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At least 793 records · Page 44Linked to original sources
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↗
PubMedDate not supplied

Effects of the antiestrogens tamoxifen and raloxifene on the estrogen receptor transactivation machinery.

The influence of 17beta-estradiol (E2), tamoxifen (TAM) and raloxifen (RLX) on the proliferation of breast (BC) and endometrial carcinoma cell lines (EC) and the expression of different compounds of the estrogen receptor (ER)-transactivation machinery were studied. E2 stimulated the proliferation of BC, but had no effect on the EC. TAM showed a biphasic effect on ER-positive cell lines. RLX showed an antagonistic suppression or no effect. The expression of ERalpha was down-regulated by E2, but not affected by selective estrogen receptor modulators. ERbeta and progesterone receptor expressions were up-regulated by E2, TAM and OHT. This supports the hypothesis that ERbeta expression is also regulated via the ERalpha-pathway. The steroid receptor coactivator (SRC) AIB1 expression was slightly decreased by E2 but not by antiestrogens (antiE). TIF2 expression was increased by E2, TAM and RLX, but SRC-1 expression was not. In comparison, the expressions of ERbeta and progesterone receptor were strongly influenced by antiE, while the expression of SRCs was only slightly affected.

Breast Neoplasms↗
PubMed2004

Hormonal manipulation of benign metastasizing leiomyomas: report of two cases and review of the literature.

Benign metastasizing leiomyomas (BMLs) occur predominantly in women during reproductive years. The condition is characterized by uterine leiomyomas associated with the development, typically years later, of slow-growing metastatic lesions. The most commonly affected organs are the lungs, but BMLs have been reported in lymph nodes, deep soft tissues, mesentery, bones, the central nervous system, and the heart. In many cases, these lesions have an indolent course and are discovered rather incidentally. However, occasionally they can present with debilitating symptoms or even life-threatening complications. The presence of estrogen and progesterone receptors in these tumors supports their origin from uterine smooth muscle and, more importantly, makes them amenable to hormonal manipulation. Radical interventions, such as extensive tumor debulking and oophorectomy for hormonal control, although effective in many cases, are not always possible or desirable and carry significant morbidity. Here we present two cases of BMLs to illustrate the role of newer therapeutic agents, the estrogen receptor modulators and the aromatase inhibitors, in the hormonal manipulation of these tumors.

Adult↗
PubMed2001

A review of cancer chemopreventive agents.

In the late 20(th) century, the treatment of cancer began to include its prevention. Today, compounds exist that will lower the risk of developing certain types of cancer. This has been demonstrated in studies where chemically induced tumor growth has been slowed or reversed. Anti-inflammatory compounds having chemopreventive activity are piroxicam, sulindac, aspirin, celecoxib and curcumin. The selective estrogen receptor modulators, tamoxifen and raloxifene, are beneficial in the prevention of estrogen dependent tumors. Retinoids, vitamin A derivatives, such as targretin and fenretinide are useful in the prevention of tumors. Compounds containing sulfur, such as sulforaphane and oltipraz, are even useful as radioprotective agents. The steroid dehydroepiandosterone can inhibit experimental carcinogenesis. All of these chemical classes provide a start for the medicinal chemist to design more effective chemopreventive agents. The biomarkers used to determine the chemopreventive activity of new compounds are quite often activities of enzymes. The identification of those individuals at high risk is still in its infancy and presents a troubling dilemma.

Animals↗
PubMed2004

Tamoxifen stimulates cancellous bone formation in long bones of female mice.

Selective estrogen receptor modulators (SERMs) have been developed as a means of targeting estrogen's protective effect on the skeleton in the treatment of postmenopausal osteoporosis. Although it is well established that SERMs such as tamoxifen inhibit bone resorption in a similar manner to estrogen, whether this agent shares estrogen's stimulatory action on bone formation is currently unclear. To address this question, we compared the effect of treatment for 28 d with 17beta-estradiol (E2; 0.1, 1.0 mg/kg x d) and tamoxifen (0.1, 1.0, or 10 mg/kg x d) on cancellous bone formation at the proximal tibial metaphysis of intact female mice. E2 stimulated the formation of new cancellous bone throughout the metaphysis. A similar response was observed after administration of tamoxifen, the magnitude of which was approximately 50% of that seen after E2. As expected, E2 was found to suppress longitudinal bone growth, but in contrast, this parameter was stimulated by tamoxifen. We conclude that tamoxifen acts as an agonist with respect to estrogen's stimulatory action on bone formation but as an antagonist in terms of estrogen's inhibition of longitudinal growth, suggesting that the protective effect of SERMs on the skeleton is partly mediated by stimulation of osteoblast activity.

Animals↗
PubMed2005

Dose-dependent effects of 4-hydroxytamoxifen, the active metabolite of tamoxifen, on estrogen receptor-alpha expression in the rat uterus.

Tamoxifen, a selective estrogen receptor modulator, has agonist or antagonist activity, depending on the target tissue. The estrogen-like agonist effects of tamoxifen in the uterus are mediated primarily by 4-hydroxytamoxifen (4OH), the major active metabolite. Tamoxifen, 4OH and estradiol-17beta (E2) all bind to estrogen receptors (ERalpha and ERbeta), but with different affinities, suggesting that these ligands are capable of producing differential in vivo effects on the uterus. However, differences in short-term effects of tamoxifen, 4OH and E2 on the uterus have not been compared in the rat in vivo. Thus, we treated adult, ovariectomized rats (225-250 g) with vehicle (sesame oil), tamoxifen (1 mg/kg body weight), 4OH (0.01, 0.1 or 1.0 mg/kg body weight), E2 (40 microg/kg body weight), estradiol valerate (a long-lasting estrogen; 40 microg/kg body weight) or ICI 182,780 (a pure anti-estrogen; 1 mg/kg body weight). Animals were sacrificed at 0, 3, 6, 12 or 24 h post-injection, and protein and mRNA levels for ERalpha and two estrogen-regulated early response genes, c-fos and jun-B, were examined. Administration of E2 and 4OH (1 mg/kg body weight dose) resulted in down-regulation of uterine ERalpha protein in the uterine luminal and glandular epithelium by 6 h post-treatment. In contrast, no change in ERalpha level was observed after treatment with tamoxifen. Rapid (by 3 h) and transient increases in c-fos and jun-B mRNA levels were observed after E2 treatment; however, c-fos and jun-B induction by 4OH was highly dose dependent, and higher 4OH doses induced rapid but persistent proto-oncogene expression in vivo. Our results demonstrate that tamoxifen and its major metabolite have differential effects on uterine gene expression, and 4OH is highly estrogenic in the rat uterus.

Animals↗
PubMed2007

[Therapeutic agents for disorders of bone and calcium metabolism: Bazedoxifene].

Selective estrogen receptor modulators (SERMs) have the potential to provide the skeletal benefits of estrogen without the increased risk of uterine and breast cancer. Raloxifene, second generation SERM has been approved for the prevention and treatment of osteoporosis. Bazedoxifene (BZA, TSE-424Z), novel SERM, acts as a tissue selective estrogen antagonist or agonist. Bazedoxifene inhibited bone turnover and prevented bone loss caused estrogen deficiency. Furthermore, this SERM did not affect the uterine endometrial thickness and reduced serum cholesterol. These date suggest that Bazedoxifene is novel potential drug for the prevention of osteoporosis in postmenopausal women.

Animals↗
PubMed1999

Targeted antiestrogens for the prevention of breast cancer.

This commentary explores the recent experience with and the basis for the use of selective estrogen receptor modulators (SERMs) to prevent breast cancer. Chemoprevention has been a goal for many years. As newer agents are unveiled, they will continue to be tested against tamoxifen, the current standard for the treatment and prevention of breast cancer. Raloxifene holds the promise of treating osteoporosis with the beneficial side effect of breast cancer prevention. The Study of Tamoxifen and Raloxifene (STAR) trial and prior prevention studies will be discussed in an attempt understand the bridge from the laboratory to the clinic.

Breast Neoplasms↗
PubMed2000

[Alternatives to hormone replacement therapy: raloxifene and tibolone].

The bone is an active metabolic organ influenced by many substances like calcium, vitamin D, bisphosphonates etc. The postmenopausal osteoporosis is mainly caused by estrogen deficiency and hormone replacement therapy (HRT) has been shown to prevent the progress of osteoporosis. The following paper describes two alternatives to the classical HRT: raloxifen and tibolon. Raloxifen belongs to the selective estrogen receptor modulators (SERM) showing an estrogen-agonistic effect on bone. There is evidence that bone mineral density (BMD) is growing with treatment. In a three year study (MORE), a statistically significant decrease of lumbar spine fractures was demonstrated (RR 0.5-0.7). Furthermore there was a statistically significant reduction of receptor positive breast cancer (RR 0.10). Raloxifen shows beneficial effects on the lipids and does not induce endometrial proliferation. In the field of climacteric complaints, it is an estrogen-antagonist and therefore inappropriate for this indication. Tibolon--a steroid hormone--and their three metabolites have estrogenic, gestagenic and weak androgenic effects on the different target organs. As expected, there is an increase of bone mineral density comparable to that of HRT or raloxifen; data of fracture rates with long-term therapy are missing. The substance and their metabolites are equivalent to HRT in the treatment of climacteric complaints. Tibolon shows some beneficial effects on the lipids and a lower bleeding rate compared to HRT. Raloxifen and tibolon are interesting alternatives to HRT which allow a more individual treatment of patients in the postmenopause.

Antihypertensive Agents↗
PubMed2005

Discovery of novel quinoline-based estrogen receptor ligands using peptide interaction profiling.

Traditional approaches to discovery of selective estrogen receptor modulators (SERMs) have relied on ER binding and cell-based estrogen response element-driven assays to identify compounds that are osteoprotective but nonproliferative in breast and uterine tissues. To discover new classes of potential SERMs, we have employed a cell-free microsphere-based binding assay to rapidly characterize ERalpha interactions with conformation-sensing cofactor or phage display peptides. Peptide profiles of constrained triarenes were compared to known proliferative and nonproliferative ER ligands to discover potent quinoline-based ligands with minimal Ishikawa cell stimulation.

Alkaline Phosphatase↗
PubMed2003

Discovery and preclinical characterization of (+)-3-[4-(1- piperidinoethoxy)phenyl]spiro[indene- 1,1'-indane]-5,5'-diol hydrochloride: a promising nonsteroidal estrogen receptor agonist for hot flush.

In our studies of the development of a novel class of selective estrogen receptor modulators, (+)-3-[4-(1-piperidinoethoxy)phenyl]spiro[indene-1,1'-indane]-5,5'-diol hydrochloride (1) was found to be an estrogen receptor ligand with beneficial effects in rat models for human hot flush. Moreover, 1 was found to have beneficial effects on lipid and bone metabolism while maintaining marginal effects on the uterus and breasts. These findings suggest that 1 would provide a new treatment for hot flush.

Animals↗
PubMed2004

Requirements of a brain selective estrogen: advances and remaining challenges for developing a NeuroSERM.

Our goal is to develop therapeutic agents that prevent age-associated neurodegenerative disease such as Alzheimer's. To achieve this goal, we are building on extensive knowledge regarding mechanisms of estrogen action in brain and the epidemiological human data indicating that estrogen/hormone therapy reduces the risk of developing Alzheimer's disease when administered at the time of the menopause and continued over several to many years. The mechanisms of estrogen action in neurons provides a systematic mechanistic rationale for determining why estrogen therapy is efficacious for prevention of Alzheimer's disease and why it is not efficacious for long-term treatment of the disease. Our preclinical research plan is a hybrid of both discovery and translational research to develop a brain selective estrogen receptor modulator (SERM). We have termed such molecules NeuroSERMs to denote their preferential selectivity for activating estrogen mechanisms in brain. Our strategy to develop NeuroSERMs is threefold: (1) determine the target of estrogen action in brain, specifically the estrogen receptor in hippocampal and cortical neurons required for the neurotrophic and neuroprotective actions of estrogen; (2) develop NeuroSERM candidate molecules using three in silico discovery and design strategies and (3) determine the neurotrophic and neuroprotective efficacy of candidate molecules using neuronal responses predictive of clinical efficacy. Using an academic translational research model, a team of scientists with expertise in molecular biology, computational chemistry, synthetic chemistry, proteomics, neurobiology and mitochondrial function have been assembled along with state of the art technologies required to develop candidate NeuroSERM molecules.

Aged↗
PubMed2000

Raloxifene hydrochloride.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and therapeutic role of raloxifene hydrochloride are reviewed. Raloxifene is a selective estrogen-receptor modulator (SERM) that has been approved for use in the prevention and treatment of osteoporosis in postmenopausal women. A SERM interacts with estrogen receptors, functioning as an agonist in some tissues and an antagonist in other tissues. Because of their unique pharmacologic properties, these agents can achieve the desired effects of estrogen without the possible stimulatory effects on the breasts or uterus. Raloxifene is rapidly absorbed from the gastrointestinal tract and undergoes extensive first-pass glucuronidation. Approximately 60% of a dose is absorbed; however, absolute bioavailability is only 2%. The volume of distribution is 2348 L/kg for a single oral dose of 30-150 mg, and the elimination half-life averages 32.5 hours. In clinical trials in postmenopausal women, raloxifene had an estrogen-like effect on bone turnover and increased bone mineral density. It reduced the risk of fractures in women with osteoporosis. Raloxifene also seemed to reduce the risk of breast cancer and positively influenced blood lipid markers of cardiovascular disease. Raloxifene is generally well tolerated; the most common adverse effects are hot flashes and leg cramps. A serious adverse effect is venous thromboembolism. The recommended dosage is 60 mg/day orally without regard to meals. Ultimately, it will be information on cardiovascular or breast cancer benefits that will determine the future role of raloxifene. Raloxifene is an alternative to traditional hormone replacement therapy for the prevention and treatment of osteoporosis in selected postmenopausal women. More study is needed to verify possible benefits related to heart disease and breast cancer.

Administration, Oral↗
PubMed2006

Chronic exposure to estrogen and tamoxifen regulates synaptophysin and phosphorylated cAMP response element-binding (CREB) protein expression in CA1 of ovariectomized rat hippocampus.

We report here the in vivo effects of estrogen (E2) on modulation of synaptic plasticity and the agonistic (estrogen-like) role of selective estrogen receptor modulator (SERM), tamoxifen (TAM) in the CA1 of the rat hippocampus. Effects on synaptophysin (SYP), a presynaptic vesicular protein, and phosphorylated cyclic AMP responsive element-binding (p-CREB) protein, a signal transduction pathway molecule, were studied using the ovariectomized (OVX) experimental rat model. Bilateral ovariectomy was performed on 40 rats and these were divided into 4 groups based on the treatment they received (at 2 weeks post-ovariectomy, a subcutaneous injection daily for 4 weeks) viz., OVX+E2 (0.1 mg/kg body weight), OVX+TAM (0.05 mg/kg body weight), OVX+vehicle and one group served as OVX control. An additional 10 animals served as the ovary intact control group. At the end of the treatment schedule, five animals/group were used for immunohistochemical staining of SYP and p-CREB using specific antibodies with peroxidase anti-peroxidase technique on paraformaldehyde-fixed cryostat sections. Protein estimation and Western blot analysis coupled with densitometric analysis (using gel-documentation system and image analysis software) were performed on unfixed hippocampus collected from rest of the five animals/group. Serum estradiol levels were estimated with radioimmunoassay prior to sacrifice. The results revealed that ovariectomy reduced SYP and p-CREB expression whereas E2 or TAM administration resulted in their upregulation. Serum estradiol levels of E2 administered animals were comparable with the ovary intact group whereas those of TAM administered group persisted in the range of OVX controls. To conclude, long-term estrogen therapy modulates the synaptic plasticity of hippocampal neurons and presumably, the agonist biocharacter of TAM as observed in the present investigations, may in the long run have a potential in the treatment and prevention of various estrogen-related disorders.

Animals↗
PubMed2003

Phase II, randomized, double-blind study of two dose levels of arzoxifene in patients with locally advanced or metastatic breast cancer.

PURPOSE: To select a daily dose of arzoxifene (LY353381), a selective estrogen receptor modulator, for use in future studies in women with locally advanced or metastatic breast cancer who are either potentially tamoxifen sensitive (TS) or tamoxifen refractory (TR). PATIENTS AND METHODS: This trial was a randomized, double-blind, phase II study of arzoxifene 20 mg (n = 55) and 50 mg (n = 57) in women with advanced or metastatic breast cancer. Patients were randomly assigned to balance for number of metastatic disease sites, prior tamoxifen therapy, and estrogen receptor status. The primary end point was tumor response rate (RR). Secondary end points included clinical benefit rate (CBR), time to progression (TTP), and toxicity. RESULTS: Forty-nine patients were TS and 63 were TR. According to independent review, among TS patients, RR was higher in the 20-mg arm than the 50-mg arm (26.1% v 8.0%), with a longer TTP (8.3 v 3.2 months; P >.05). Among the TR patients, response rate was the same in the 20-mg and 50-mg arms (10.3%) with similar TTP (2.7 and 2.8 months, respectively; P >.05). CBR was higher in the 20-mg arm than in the 50-mg arm among TS patients (39.1% v 20.0%) and TR patients (13.8% v 10.3%). Arzoxifene was well tolerated. Dose-dependent toxicity was not demonstrated. There were no deaths during study. CONCLUSION: Arzoxifene is effective in the treatment of TS and TR patients with advanced or metastatic breast cancer at the 20-mg and 50-mg dose levels. Toxicities are minimal, and the therapy is tolerated. The 20-mg dose seems to be at least as effective as the 50-mg dose. Accordingly, arzoxifene 20 mg/d was selected for further study in patients with breast cancer.

Adult↗
PubMed2002

[Antiestrogen therapy in the treatment of breast neoplasms].

During recent years the development of hormone therapy for the treatment breast neoplasms has seen, in addition to classic aspecific antiestrogens (AE) like tamoxifen (TAM) and to a lesser extent toremifen, a major development of new molecules divided into two groups: the first is the so-called selective estrogen receptor modulators (SERMs), the most important of which is Raloxifen, which mediate estrogen-agonist effects in some tissues and estrogen-antagonist effects in others; the second group includes the aromatase inhibitors (AI), important enzymes for peripheral estrogen conversion. Some studies compare or associate classic AE with the new SERMs and AI, both in adjuvant therapy and in treatment for advanced forms. Other trials assess the anti-osteoporotic activity of some SERMs which present concomitant inhibitory activity on the breast and endometrium.

Adult↗
PubMed2002

Raloxifene improves endothelial dysfunction in hypertension by reduced oxidative stress and enhanced nitric oxide production.

BACKGROUND: It has not been completely clarified whether selective estrogen receptor modulators (SERMs) such as raloxifene exert vasoprotective effects similar to those of estrogens. METHODS AND RESULTS: To investigate vascular effects of raloxifene, male spontaneously hypertensive rats were treated for 10 weeks with either raloxifene (10 mg x kg(-1) x d(-1)) or vehicle. Raloxifene improved endothelium-dependent vasodilatation but had no effect on either endothelium-independent vasorelaxation or phenylephrine-induced vasoconstriction. Raloxifene treatment increased the release of NO from the vessel wall by enhanced expression and activity of endothelial NO synthase. Blood pressure reduction after bradykinin infusion was more pronounced in animals treated with SERMs. The production of superoxide in intact aortic segments was decreased by raloxifene treatment. Administration of raloxifene had no effect on the expression of the essential NAD(P)H oxidase subunits p22phox and nox1 in the vasculature but reduced the activity and expression of vascular membrane-bound rac1, a GTPase required for the activation of the NAD(P)H oxidase. Finally, blood pressure levels were significantly decreased in spontaneously hypertensive rats treated with raloxifene. All SERM effects were also detected in healthy age-matched Wistar rats. In cultured rat aortic vascular smooth muscle cells, raloxifene inhibited angiotensin II-induced reactive oxygen species production dependent on estrogen receptor activation. CONCLUSIONS: Raloxifene treatment improves hypertension-induced endothelial dysfunction by increased bioavailability of NO. This is achieved by an increased activity of endothelial NO synthase and by an estrogen receptor-dependent reduction in release of reactive oxygen species from vascular cells. These vascular effects cause a profound blood pressure reduction and lead to decreased vascular damage in male spontaneously hypertensive rats.

Animals↗
PubMed2004

Histone deacetylase inhibition and estrogen receptor alpha levels modulate the transcriptional activity of partial antiestrogens.

In this study, we have analysed the effects of histone deacetylase (HDAC) inhibition on estrogen receptor (ER) expression and on its transcriptional activity in response to antiestrogens. In several breast cancer cell lines, trichostatin A (TSA), a potent HDAC inhibitor, strongly decreases ERalpha expression in a dose-dependent manner. This repression is observed independently of the presence of ligand and also occurs in ovarian and endometrial cell lines. In addition, we show that in MCF7 cells bearing a stably transfected reporter plasmid (MELN cells), partial antiestrogens such as 4-OH-tamoxifen (OHTam), raloxifen or LY117018, switch to an agonist activity upon HDAC inhibition. This effect is blocked by the pure antiestrogen ICI182780 and exhibits a half-maximal concentration of OHTam equivalent to its affinity for ERalpha. The TSA-dependent decrease of ERalpha expression is required to induce the agonist switch of OHTam properties as it is lost in cells constitutively expressing exogenous receptors (MELN-ERalpha or ERbeta). By contrast, the transrepression activity of OHTam is abolished by TSA independently of the decrease of ERalpha expression. Interestingly, in MELN-ERalpha, ICI182780 remains inhibitory suggesting the involvement of HDAC-independent mechanisms. Finally, in the absence of TSA, transcriptional activity in response to OHTam is significantly raised in MELN cells expressing low levels of ERalpha after transfection of antisense oligonucleotides. In conclusion, inhibition of HDAC enzymatic activity and modulation of ERalpha levels tightly control the relative agonist activity of partial antiestrogens on a stably integrated reporter transgene.

Breast Neoplasms↗