloxifene. The control mice were treated with vehicle plus DMBA only. At the end of the first 6 weeks, DMBA treatment was discontinued, however, daily drug treatments
Discussion
Two separate studies were conducted to determine the ability of ospemifene compared to tamoxifen to prevent development of DMBA-induced mammary carcinoma in a Sencar mouse model. The first, comparing ospemifene to tamoxifen and raloxifene, ran for a period of 37 weeks. To verify the effects of ospemifene observed in the first study, a second, longer-term (52 weeks) study comparing ospemifene to tamoxifen was performed. In both studies, ospemifene and tamoxifen were able to prevent the
Acknowledgements
This work was supported in part by National Institutes of Health (NIH) grant ES007059-NIEHS traineeship, Department of Environmental Toxicology (K.C. Read), Hormos Medical Corporation, Turku, Finland (G.T. Wurz and M.W. DeGregorio), Grant R01-CA89140-01 from the National Cancer Institute (J.P. Gregg), Grant 9WB-0150 from the California Breast Cancer Research Program (G.T. Wurz, C. Marchisano-Karpman and M.W. DeGregorio), and the UC Davis Cancer Center Support Grant NIH #1 P30 CA93373-01 (G.T.
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