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Results for “Estrogen Receptor Modulators”

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At least 19 recordsLinked to original sources
PubMed2001

Estrogen receptors in rat bone: their interaction with estrogen receptor modulators.

Estrogen receptors (ER) were studied in rat bone cytosol using immunoprecipitation, and Western blot technique. Ligand specificity of bone ER was studied using various known modulators of ER. Competitive experiments were performed under exchange conditions in bone tissue obtained from one day old rats. ER alpha and beta subtypes were identified using immunoblotting experiments compared with that of ovarian and uterine tissues. In competitive binding assay, maximum inhibition in specific 3H-E2 binding was shown by E2 followed by tamoxifen and diethylstilbestrol. 7-Hydroxycentchroman and 85/287 also inhibited specific 3H-E2 binding but were less potent as compared to tamoxifen and diethylstilbestrol. However, 85/287 was less effective (81%) as compared to 7-hydroxycentchroman. Polyacrylamide gel electrophoresis of cytosol and Western blot analysis revealed the presence of 55 kD and 66 kD ER immunoreactive bands corresponding to alpha and beta subtypes, respectively, in bone as well as in uterus. Interestingly, the concentration of 55 kD ER was 3-fold higher than that of 66 kD ER. Ovarian cytosol revealed the presence of a 55 kD band only in Western blot analysis. These studies suggest the action of estrogens/ER modulators on osteoblasts which contain a limited number of classical alpha as well as beta sub types of ER that are known to be structurally different in their hormone-binding domains.

Animals↗
PubMed2001

Silencing and reactivation of the selective estrogen receptor modulator-estrogen receptor alpha complex.

4-Hydroxytamoxifen (4-OHT), a selective estrogen receptor modulator, is an agonist at a transforming growth factor-alpha (TGF-alpha) target gene in situ in MDA-MB-231 human breast cancer cells stably transfected with wild-type human ERalpha. In contrast, raloxifene (Ral) is a complete antiestrogen silencing activation function (AF) 1 and AF2 in this system. A natural mutation D351YERalpha enhances 4-OHT agonist activity and changes Ral-like compounds from antagonists to partial agonists. We reasoned that: either the conformation of the Ral-D351YERalpha is altered, thereby reactivating AF2 in the ligand binding domain, or the change at amino acid 351 allosterically reactivates AF1 in the Ral-D351YERalpha complex. Unlike the estradiol-ERalpha complex, agonist activity of 4-OHT and raloxifene through ERalpha and D351YERalpha were not attributed to coactivator (such as SRC-1, AIB1) binding to the ligand binding domain. We conclude that the classic AF2 is not responsible for the agonist activities of 4-OHT-ERalpha, 4-OHT-D351YERalpha, and Ral-D351YERalpha. To address the role of AF1, stable transfectants of ERalpha or D351YERalpha with an AF1 deletion (D351deltaAF1, D351YdeltaAF1) were generated in MDA-MB-231 cells. Additionally, D538A/E542A/D545A triple mutations within helix 12 (D351-3m, D351Y3m) or the COOH-terminal 537 deletion (D351delta537) were tested. The agonist activities of 4-OHT and raloxifene were lost in these stable transfectants, but antiestrogenic action was retained. The reactivation of an estrogen-like property of the Ral-ERalpha complex through AF1 with the D351Y mutation illustrates a novel allosteric mechanism for the selective estrogen receptor modulator ERalpha complex.

Allosteric Regulation↗
PubMed2000

Mechanism of action of estrogens and selective estrogen receptor modulators.

Estrogen, one of several sex steroid hormones, mediates its actions through the estrogen receptor. The estrogen receptor (ER) has two subtypes, ER alpha and ER beta, each of which predominates in specific tissues and organs. Cofactor proteins interact with the ER to maximize ligand-dependent transactivation of target-gene promoters. The estrogen response element is the final step in estrogen-mediated gene regulation, and current research is focused on alternate response elements. The resulting biologic action can vary according to the specific type of ER, cofactor milieu, response element, and ligand. Selective estrogen receptor modulators (SERMs) exhibit tissue-specific estrogen agonist or antagonist activity. The SERM raloxifene, which binds to ER and targets a distinct DNA element, may distinguish agonist vs antagonist activity by ER subtype and has unique activity among other SERMs because of its molecular conformation. Phytoestrogens, a potential alternative to hormone replacement therapy and for cancer prevention, do not consistently mimic estrogen's activity. Different types of phytoestrogens have different potencies, and taking high-dose supplements after menopause may not emulate the apparent benefits of lifelong consumption of phytoestrogen-rich diets. In conclusion, the complexity of estrogen action--through different ER subtypes, with various cofactors, on alternate response element--is further enhanced by ligands with selective estrogen activity. Additional research is needed to elucidate these pathways and the resulting biological effects.

Estrogens↗
PubMed1999

Selective estrogen receptor modulators.

Selective estrogen receptor modulators are a growing class of nonsteroidal compounds with estrogen-like actions in bone, lipid metabolism, and antiestrogenic actions in the breast. Tamoxifen and its derivatives have a weak estrogenic action in the uterus and are responsible for endometrial hyperplasia. Raloxifene does not stimulate endometrial growth but is less effective than tamoxifen for the treatment of patients with breast cancer. The duality of selective estrogen receptor modulators and 1 7B-estradiol actions is explained by several hypotheses referring to the molecular biology of estrogen receptor. Clinical trials are conducted with raloxifene in post-menopausal women. The results show a significant decrease in vertebral fracture risk and a decrease of low-density lipoprotein cholesterol, with no change in triglyceride levels. Endometrial thickness does not change. Interestingly, the risk for newly diagnosed breast cancer decreases significantly with no change in risk for estrogen receptor-negative tumors. Selective estrogen receptor modulators might change the way we manage hormone replacement therapy of postmenopausal women.

Bone Density↗
PubMed1997

In search of optimal long-term female hormone replacement: the potential of selective estrogen receptor modulators.

Selective estrogen receptor modulators (SERMs) comprise a group of structurally diverse compounds which are distinguished from estrogens by their ability to interact with the estrogen receptor but to act as either an estrogen agonist or antagonist depending on the target tissue and hormonal milieu. The mechanisms by which SERMs elicit tissue-specific responses are being intensively investigated, and recently a novel pathway for estrogen receptor-mediated gene activation by the SERM raloxifene has been demonstrated. The tissue-specific activity of SERMs suggests that they may be clinically useful as, for example, potential substitutes for long-term female hormone replacement therapy. Large-scale clinical testing currently in progress for raloxifene, and soon to begin for other SERMs, will evaluate this important potential.

Aged↗
PubMed2000

Clinical use of selective estrogen receptor modulators.

Selective estrogen receptor modulators (SERMs) are an exciting category of drugs for physicians providing healthcare to women. This article explores their pharmacology, effects on target organs and clinical effectiveness.

Breast Neoplasms↗
PubMed1999

[Effect of selective estrogen receptor modulators on estrogen-sensitive tissues].

Selective estrogen receptor modulators (SERMs) act exclusively through estrogen receptors and possess tissue-specific agonistic or antagonistic properties. The effects of all referred SERMs in bone and cardiovascular system are estrogenic, namely they inhibit postmenopausal bone loss and favorably influence plasma lipoproteins and some coagulation factors. The aim of this paper is to review the effects of SERMs on estrogen-dependent breast tissues and on the endometrium. There are two types of SERMs in clinical use, based on their chemical structure: the triphenylethylenes and the benzothiophenes. The prototype of the SERMs with triphenylethylene structure is tamoxifen. Tamoxifen, like all other SERMs, is an estrogen antagonist in the breast and is widely used for adjuvant treatment of breast cancer. A recent study suggests that tamoxifen also may prevent breast cancer in patients at risk. Because of the partial estrogenic activity of tamoxifen in the endometrium, its clinical use is associated with uterine hypertrophy and an increased risk of endometrial cancer. Other triphenylethylene SERMs, droloxifene, toremifene, and idoxifene, also show efficacy in the treatment of breast cancer, in a manner similar to tamoxifen. A better toxicology profile and a decreased endometrial estrogen agonism may be advantages of the new triphenylethylene SERMs. Raloxifene is a SERM with a chemical structure different from triphenylethylenes. Raloxifene, a benzothiophene, possesses an estrogen-antagonistic effect in the breast similar to triphenylethylenes. Clinical studies on postmenopausal osteoporotic women on raloxifene as compared with placebo show a significant decrease in the rate of newly diagnosed breast cancers. In clinical studies, in contrast to tamoxifen, no stimulatory effect in the endometrium could be observed with raloxifene.

Animals↗
PubMed2001

The human estrogen receptor-alpha is a ubiquitinated protein whose stability is affected differentially by agonists, antagonists, and selective estrogen receptor modulators.

The human estrogen receptor alpha-isoform (ERalpha) is a nuclear transcription factor that displays a complex pharmacology. In addition to classical agonists and antagonists, the transcriptional activity of ERalpha can be regulated by selective estrogen receptor modulators, a new class of drugs whose relative agonist/antagonist activity is determined by cell context. It has been demonstrated that the binding of different ligands to ERalpha results in the formation of unique ERalpha-ligand conformations. These conformations have been shown to influence ERalpha-cofactor binding and, therefore, have a profound impact on ERalpha pharmacology. In this study, we demonstrate that the nature of the bound ligand also influences the stability of ERalpha, revealing an additional mechanism by which the pharmacological activity of a compound is determined. Of note we found that although all ERalpha-ligand complexes can be ubiquitinated and degraded by the 26 S proteasome in vivo, the mechanisms by which they are targeted for proteolysis appear to be different. Specifically, for agonist-activated ERalpha, an inverse relationship between transcriptional activity and receptor stability was observed. This relationship does not extend to selective estrogen receptor modulators and pure antagonists. Instead, it appears that with these compounds, the determinant of receptor stability is the ligand-induced conformation of ERalpha. We conclude that the different conformational states adopted by ERalpha in the presence of different ligands influence transcriptional activity directly by regulating cofactor binding and indirectly by modulating receptor stability.

Estrogen Antagonists↗
PubMed2001

Photochemical synthesis of N-arylbenzophenanthridine selective estrogen receptor modulators (serms).

Selective estrogen receptor modulators are an emerging class of pharmaceutically important molecules. Many compounds in this class contain an aminoethoxyaryl moiety attached to a polycyclic framework at an asymmetric carbon atom. To assess whether this carbon atom can be replaced by nitrogen, we have employed a Ninomiya enamide photocyclization for the rapid synthesis of a novel N-arylbenzophenanthridine framework, 4. Further elaboration of 4 into a new structural class of achiral, nonsteroidal estrogen receptor modulators is described.

Animals↗
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↗
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↗
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↗
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↗
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↗
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↗
PubMed2001

Clinical use of selective estrogen receptor modulators.

The concept of selective estrogen receptor modulators (SERMs) is derived from the observation that tamoxifen, an effective adjuvant therapy of breast cancer that has an antiestrogenic effect on breast tissue, has estrogen-like effects on the skeleton and on plasma lipoproteins. Raloxifene is a SERM that has undergone extensive clinical investigation in the prevention and treatment of postmenopausal osteoporosis. It prevents bone loss at all skeletal sites, and in a large trial in osteoporotic women, the incidence of vertebral fractures was significantly decreased (relative risk 0.64) after up to 4 years of treatment with raloxifene 60 mg. The decrease of nonvertebral fractures did not reach the level of significance. Raloxifene decreased significantly the incidence of breast cancer (relative risk 0.28) and has no effect on the risk of endometrial cancer. SERMs are likely to play an important role in the management of postmenopausal women.

Bone Density↗