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PubMed2001

Selective estrogen receptor modulation: the search for an ideal hormonal therapy for breast cancer.

Female hormones, especially estrogens, play an important role in the pathogenesis of breast neoplasms and are a principal determinant of their biological behavior. Endocrine manipulation through medical or surgical means can often lead to objective shrinkage of breast tumors. Tamoxifen, a triphenylethylene estrogen receptor modulator, is currently the most widely used hormonal treatment for breast cancer. It has been conclusively demonstrated to reduce the risk of relapse following definitive local therapy (and systemic chemotherapy, when indicated) of invasive or noninvasive breast cancer. Recently, it has also been shown to reduce the incidence of breast cancer in healthy women who are at high risk of developing the disease. In addition, it can prevent osteoporosis and reduce the risk of fractures in postmenopausal women. However, its use is also complicated by an increased incidence of endometrial hyperplasia/carcinoma, venous thromboembolism, cataracts, and in some cases, emergence of tamoxifen-dependent clones of breast cancer. These side effects (except cataracts) are believed to be related to estrogen-agonist effects of tamoxifen. Newer drugs, which are "pure antiestrogens" or inhibitors of estrogen biosynthesis, are devoid of such estrogen-agonist activity and may not have the liability of many of these side effects. However, these agents would also be expected to lack the potentially beneficial effects of tamoxifen on lipids and skeletal system. The ability of tamoxifen to act as an estrogen-agonist or estrogen-antagonist in a tissue-specific fashion has led to the concept of selective estrogen-receptor modulation. Selective estrogen receptor modulators (SERMs), which are devoid of estrogen-agonist effects on the uterus or breast cancer cells but retain potentially beneficial effects on bones and lipids, have been described as "ideal" SERMs. A number of such compounds are currently being tested. Raloxifene is already approved for prevention of osteoporosis and has potential efficacy for prevention and treatment of breast cancer. An analogue of raloxifene, LY353381, is currently in Phase II clinical trials for treatment of breast cancer, with promising early results. EM800 and CP336156 are other promising ideal SERMs in clinical trials. These compounds may provide better treatment and chemoprevention alternatives for breast cancer as compared to tamoxifen, aromatase inhibitors, and pure antiestrogens. In addition, they may also prove to be useful for the treatment and prevention of prostate cancer as well as for treating benign gynecological diseases such as fibroids and endometriosis. Future laboratory efforts should focus on further broadening the efficacy profile of SERMs (e.g., prevention of Alzheimer's disease and elevation of high-density lipoproteins to improve the likelihood of cardiovascular benefit) and narrowing their side-effect profile (e.g., risk of thromboembolism and hot flashes).

Antineoplastic Agents, Hormonal↗

PubMed1999

The evolving role of specific estrogen receptor modulators (SERMs)

Estrogens are the most effective therapy for women with postmenopausal problems. However, relatively few women use estrogen and then often for a limited time because of the fear of its carcinogenic effects on the uterus and breast; in addition, estrogen is not advised for women who have had breast cancer. Selective estrogen receptor modulators (SERMs) are agents with antagonist action on the uterus and breast and agonist action on the bones, cardiovascular system, and brain. Unlike estrogens, however, existing SERMs do not help alleviate the vasomotor and urogenital problems associated with menopause. A comprehensive review of the literature published from January 1995 to June 1999 was conducted. Reports were identified using Medline and Cancer Lit. The effect of menopausal problems on the health of women and the socioeconomic effects of menopause are discussed. All currently available and investigational SERMs are reviewed and discussed, including their mechanism of action, metabolism, dose scheduling, antitumor activity, and potential role in maintaining the health of menopausal women and in preventing breast cancer.

Aged↗

PubMed2002

A new series of estrogen receptor modulators that display selectivity for estrogen receptor beta.

A series of 1,3,5-triazine-based estrogen receptor (ER) modulators that are modestly selective for the ERbeta subtype are reported. Compound 1, which displayed modest potency and selectivity for ERbeta vs ERalpha, was identified via high-throughput screening utilizing an ERbeta SPA-based binding assay. Subsequent analogue preparation resulted in the identification of compounds such as 21 and 43 that display 25- to 30-fold selectivity for ERbeta with potencies in the 10-30 nM range. These compounds profile as full antagonists at ERbeta and weak partial agonists at ERalpha in a cell-based reporter gene assay. In addition, the X-ray crystal structure of compound 15 complexed with the ligand binding domain of ERbeta has been solved and was utilized in the design of more conformationally restrained analogues such as 31 in an attempt to increase selectivity for the ERbeta subtype.

Crystallography, X-Ray↗

PubMed2001

Selective estrogen receptor modulators: the ideal estrogen replacement?(2)(2).

The ultimate estrogen for replacement therapy should exert beneficial actions upon the skeletal, cardiovascular, and central nervous systems while displaying minimal side effects in the uterus and breast. Selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, have recently been studied to achieve these aims. Not only are these agents potentially effective in reducing a patient's risk of breast carcinoma but they have also been shown to increase bone mineral density and prevent osteoporosis. Displaying favorable effects on lipid metabolism, SERMs also may be protective against coronary heart disease and myocardial infarction. Tamoxifen's adverse side effects on the uterus have not been noted with raloxifene, because the latter behaves as an estrogen antagonist in the endometrium. Ongoing studies, such as the Study of Tamoxifen and Raloxifene and the Raloxifene Use for the Heart trials, may help to further determine whether SERMs are the ideal estrogen for the postmenopausal female patient.

Journal Article↗

PubMed2002

Regulation of estrogen target genes and growth by selective estrogen-receptor modulators in endometrial cancer cells.

OBJECTIVE: Tamoxifen has mixed agonist/antagonist activities, leading to tissue-specific estrogen-like actions and endometrial cancer. The purpose of this study was to evaluate the effects of antiestrogens on the growth of estrogen receptor (ER)-positive ECC-1 endometrial cancer cells in vitro and in vivo. METHODS: We performed growth studies and luciferase assays using ERE-tK and AP-1 reporters. ERalpha protein expression was measured by Western blot after antiestrogen treatments. We investigated the actions of antiestrogens on the transcription of the pS2 gene in situ measured by Northern blot and the actions of antiestrogens on the VEGF protein secreted by ELISA. ERalpha, ERbeta, EGFR, and HER2/neu mRNAs were determined by RT-PCR. Last, ECC-1 tumors were developed by inoculation of cells into ovariectomized athymic mice and treated with estradiol (E2), tamoxifen, raloxifene, and a combination. RESULTS: E2 induced cell proliferation while antiestrogens did not. E2 and raloxifene down regulated ERalpha protein; in contrast, 4OHT did not. ICI182,780 completely degraded the receptor. ECC-1 cells express ERbeta at insignificant levels. Luciferase assays did not show any induction in ERE- nor AP-1-mediated transcription by antiestrogens. E2 caused a concentration-dependent increase in pS2 mRNA but antiestrogens did not. E2 increased VEGF expression in a dose-dependent manner and antiestrogens blocked E2 action. E2 down regulated HER2/neu while 4OHT and raloxifene did not change HER2/neu levels compared to control. In addition, EGFR mRNA was down regulated by E2 but raloxifene did not change it. Tamoxifen and raloxifene did not promote tumor growth in vivo. However, raloxifene (1.5 mg daily) only partially blocked E2-stimulated growth. CONCLUSION: Tamoxifen and raloxifene are antiproliferative agents and antiestrogens in ECC-1 endometrial cells in vitro and in vivo. The observation that selective estrogen-receptor modulators do not down regulate EGFR and HER2/neu mRNA may provide a potential role for these oncogenes in the development of raloxifene- or tamoxifen-stimulated endometrial cancer. The ECC-1 cell line could provide important new clues about the evolution of drug resistance to tamoxifen and raloxifene.

Adenocarcinoma↗

PubMed2002

Elucidation of the molecular mechanism of action of selective estrogen receptor modulators.

The term selective estrogen receptor modulator (SERM) describes a group of pharmaceuticals that manifest estrogen receptor (ER) agonist activity in some tissues but opposes estrogen action in others. Although the name describing this class of drugs is new, the concept is not, as compounds exhibiting tissue-selective ER agonist/antagonist properties have been available for nearly 40 years. What is new is the idea that it may be possible to capitalize on the paradoxical activities of SERMs and develop them as target organ-selective ER agonists for the treatment of osteoporosis and other estrogenopathies. This realization has provided the impetus for research in this area, the progress of which is described in this review.

Estradiol↗

PubMed2002

Definition of the molecular and cellular mechanisms underlying the tissue-selective agonist/antagonist activities of selective estrogen receptor modulators.

The term selective estrogen receptor modulators describes a group of pharmaceuticals that function as estrogen receptor (ER) agonists in some tissues but that oppose estrogen action in others. Although the name for this class of drugs has been adopted only recently, the concept is not new, as compounds exhibiting tissue-selective ER agonist/antagonist properties have been around for nearly 40 years. What is new is the idea that it may be possible to capitalize on the paradoxical activities of these drugs and develop them as target organ-selective ER agonists for the treatment of osteoporosis and other estrogenopathies. This realization has provided the impetus for research in this area, the progress of which is discussed in this review.

Animals↗

PubMed2004

[Selective estrogen receptor modulator].

SERMs (selective estrogen-receptor modulators) selectively act on various target tissues under estrogen influence as estrogen-agonists or antagonists. Following publication of an interim report from the Women's Health Initiative (WHI) randomized trial, SERMs have drawn considerable attention as agents of interest, in that they allow almost all beneficial effects of estrogen to be retained while at the same time avoiding the harmful side effects associated with HRT. In this regard, raloxifene is reported to act on bone as an estrogen-agonist as does HRT thereby contributing to a significant decrease in the incidence of osteoporotic fractures, while, in contrast, acting on the breast as an estrogen-antagonist unlike HRT to reduce the incidence of breast cancer, and its further role is expected in the treatment of coronary heart disease. Thus, SERMs are emerging as a class of versatile agents with great potential, and their indications are expected to widen with further research evidence.

Female↗

PubMed2003

The combination of a novel selective estrogen receptor modulator with an estrogen protects the mammary gland and uterus in a rodent model: the future of postmenopausal women's health?

The Women's Health Initiative Study and other reports have created major uncertainty among postmenopausal women and physicians concerning hormone replacement therapy. We have thus investigated the possibility of replacing the progestin in hormone replacement therapy by a novel selective estrogen receptor (ER) modulator having potent and pure antiestrogenic activity in the mammary gland and uterus. As measured by changes in histology and Cdc47 labeling in the rat model, the present study shows that the stimulatory effect of estradiol in the mammary gland and uterus is efficiently blocked by simultaneous administration of the novel selective ER modulator EM-652, but bone mineral density is preserved and serum cholesterol is decreased. After the administration of 14C-labeled EM-652, we observed that there is no detectable radioactivity in the brain. Moreover, ER alpha immunoreactivity remained constant in the hypothalamus after EM-652 treatment, whereas ER alpha became almost undetectable in the mammary gland and uterus. The present data show the poor or absent access of EM-652 to the brain, whereas the effects of estrogens are efficiently neutralized in the mammary gland and uterus. Such data support the exciting possibility of a novel approach that could meet most of the needs of women's health at menopause, namely control of hot flushes and prevention of breast, uterine, and ovarian cancer as well as osteoporosis and potentially helping brain function and preventing Alzheimer's disease with no identifiable risk or negative effect.

Animals↗

PubMed2001

The past, present, and future of selective estrogen receptor modulation.

The recognition of selective estrogen receptor modulation in the mid-1980s provided a unique opportunity to develop multifunctional drugs. Tamoxifen, the first selective estrogen receptor modulator (SERM), is the first antiestrogen to be tested successfully for the prevention of breast cancer in high-risk women. However, the recognition that SERMs maintain bone density and lower circulating cholesterol suggested that the prevention of osteoporosis and coronary heart disease would be beneficial side effects of tamoxifen treatment. This hypothesis has not been pursued in clinical trial, but an alternate hypothesis, that SERMs could be developed to prevent osteoporosis and potentially reduce the risk of breast cancer, has been pursued with raloxifene. Current molecule modeling of the SERM-ER complex has identified the reason for the promiscuous estrogen-like actions of tamoxifen compared with raloxifene. Future studies of the signal transduction pathways of the ER alpha (alpha)- and beta (beta)-SERM complexes hold the promise of new drug discoveries and a menu of preventive medicine in clinical practice.

Animals↗

PubMed1999

Selective estrogen receptor modulators: a look ahead.

Selective estrogen receptor modulators (SERMs) are structurally diverse compounds that bind to estrogen receptors (ER) and elicit agonist or antagonist responses depending on the target tissue and hormonal milieu. They are being evaluated primarily for conditions associated with aging, including hormone-responsive cancer, osteoporosis and cardiovascular disease. Several SERMs are marketed or are in clinical development, including triphenylethylenes (tamoxifen and its derivatives: toremifene, droloxifene and idoxifene), chromans (levormeloxifene), benzothiophenes (raloxifene, LY353381) and naphthalenes (CP336,156). Tamoxifen and toremifene, both used to treat advanced breast cancer, also have beneficial effects on bone mineral density and serum lipids in postmenopausal women. Tamoxifen was recently shown to decrease the risk of invasive breast cancer in women at high risk. Unfortunately, both drugs also have stimulatory effects on the endometrium. Raloxifene, used for prevention of postmenopausal osteoporosis and fragility fractures, also has favourable effects on bone mineral density, serum lipids and the incidence of invasive breast cancer in postmenopausal women but does not stimulate the endometrium. Like replacement estrogens, SERMs increase the risk of venous thromboembolism. SERMs offer post-menopausal women many of the advantages of estrogen replacement while mitigating some of the disadvantages, particularly the concern over breast cancer. Newer SERMs, exemplified by raloxifene, also eliminate the concerns over endometrial stimulation that were not addressed by first generation SERMs. The clinical success of SERMs has set the stage for a variety of drug therapies based on selective modulation of nuclear receptor activity.

Estrogen Antagonists↗

PubMed2004

Breast cancer chemoprevention phase I evaluation of biomarker modulation by arzoxifene, a third generation selective estrogen receptor modulator.

PURPOSE: Arzoxifene, a new selective estrogen receptor modulator with strong breast antiestrogen activity and absence of uterine agonist activity, was explored as a potential chemoprevention agent. We performed a multi-institutional evaluation of arzoxifene in women with newly diagnosed ductal carcinoma in situ or T1/T2 invasive cancer. EXPERIMENTAL DESIGN: In a Phase IA trial, 50 pre- or postmenopausal women were randomized to 10, 20, or 50 mg of arzoxifene daily in the interval between biopsy and re-excision or were enrolled as no-treatment controls. In a Phase IB trial, 76 postmenopausal women were randomized to 20 mg of arzoxifene versus matched placebo. Serum specimens collected at entry and at re-excision were assayed for various hormones and growth factors. Tissue from biopsies (estrogen receptor + and/or progesterone receptor +) and re-excision specimens was evaluated immunohistochemically for proliferation (Ki-67 by MIB-1 and proliferating cell nuclear antigen) and other biomarkers. RESULTS: In both trials, increases in serum sex hormone binding globulin were noted, as were decreases in insulin-like growth factor (IGF)-I and the IGF-I:IGF binding protein-3 ratio (P < 0.007 versus control/placebo). For 45 evaluable women in Phase IA, decreases in proliferation indices were more prevalent for arzoxifene (particularly 20 mg) than for controls. For 58 evaluable women in Phase IB, a decrease in estrogen receptor expression for arzoxifene was observed compared with no change with placebo (P = 0.0068). However, decreases in proliferation indices for arzoxifene were not statistically different from placebo, perhaps due to a confounding effect of stopping hormone replacement therapy before entry. CONCLUSION: Given the favorable side effect profile and the biomarker modulations reported here, arzoxifene remains a reasonable candidate for additional study as a breast cancer chemoprevention agent.

Anticarcinogenic Agents↗

PubMed2000

Selective estrogen receptor modulators--a new age of estrogens in cardiovascular disease?

A large body of evidence suggests hormone replacement therapy (HRT) reduces cardiovascular risk in postmenopausal women. It is, however, associated with serious side effects, such as increased risk of breast and endometrial cancer. This has likely caused uneasiness among both women and health care providers. A new class of compounds, called selective estrogen receptor modulators (SERMs), have emerged. Through their interactions at the estrogen receptor level they have become a class of compounds distinct from estrogen. While they share similar effects with estrogen on such factors as lipid profile and bone density, they affect other tissues differently. Specifically, they do not induce endometrial hyperplasia and are therefore not associated with endometrial cancer. In vitro studies have also shown that they inhibit lipoprotein oxidation and vascular smooth muscle cell proliferation. The cumulative effects of these compounds may prove quite beneficial in reducing cardiovascular risk in postmenopausal women while avoiding serious side effects. This may, in turn, ease much of the anxiety surrounding the issue of HRT. Clinical trials are presently being conducted to evaluate the effectiveness of raloxifene, a SERM, on cardiovascular risk reduction in postmenopausal women.

Adult↗

PubMed2004

Benzoxepin-derived estrogen receptor modulators: a novel molecular scaffold for the estrogen receptor.

We present and examine the efficacy of a novel benzoxepin-based scaffold for modulation of the human estrogen receptor. Receptor tolerance of this new molecular scaffold is examined through presentation of experimentally determined antiproliferative effects on human MCF-7 breast tumor cells and measured binding affinities. The effect of functional group substitution on the benzoxepin scaffold is explored through a brief computational structure-activity relationship investigation with molecular simulation.

Antineoplastic Agents↗

PubMed2001

Future use of selective estrogen receptor modulators and aromatase inhibitors.

Selective estrogen receptor modulators (SERMs) may act as estrogens or antiestrogens depending on the cell and tissue targets. The triphenylethylene SERMs are represented by tamoxifen and toremifene and a new agent with a novel carboxylic acid side chain (GW5638). Because of isomerization in the triphenylethylene molecule, "fixed ring" SERMs were introduced. The major one in development is the benzothiophene arzoxiphene (LY353381), which is now in Phase III clinical trial versus tamoxifen. A fourth group of SERMs is based on the estrogen molecule and comprises the so-called "pure" antiestrogen ICI 182,780 (fulvestrant, Faslodex) and a new oral analogue just entering trials, SR16234. The steroidal aromatase inhibitors [AIs (40H androstenedione 'and exemestane)] inactivate aromatase, whereas the triazole AIs (anastrozole and letrozole) inhibit the enzyme via the heme prosthetic group. Thus, there are two groups of AIs that show relative non-cross-resistance in advanced breast cancer and four groups of SERMs that also show a high degree of non-cross-resistance. With six different treatments and six or more clinical situations (prevention, neoadjuvant, adjuvant, and first- and second-line treatments for advanced disease) in which they may be used, the possible combinations of treatment are enormous. At present, we have few clinical pointers to optimal sequence of treatments. Now that most of the appropriate comparative trials have been performed, it may be the time to initiate novel approaches. These include alternating and sequential treatments, preferably with treatments changed before overt progression occurs.

Aromatase Inhibitors↗

PubMed2000

[Clinical results of selective estrogen receptor modulators (SERM)].

The SERMs (selective estrogen receptor modulators) are a new class of molecules that bind to the estrogen receptor, resulting in an estradiol agonist or antagonist response according to the target tissue. Raloxifene, a new SERM, has been shown to prevent postmenopausal bone loss, to reduce the risk of vertebral fractures in osteoporotic women, to decrease serum cholesterol and its LDL fraction, and to reduce significantly the risk of breat cancer. Raloxifene is available in France for the prevention of post-menopausal osteoporosis.

Bone and Bones↗

PubMed2004

[Lasofoxifene, a next generation estrogen receptor modulator: preclinical studies].

Estrogen replacement therapy, in spite of efficacy in the prevention of osteoporotic fractures, has significant side effects and risks that limit its widespread usage in postmenopausal women. Thus significant medical need exists to find modalities that prevent osteoporosis, but without the side effects of estrogen. Selective estrogen receptor modulators (SERMs) have the potential to provide the skeletal benefits of estrogen without the increased risk of uterine and breast cancer. Tamoxifen, a first generation SERM is approved for the prevention and treatment of breast cancer, and raloxifene, a second generation SERM has been approved for the prevention and treatment of osteoporosis. Lasofoxifene, a new potent, nonsteroidal SERM, binds with high affinity to human estrogen receptors and acts as a tissue selective estrogen antagonist or agonist. In preclinical models of postmenopausal osteoporosis, lasofoxifene inhibited bone turnover and prevented bone loss throughout the skeleton. In studies designed to investigate the combination of lasofoxifene with estrogen, lasofoxifene blocked the hypertrophic effects of estrogen in the uterus, but did not block the bone protective effects. In immature and aged female rats, lasofoxifene did not affect the uterine weight and uterine histology. In preclinical studies designed to evaluate the effects of lasofoxifene on the uterus, a slight increase in wet uterine weight was observed in immature and aged female rats, but this difference was not observed in dry uterine weight suggesting that the increased uterine weight was due to increased water content in the tissue. In preclinical studies designed to evaluate the effects of lasofoxifene in breast cancer, lasofoxifene inhibited breast tumor formation in mice injected with human MCF-7 breast cancer cells and in rats bearing mammary carcinomas. Thus, in preclinical models, lasofoxifene, a next generation SERM, prevents estrogen deficiency-induced bone loss, inhibits breast tumor formation, and reduces serum cholesterol, without causing uterine hypertrophy. These data suggest that lasofoxifene is a new potential therapy for the prevention of osteoporosis in postmenopausal women.

Animals↗

PubMed1997

Molecular determinants of tissue selectivity in estrogen receptor modulators.

Interaction of the estrogen receptor/ligand complex with a DNA estrogen response element is known to regulate gene transcription. In turn, specific conformations of the receptor-ligand complex have been postulated to influence unique subsets of estrogen-responsive genes resulting in differential modulation and, ultimately, tissue-selective outcomes. The estrogen receptor ligands raloxifene and tamoxifen have demonstrated such tissue-specific estrogen agonist/antagonist effects. Both agents antagonize the effects of estrogen on mammary tissue while mimicking the actions of estrogen on bone. However, tamoxifen induces significant stimulation of uterine tissue whereas raloxifene does not. We postulate that structural differences between raloxifene and tamoxifen may influence the conformations of their respective receptor/ligand complexes, thereby affecting which estrogen-responsive genes are modulated in various tissues. These structural differences are 4-fold: (A) the presence of phenolic hydroxyls, (B) different substituents on the basic amine, (C) incorporation of the stilbene moiety into a cyclic benzothiophene framework, and (D) the imposition of a carbonyl "hinge" between the basic amine-containing side chain and the olefin. A series of raloxifene analogs that separately exemplify each of these differences have been prepared and evaluated in a series of in vitro and in vivo assays. This strategy has resulted in the development of a pharmacophore model that attributes the differences in effects on the uterus between raloxifene and tamoxifen to a low-energy conformational preference imparting an orthogonal orientation of the basic side chain with respect to the stilbene plane. This three-dimensional array is dictated by a single carbon atom in the hinge region of raloxifene. These data indicate that differences in tissue selective actions among benzothiophene and triarylethylene estrogen receptor modulators can be ascribed to discrete ligand conformations.

Animals↗