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PubMed2003

Selective modulation of postmenopausal women: cutting the Gordian knot of hormone replacement therapy with breast carcinoma.

BACKGROUND: Hormone replacement therapy (HRT) has proven and presumable benefits for women desiring postmenopausal health preservation. Among HRT-associated risks, the fear of breast carcinoma intimidates women and physicians contemplating hormonal treatment and limits long-term compliance. Identifying effective alternative medications that are not associated with breast carcinoma or that even may prevent its development would be a major advance. METHODS: This article discusses the clinical perspective of HRT and selective estrogen receptor modulators (SERMs) in light of the molecular and cellular mechanisms of estrogen and progesterone action on the breast. Emphasis is placed on the potential of selective receptor modulation as the future of postmenopausal treatment. RESULTS: Current epidemiologic evidence suggests that HRT is associated with a small but substantial increase in the risk of breast carcinoma, and combined estrogen-progesterone regimens further increase this hazard. Ample biologic data support this clinical association and propose multiple molecular mechanisms for the effects of estrogen and progesterone on breast cells. SERMs are a novel class of drugs that demonstrate estrogen agonistic and antagonistic actions in a tissue specific manner. SERMs act by binding the estrogen receptor and selectively modulating its effect on gene transcription at target tissues. CONCLUSIONS: SERMs offer an alternative to HRT that can successfully circumvent the intimidating side-effect of breast carcinoma. Further insight into the molecular mechanisms of SERM action may enable the development of agents with improved target-tissue selectivity. Identifying selective modulators with unique pharmacologic properties would facilitate the creation of individualized treatment for the postmenopausal woman according to her particular predisposition for menopause-related morbidities and her overall clinical profile.

Breast Neoplasms↗
PubMed2002

Calmodulin is a selective modulator of estrogen receptors.

In the search for differences between ERalpha and ERbeta, we analyzed the interaction of both receptors with calmodulin (CaM) and demonstrated that ERalpha but not ERbeta directly interacts with CaM. Using transiently transfected HeLa cells, we examined the effect of the CaM antagonist N-(6-aminohexyl)-5-chloro-naphthalene sulfonilamide hydrochloride (W7) on the transactivation properties of ERalpha and ERbeta in promoters containing either estrogen response elements or activator protein 1 elements. Transactivation by ERalpha was dose-dependently inhibited by W7, whereas that of ERbeta was not inhibited or even activated at low W7 concentrations. In agreement with these results, transactivation of an estrogen response element containing promoter in MCF-7 cells (which express a high ERalpha/ERbeta ratio) was also inhibited by W7. In contrast, transactivation in T47D cells (which express a low ERalpha/ERbeta ratio) was not affected by this CaM antagonist. The sensitivity of MCF-7 cells to W7 was abolished when cells were transfected with increasing amounts of ERbeta, indicating that the sensitivity to CaM antagonists of estrogen-responsive tissues correlates with a high ERalpha/ERbeta ratio. Finally, substitution of lysine residues 302 and 303 of ERalpha for glycine rendered a mutant ERalpha unable to interact with CaM whose transactivation activity became insensitive to W7. Our results indicate that CaM antagonists are selective modulators of ER able to inhibit ERalpha-mediated activity, whereas ERbeta actions were not affected or even potentiated by W7.

Binding Sites↗
PubMedDate not supplied

Tofupill/Femarelle (DT56a): a new phyto-selective estrogen receptor modulator-like substance for the treatment of postmenopausal bone loss.

OBJECTIVE: To evaluate the efficacy of Tofupill/Femarelle (DT56a), a novel phyto-selective estrogen receptor modulator (SERM), in preserving bone mineral density (BMD) in postmenopausal women. DESIGN: The study sample consisted of 98 healthy, postmenopausal women who were randomly allocated, on a double-blind basis, to receive either 644 mg/d DT56a (study group) or 344 mg/d DT56a supplemented with calcium (low-dose group) for 12 months. Each participant was assessed with a comprehensive health questionnaire, a detailed physical, and laboratory and pelvic sonogram examinations at entry and every 3 months thereafter. BMD was assessed by dual-energy x-ray absorptiometry (Lunar) of the lumbar spine and femoral neck before the study began and after 12 months of treatment. RESULTS: After 12 months of treatment, BMD had increased in the study group by 3.6% in the lumbar spine (P = 0.039) and by 2.0% in the femoral neck (NS). In the low-dose group, BMD had decreased in the lumbar spine by 0.6% (NS) and by 0.6% in the femoral neck (NS). Comparison of the change in bone density between the groups yielded a significant difference for the lumbar spine (P = 0.037). Neither group showed a change in endometrial thickness and sex hormone levels nor reported any side effects of treatment. CONCLUSIONS: Tofupill treatment in postmenopausal women increases BMD without unwanted estrogenic effect. Tofupill appears to be a promising phyto-SERM for the prevention of postmenopausal osteoporosis.

Bone Density↗
PubMed2005

Selective reduction of estrogen receptor (ER) positive breast cancer occurrence by estrogen receptor modulators supports etiological distinction between ER positive and ER negative breast cancers.

Reports that selective estrogen receptor modulators (SERMs) reduce occurrence of only estrogen receptor (ER) positive tumors strongly support the etiological distinction between ER positive and ER negative breast cancers. Based on these evidences three concepts are described: Concept I. The occurrence of ER negative tumor cells might be a consequence of the clonal selection among tumor cells. This would lead to mosaicism in the ER expression. If ER negative cells become the most prevalent clone, the patient will be diagnosed to have an ER negative breast cancer. Since all cancers start as ER positive, SERMs should equally prevent occurrence of ER positive and ER negative breast cancers, but this prediction is evidently wrong. Concept II. Mammary ducts normally contain ER positive and ER negative cells, both prone to malignancy. Cancer occurrence in ductal cells that normally lack ER would be unrelated to estrogen exposure or SERMs protection. Estrogen and SERMs can influence cancer occurrence only in ER positive ductal cells. The main drawback is that this concept does not predict occurrence of mosaicism in ER expression among tumor cells. Unified Concept I and II. To overcome limitations of described concept a unified concept is presented. Cancers from ER positive ductal cells start as pure ER positive tumors and those from ER negative ductal cells as pure ER negative tumors. During the preclinical phase, in some ER positive tumors, clonal selection introduces ER negative clones. These tumors become mosaic in the cellular ER expression, some of them predominantly ER positive other ER negative. Estrogen deprivation, or SERMs can help mostly to patients with pure ER positive, or mosaic ER positive tumors. Since the dominant metastatic clone can have different ER status from the primary breast tumor, both surprising successes and failures of endocrine therapy can be expected in tumors with mosaic ER expression.

Breast Neoplasms↗
PubMed2006

What can be learned from the levormeloxifene experience?

Levormeloxifene is a selective estrogen receptor modulator that was developed as an alternative to estrogen replacement therapy for the treatment and prevention of postmenopausal bone loss. In animal models, levormeloxifene prevented increased bone turnover and vertebral bone loss following ovariectomy. Studies of healthy postmenopausal women showed that levormeloxifene 1.25-20 mg/day decreased bone turnover and increased bone mineral density to a comparable extent to that observed during conventional hormone replacement therapy. However, in the phase II and III studies, the effect on bone turnover and bone mineral density was similar for each dose of levormeloxifene and the minimal effective dose was never established. The development of levormeloxifene was discontinued during the phase III trial due to a significant incidence of gynecologic adverse events in the levormeloxifene-treated groups. This article reviews the preclinical and clinical studies of levormeloxifene and the circumstances for the premature termination of the development of the drug. Other selective estrogen receptor modulators such as tamoxifen and raloxifene and the perspectives for selective estrogen receptor modulators in development are furthermore discussed.

Animals↗
PubMed2004

Agents with selective estrogen receptor (ER) modulator activity induce apoptosis in vitro and in vivo in ER-negative glioma cells.

Tamoxifen, a member of the selective estrogen receptor modulator (SERM) family, is widely used in the treatment of estrogen receptor (ER)-expressing breast cancer. It has previously been shown that high-dose tamoxifen has cytotoxic activity against glioma cells, but whether this effect is drug specific or represents a general property of SERMs is unknown. In this study, we demonstrate that tamoxifen and CC-8490, a novel benzopyranone with SERM activity, induce glioma cell apoptosis in a dose- and time-dependent manner. Moreover, administration of tamoxifen and CC-8490 suppresses tumor growth in vivo and extends animal survival in glioma xenograft models. None of the eight glioma cell lines examined express either ER-alpha or -beta, suggesting the mechanism for tamoxifen- and CC-8490-induced glioma cell apoptosis is independent of the ER signaling pathway. Complementary DNA microarray expression profiling allowed us to identify a subset of genes specifically regulated by tamoxifen and CC-8490, and not by other apoptotic stimuli, including nuclear factor (NF)-kappaB with its target genes IEX-3, SOD2, IL6, and IL8. We demonstrate that suppression of NF-kappaB activation markedly enhances SERM-induced apoptosis, suggesting a role for NF-kappaB in protecting glioma cells from SERM-induced cytotoxicity. These findings demonstrate for the first time that a SERM other than tamoxifen can induce glioma cell apoptosis in vitro and in vivo and that the clinical efficacy of SERMs for the treatment of malignant gliomas could potentially be enhanced by simultaneous inhibition of the NF-kappaB pathway.

Animals↗
PubMed2002

Selective estrogen receptor (ER) modulators differentially regulate phospholipase D catalytic activity in ER-negative breast cancer cells.

Recent successes in the pharmacotherapeutic treatment of breast cancer are associated with the use of selective estrogen receptor modulators. Two commonly prescribed pharmaceuticals in this class, tamoxifen and raloxifene, have been shown to have effects through estrogen receptor (ER)-independent mechanisms. Hyperactivation of phospholipase D (PLD) in certain tumor-derived cell lines have been reported, and recent findings suggest a role for PLD in transformation and metastasis. In the present study, we compare the effects of tamoxifen and raloxifene on PLD in the ER-positive mammary epithelial cell line MCF-12A, and the ER-negative, highly tumorigenic mammary carcinoma cell line MDA-MB-231. Our data demonstrate that tamoxifen and raloxifene have differential effects on PLD catalytic activity. Tamoxifen stimulates PLD in both ER-positive and -negative cells in vivo, whereas raloxifene inhibits PLD activity in these same cell types. In addition, we show that the active metabolite 4-OH-tamoxifen can be used to pharmacologically discriminate the two isoforms of PLD, through a stimulatory effect on PLD1 and an inhibitory effect on PLD2. Using recombinant PLD1, we show stimulation by tamoxifen requires a factor present in Sf21 insect cells that is not required for inhibition of PLD1 by raloxifene. Furthermore, tamoxifen stimulation and raloxifene inhibition of PLD activities are independent of the amino-terminal portion of PLD1 (amino acids 1-324). Knowledge of the mechanisms of action of these drugs on PLD may provide insights into the pharmacological action of these drugs and the role of PLD in some cancers.

Antineoplastic Agents, Hormonal↗
PubMed1999

[Selective estrogen-receptor modulators (SERM's) in postmenopausal women].

Selective oestrogen receptor modulators (SERMs) constitute a group of new drugs which mimic oestrogen in some organs and tissues but have an oestrogen antagonistic mode of action in other tissues. In postmenopausal women these compounds have a favourable effect on lipoprotein cholesterol levels in the blood and bone mineral density, thereby reducing fracture risk, especially in the vertebral column. In contrast to oestrogen therapy SERMs reduce the risk of mammary carcinoma. Currently tamoxifen and raloxifene are the best known SERMs. Tamoxifen increases endometrial hyperplasia and the risk of endometrial carcinoma. Raloxifene inhibits uterine tissue proliferation and does not appear to influence the endometrium directly. Raloxifene appears to be finding a place for itself in the treatment and prevention of osteoporosis in postmenopausal women. At this moment it is not yet possible to foresee what the impact of SERMs will be in the treatment and prevention of cardiovascular diseases and breast cancer.

Aged↗
PubMed2000

New approaches to the treatment of osteoporosis.

Under physiological conditions, maintenance of skeletal mass is the result of a tightly coupled process of bone formation and bone resorption. Disease states, osteoporosis included, arise when this delicate balance is disrupted such as in menopause, when estrogen levels decrease dramatically corresponding with the cessation of ovarian function. Current therapies for the treatment of osteoporosis, including estrogen replacement therapy, selective estrogen receptor modulators and bisphosphonates, are primarily based on blunting the resorption component of bone homeostasis. Although selective estrogen receptor modulators offer bone protection without the side effects of estrogen replacement therapy, there are some areas of improvement for the current generation of selective estrogen receptor modulators; particularly in reducing their antagonistic properties in the central nervous system that lead to vasomotor symptoms. There are few therapies that are focused on increasing bone formation, but they offer promising avenues in which to expand the repertoire of drugs to restore bone mass. Selective androgen receptor modulators, parathyroid hormone analogs, oxytocin analogs and statins, all with improved pharmacological properties in bone, are among the potential approaches to eliciting anabolic effects in the skeleton.

Androgens↗
PubMed2003

Advances in the science of estrogen receptor modulation.

This work details recent advances in the science of estrogen receptor (ER) modulation, with emphasis on the discovery of novel ligands for the ER ligand binding domain (LBD). A detailed examination of structural studies of the ERs is presented with analysis of the impact of such works on contemporary ligand design and the molecular pharmacology of the ER. The various classes of ER modulators are discussed on the basis of stuctural similarities including selective estrogen receptor modulators (SERMs) and 'pure' non-steroidal antiestrogens. Additionally we review the emergence of a novel selective class of modulator which we have termed the selective estrogen receptor subtype modulators (SERSMs) and, in a departure from LBD strategies we examine the discovery of novel peptide inhibitors of the ER which inhibit transcriptional activiation of agonist liganded receptor through interaction with coactivator recruitment proteins, and offer unique insight to the mechanism of action of all classes of ER modulators. Through examination of patent and classical literature we present a thorough and informative cross-section of the contemporary state of the art in this exciting field of pharmaceutical research.

Animals↗
PubMed2006

Raloxifene-induced myeloma cell apoptosis: a study of nuclear factor-kappaB inhibition and gene expression signature.

Because multiple myeloma remains associated with a poor prognosis, novel drugs targeting specific signaling pathways are needed. The efficacy of selective estrogen receptor modulators for the treatment of multiple myeloma is not well documented. In the present report, we studied the antitumor activity of raloxifene, a selective estrogen receptor modulator, on multiple myeloma cell lines. Raloxifene effects were assessed by tetrazolium salt reduction assay, cell cycle analysis, and Western blotting. Mobility shift assay, immunoprecipitation, chromatin immunoprecipitation assay, and gene expression profiling were performed to characterize the mechanisms of raloxifene-induced activity. Indeed, raloxifene, as well as tamoxifen, decreased JJN-3 and U266 myeloma cell viability and induced caspase-dependent apoptosis. Raloxifene and tamoxifen also increased the cytotoxic response to vincristine and arsenic trioxide. Moreover, raloxifene inhibited constitutive nuclear factor-kappaB (NF-kappaB) activity in myeloma cells by removing p65 from its binding sites through estrogen receptor alpha interaction with p65. It is noteworthy that microarray analysis showed that raloxifene treatment decreased the expression of known NF-kappaB-regulated genes involved in myeloma cell survival and myeloma-induced bone lesions (e.g., c-myc, mip-1alpha, hgf, pac1,...) and induced the expression of a subset of genes regulating cellular cycle (e.g., p21, gadd34, cyclin G2,...). In conclusion, raloxifene induces myeloma cell cycle arrest and apoptosis partly through NF-kappaB-dependent mechanisms. These findings also provide a transcriptional profile of raloxifene treatment on multiple myeloma cells, offering the framework for future studies of selective estrogen receptor modulators therapy in multiple myeloma.

Apoptosis↗
PubMed2004

Estrogen receptor ligands. II. Discovery of benzoxathiins as potent, selective estrogen receptor alpha modulators.

The discovery and synthesis of dihydrobenzoxathiins as potent, ERalpha subtype selective ligands are described. The most active analogue, 4-D, was found to be 50-fold selective in a competitive binding assay and 100-fold selective in a transactivation assay in HEK-293 cells. The alpha selectivity was postulated to lie in the interaction of the sulfur atom of the benzoxathiin ring with the two discriminating residues in the binding pocket of the receptor isoforms.

Animals↗
PubMed1999

Clinical effects of raloxifene hydrochloride in women.

PURPOSE: To review clinical data on raloxifene hydrochloride, a selective estrogen receptor modulator that was recently approved for the prevention of osteoporosis in postmenopausal women. DATA SOURCES: English-language articles published from 1980 to May 1998 were identified through MEDLINE searches. Bibliographies, book chapters, and meeting abstracts were reviewed for additional relevant publications. STUDY SELECTION: Publications that contained information on the background of development, structure, mechanism of action, tissue-selective effects, and adverse effects of raloxifene hydrochloride were included. DATA EXTRACTION: Data in selected articles were reviewed, and relevant clinical information was extracted. DATA SYNTHESIS: Raloxifene hydrochloride was developed in an effort to find a treatment for breast cancer and osteoporosis. It binds to the estrogen receptor and shows tissue-selective effects; thus, it belongs to a class of drugs recently described as selective estrogen receptor modulators. Tissue selectivity of raloxifene may be achieved through several mechanisms: the ligand structure, interaction of the ligand with different estrogen receptor subtypes in various tissues, and intracellular events after ligand binding. Raloxifene has estrogen-agonistic effects on bone and lipids and estrogen-antagonistic effects on the breast and uterus. An increase in bone mineral density at the spine, total hip, and total body has been reported with raloxifene but seems to be less than that seen with estrogen or alendronate therapy. Raloxifene has been shown to produce a reduction in total and low-density lipoprotein cholesterol concentrations similar to that produced by estrogen therapy, but high-density lipoprotein cholesterol and triglyceride concentrations do not increase during raloxifene therapy. In the uterus, raloxifene does not stimulate the endometrium. Long-term data on the effects of raloxifene in reduction of risk for fracture; prevention of cardiovascular events; cognitive function; and the incidence of breast, ovarian, and uterine cancer are not available. The most common adverse effect of raloxifene is hot flashes. CONCLUSIONS: Raloxifene has been shown to have beneficial effects in selected organs in postmenopausal women. Although estrogen remains the drug of choice for hormonal therapy in most postmenopausal women, raloxifene may be an alternative in certain groups of women at risk for osteoporosis.

Animals↗
PubMed2003

[The current state of hormonal prevention of coronary heart disease in menopausal women].

The increased incidence and prevalence of coronary heart disease among older women, coupled with the less favorable prognosis for women who sustain coronary events than for men, has resulted in the medical community's attention to the potential beneficial effects of hormone therapy in menopausal women. Much biological evidence supports a protective mechanism of estrogen; nevertheless, some aspects are contradictory. Although observational studies have shown a clear cardiovascular benefit associated with hormone therapy, the significant skew inherent in these data has resulted in overestimation of benefits and underestimation of risks. Recent reanalysis of these observational data controlling for confounding variables failed to show cardiovascular benefit. Several randomized, double-blind, placebo-controlled studies have failed to show improvement in clinical cardiovascular outcomes with menopausal hormone therapy both in healthy women and in women with established coronary heart disease. Current research has also focused on pharmacologic agents that selectively modulate estrogen receptors, such as raloxifene, which are useful for the prevention and treatment of osteoporosis without increasing the risk of breast cancer. A clinical trial is now underway to evaluate the effects of raloxifene on coronary events and on the incidence of invasive breast cancer in menopausal women both with established coronary heart disease and at increased risk for coronary events. Current recommendations do not advocate the initiation of menopausal hormone therapy for the primary or secondary prevention of coronary events. The proven lifestyle interventions of smoking cessation, heart healthy diet, weight control, and physical activity should be undertaken, with statin use for control of elevated LDL cholesterol levels and pharmacologic blood pressure control when appropriate.

Coronary Disease↗
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↗
PubMedDate not supplied

Molecular mechanisms of estrogen actions on the vasculature.

In summary, clinical and animal studies demonstrate that the effects of estrogen in the cardiovascular system protect against the development of histologic and clinical atherosclerosis. However, because estrogen affects so many cellular processes (Figure 4), there are many known adverse effects, including oncogenic and potential negative consequences on the vasculature, including procoagulant and plaque-destabilizing effects. Selective estrogen receptor modulators may allow us to target specific pathways that selectively and favorably effect beneficial responses. However, we must first gain a better understanding of the molecular mechanisms by which estrogen induces cellular signals, both genomic and nongenomic, before we can take full advantage of selective estrogen receptor modulators. As our ability to selectively modulate vascular responses to injury improves, it will be imperative that we have the ability to assess vascular structure, function and pathology with more practical, logistically accessible and biologically targeted approaches than those currently available. Such tools will allow us to test a broad spectrum of agents aimed at pharmacologic therapy for vascular disease.

Animals↗
PubMed2001

Cardiovascular effects of raloxifene hydrochloride.

Raloxifene hydrochloride binds to the estrogen receptor and shows tissue-selective effects; thus, it belongs to a class of drugs recently described as selective estrogen receptor modulators (SERMs). Tissue selectivity of raloxifene may be achieved through several mechanisms: the ligand structure, interaction of the ligand with different receptor subtypes in various tissues, and intracellular events after ligand binding. Raloxifene has estrogen-agonist effects on bone and lipids and estrogen antagonist effects on the breast and uterus. In addition to its well established effects on osteoporosis, recent preclinical and clinical findings suggest that raloxifene also possesses beneficial effects on the cardiovascular system. These findings indicated that raloxifene may have cardioprotective properties without an increased risk of cancer or other side effects. Raloxifene has been shown to reduce total and low-density lipoprotein cholesterol concentrations in plasma, an effect similar to that produced by estrogens. Unlike estrogens, however, raloxifene does not increase high-density lipoprotein cholesterol and triglyceride levels in plasma. Endothelium is thought to play an important role in the genesis of atherosclerosis. Several lines of evidence suggest that an intervention with endothelial function might influence the progression of coronary disease and the incidence of cardiovascular events. Raloxifene increases the nitric oxide/endothelin-1 ratio, and improves endothelium-dependent vasomotion in post-menopausal women to the same extent as estrogens. Furthermore, in two randomized trials on post-menopausal women raloxifene reduced homocysteine levels, another independent risk factor for the development of cardiovascular disease. Although estrogens remain the drugs of choice in the hormonal therapy of most postmenopausal women, raloxifene may represent and alternative in women who are at risk of coronary artery disease.

Animals↗