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PubMed2006

[Molecular mechanism of tissue-specific actions of SERM].

Selective estrogen receptor modulator (SERM) is designated as synthetic ligands for estrogen receptors (ERs), exhibiting tissue-specific agonisitic/antagonisitic activities. Among SERM, raloxifen is a most clinically successful as an anti-oseteoporotic agent. Such tissue-specific actions of SERM are presumed to mediate through unusual structure alteration of liganded ERs coupled with co-regulator recruitments.

Bone Density Conservation Agents↗

PubMedDate not supplied

Osteoporosis management.

About 40% of women who reach the age of 50 are expected to suffer from osteoporosis during their remaining life. The morbidity associated with hip, spinal and wrist fractures, resulting from osteoporosis, and the mortality resulting from hip fractures justify the development of prevention strategies. Optimal management of osteoporosis consists of maximizing peak bone mass in early adulthood and preventing the rapid bone loss that occurs soon after the menopause. Peak bone mass will be reached in most women if adequate nutrition is taken and exercise is encouraged, while major risk factors are avoided. At the menopause, prescription of hormone replacement therapy (HRT) constitutes the primary prevention strategy. There are, however, questions that remain unanswered or debated. What is the optimal dose of HRT, when should it be started, and for how long should it be maintained? In women who do not, or may not, take HRT, and who have osteoporosis, alternative therapeutic options include diphosphonates (e.g., alendronate) and Selective Estrogen Receptor Modulators (such as raloxifene). Other treatments to restore bone strength in women with established disease may also reduce the risk of fractures. Some of them, such as calcitonin, may not be cost effective. Others have produced conflicting data (fluoride) and others are still under evaluation (PTH or strontium). In sunlight-deprived, vitamin D-deficient elderly nursing home residents, dietary supplementation of calcium and vitamin D has been shown to prevent bone loss and fractures. Strategies to avoid falls should also be encouraged for these patients.

Aged↗

PubMed2005

Vascular effects of aromatase inhibitors: data from clinical trials.

Aromatase inhibitors (AIs) are becoming the endocrine treatment of first choice for postmenopausal women with hormone receptor-positive breast cancer and are under investigation for use in breast cancer prevention. AIs reduce circulating estrogen to barely detectable concentrations. It is possible that such a low concentration will be deleterious to the vascular system since estrogen receptors are known to be in the cell walls of blood vessels and estrogen is thought to be important in maintaining blood vessel integrity. Because most women who present with primary breast cancer are cured by surgery and systemic therapy and the major cause of female death is vascular disease, it is particularly important to investigate the vascular side effects of AIs in current breast cancer adjuvant and prevention trials. In order to set the vascular toxicities of AIs reported in the current adjuvant trials into context, here we compare them with the toxicities seen during treatment with hormone replacement therapy (HRT) and selective estrogen receptor modulators (SERMs). Clinical trial evidence indicates that HRT increases risk of coronary heart disease (CHD) whereas SERMs and AIs (to date) appear to be neutral. Cerebrovascular disease and venous thromboembotic events are increased by HRT and SERMs but appear to be unaffected by treatment with AIs. Cognitive function is also considered here since it may also have a vascular component and is potentially a serious potential side effect/benefit of AIs. Recent studies indicate that HRT has a small detrimental effect on cognitive function and is associated with a doubling of the incidence of dementia. A comprehensive study of the SERM, raloxifene, on cognitive function showed no significant effect. There are no definitive reported studies investigating tamoxifen and none for AIs on cognitive function, although there is one in progress in the context of the IBIS II prevention trial which compares anastrozole to placebo in women at high risk. At present concerns about deleterious vascular side effects are confined to HRT and SERMs. However, we have few long-term data using AIs for the treatment and prevention of breast cancer.

Antineoplastic Agents, Hormonal↗

PubMed2004

National trends in osteoporosis visits and osteoporosis treatment, 1988-2003.

BACKGROUND: Research is limited on physicians' prescribing practices for osteoporosis treatment. We investigated patterns of pharmacotherapy from 1988 to 2003 and the impact of new medications on identification and treatment of patients with osteoporosis. METHODS: We tracked trends from 1988 through 2003 in the frequency of osteoporosis visits and patterns of pharmacotherapy associated with these visits using nationally representative data on prescribing patterns by office-based US physicians from the IMS HEALTH National Disease and Therapeutic Index. RESULTS: The number of physician visits for osteoporosis increased 4-fold between 1994 (1.3 million visits) and 2003 (6.3 million visits), whereas it had remained stable in prior years. This increase coincided with the availability of oral daily bisphosphonates and the selective estrogen receptor modulator raloxifene. The annualized percentage of osteoporosis visits where medications were prescribed increased from 82% in 1988 to 97% by 2003. Prior to 1994, the leading choices for osteoporosis therapy were calcium and estrogens, with lesser roles played by calcitonins and bisphosphonates. Between 1994 and 2003, the percentage of visits where bisphosphonates and raloxifene were prescribed increased from 14% to 73% and from 0% to 12%, respectively, while prescriptions for other medications declined. CONCLUSIONS: New medications for osteoporosis offering improved efficacy and convenient dosing were associated with increased frequency of patient visits and treatment. This finding suggests that new drug therapy contributed to increased disease recognition and treatment.

Adult↗

PubMed2003

Randomized, double-blind, multicenter trial comparing two doses of arzoxifene (LY353381) in hormone-sensitive advanced or metastatic breast cancer patients.

BACKGROUND: This randomized, double-blind, phase II study assessed two doses of the selective estrogen receptor modulator arzoxifene in women with advanced breast cancer. The primary end point was to choose the best of two doses of arzoxifene based on the response rate or the clinical benefit rate (CBR). Pharmacokinetics and toxicities were also assessed. PATIENTS AND METHODS: Ninety-two patients with advanced breast cancer received arzoxifene 20 or 50 mg/day. Tumor response was assessed using World Health Organization criteria. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) system. Pharmacokinetic data were analyzed using the NONMEM software program (GloboMax, Hanover, MD, USA). RESULTS: Response rates in the 20 mg arm were numerically higher than the 50-mg arm according to the investigator (40.5% versus 36.4%) and the independent review panel (42.9% versus 27.3%). CBR was higher in the 20 mg arm according to the investigator (64.3% versus 61.4%) and the independent review panel (59.5% versus 47.7%). Arzoxifene was well tolerated. There were no study drug-related deaths. Mean observed steady-state plasma concentrations of arzoxifene were 3.62 and 7.48 ng/ml for the 20 and 50 mg doses, respectively. CONCLUSIONS: There were no significant differences in efficacy or safety between 20 and 50 mg of arzoxifene. Accordingly, arzoxifene 20 mg/day was selected for further study in patients with breast cancer.

Aged↗

PubMed2002

[What can we expect of raloxifene in the treatment of postmenopausal osteoporosis--views of a gynecologist].

OBJECTIVE: Evaluation of positive properties and side effects of raloxifene treatment with respect to its potential use as agent to improve women's health and quality of life in postmenopausal years. DESIGN: A review article. SETTING: Obstetrics and Gynaecology Department, Charles University 2nd Medical Faculty and Teaching Hospital Motol, Prague. SUBJECT: Estrogen use may protect against osteoporosis and cardiovascular disease, but may increase the risk of breast cancer in long-term treated women and also may increase the risk of irregular uterine bleeding (in combination with gestagen in non-hysterectomized women) in perimenopause and postmenopause. Drugs with tissue-specific estrogenic effects are termed selective estrogen receptor modulators (SERM). Tamoxifen is the first SERM successfully used in the prevention and treatment of breast cancer. Another SERM raloxifene is widely used in the prevention and treatment of postmenopausal osteoporosis, especially in women without climacteric complaints. Therapy with raloxifene increases bone mineral density, lowers serum concentrations of total and low-density lipoprotein cholesterol, and does not stimulate endometrium and breast. Evaluation of another potential positive effects (reducing size of uterine leiomyomas, etc.) warrants further investigation. CONCLUSION: Raloxifene can be used in postmenopausal women free of climacteric symptoms for the prevention and treatment of postmenopausal osteoporosis with no increased risk of thrombosis and with the advantage of positive side effects during the treatment.

Estrogen Replacement Therapy↗

PubMed2005

Raloxifene reduces urokinase-type plasminogen activator-dependent proliferation of synoviocytes from patients with rheumatoid arthritis.

Extracellular fibrinolysis, controlled by the membrane-bound fibrinolytic system, is involved in cartilage damage and rheumatoid arthritis (RA) synovitis. Estrogen status and metabolism seem to be impaired in RA, and synoviocytes show receptors for estrogens. Our aims in this study were to evaluate in healthy and RA synoviocytes the effects of Raloxifene (RAL), a selective estrogen receptor modulator (SERM), on: proliferation; the components of the fibrinolytic system; and chemoinvasion. The effects of RAL were studied in vitro on synoviocytes from four RA patients and four controls. Proliferation was evaluated as cell number increase, and synoviocytes were treated with 0.5 microM and 1 microM RAL with and without urokinase-plasminogen activator (u-PA) and anti-u-PA/anti-u-PA receptor (u-PAR) antibodies. Fibrinolytic system components (u-PA, u-PAR and plasminogen activator inhibitor (PAI)-1) were assayed by ELISA with cells treated with 0.5 microM and 1 microM RAL for 48 h. u-PA activity was evaluated by zymography and a direct fibrinolytic assay. U-PAR/cell and its saturation were studied by radioiodination of u-PA and a u-PA binding assay. Chemoinvasion was measured using the Boyden chamber invasion assay. u-PA induced proliferation of RA synoviocytes was blocked by RAL (p < 0.05) and antagonized by antibodies alone. The inhibitory effect of RAL was not additive with u-PA/u-PAR antagonism. RA synoviocytes treated with RAL showed, compared to basal, higher levels of PAI-1 (10.75 +/- 0.26 versus 5.5 +/- 0.1 microg/10(6) cells, respectively; p < 0.01), lower levels of u-PA (1.04 +/- 0.05 versus 3.1 +/- 0.4 ng/10(6) cells, respectively; p < 0.001), and lower levels of u-PAR (11.28 +/- 0.22 versus 23.6 +/- 0.1 ng/10(6) cells, respectively; p < 0.001). RAL also significantly inhibited u-PA-induced migration. Similar effects were also shown, at least partially, in controls. RAL exerts anti-proliferative and anti-invasive effects on synoviocytes, mainly modulating u-PAR and, to a lesser extent, u-PA and PAI-1 levels, and inhibiting cell migration and proliferation.

Arthritis, Rheumatoid↗

PubMed2002

Breast cancer risk reduction: strategies for women at increased risk.

Breast cancer risk reduction now represents an achievable medical objective. Current interventions include selective estrogen receptor modulators (SERMs), prophylactic surgery, and lifestyle change. For SERMs, current evidence supports tamoxifen use for breast cancer risk reduction whereas raloxifene requires further study. Prophylactic mastectomy and prophylactic oophorectomy, effective in retrospective clinical experiences, should be considered only for women at substantial risk willing to accept the irreversible consequences of these procedures. Although dietary fat intake is under clinical trial evaluation, lifestyle change, including weight loss, dietary change, and increased physical activity, can be recommended based on other health considerations. Use of any intervention requires careful breast cancer risk assessment, risk-benefit calculations, and informed decision making with full patient participation. Future breast cancer risk assessment may incorporate additional biologic measures of estrogen exposure and/or analyses of collected breast cells. Under active evaluation are novel SERMs, aromatase inhibitors/inactivators, gonadotrophin-releasing hormone agonists, retinoids, statins, and tyrosine kinase and cyclooxygenase-2 inhibitors.

Breast Neoplasms↗

PubMed2005

Raloxifene: bone and cardiovascular effects.

Raloxifene (RLX), a selective estrogen receptor modulator (SERM), is currently indicated for the prevention and treatment of post-menopausal osteoporosis. At present, RLX is evaluated in other areas of study that include the reduction of the risk of breast cancer and cardiovascular (CV) disease in post-menopausal women. This SERM acts as an estrogen agonist in the skeleton, on serum lipid metabolism and on a number of coagulation factors, while it is an estrogen antagonist in the breast and uterus. Although our current data are incomplete, RLX has a favourable risk-benefit safety profile and is one of the most promising medical agents not only for the prevention of osteoporosis, but also for a large number of other disorders in post-menopausal women.

Aged↗

PubMed2003

The role of estrogen and estrogen-related drugs in cardiovascular diseases.

The cardiovascular effects of estrogen have recently become a focus of basic and clinical cardiovascular medicine because of the multiplicity of its beneficial effects. Various basic and clinical studies have revealed that estrogen has potent cardiovascular effects against ischemic or non-ischemic injury of the heart and vessels, leading to the concept that administration of estrogen may reduce cardiovascular disease in postmenopausal women. Indeed, among the groups of the postmenopausal women who have a higher risk of cardiovascular diseases, the hormone therapy has been associated with improved outcomes for cardiovascular events. Estrogen binds to the estrogen receptor, which is a member of the steroid hormone family of nuclear receptors and is the estrogen response element in target genes, leading to the transcriptional regulation of many genes. In addition to these genomic effects of estrogen, it has been recently reported that estrogen can have rapid "nongenomic" effects. In contrast to such data, recent clinical prevention trials in postmenopausal women treated with a combination of estrogen and progestins have not revealed any beneficial effects on cardiovascular morbidity or mortality, and estrogen itself increases the risk of endometrial and breast cancer. Under these circumstances, a selective estrogen receptor modulator (SERM), which exerts estrogenic agonistic or antagonistic actions on various tissues, has been recently introduced for new hormone therapy because it reduces the adverse effects of estrogen. Here, we summarize the effects of estrogen and SERM on the cardiovascular system and discuss cellular mechanisms that may be involved.

Animals↗

PubMedDate not supplied

A review of combination regimens for osteoporosis--prevention and treatment.

Two long-used interventions for reducing the morbidity and mortality associated with osteoporosis are postmenopausal hormone replacement therapy (HRT) and treatment with antiresorptive agents. Postmenopausal HRT works through prevention of osteoporosis, whereas antiresorptive agents, such as the bisphosphonates, reverse low bone mass. Because of their different mechanisms, it has been thought that combining the two therapies would yield additive improvements in bone mineral density (BMD) and in fracture risk reduction. Results from several recent clinical trials in postmenopausal women with low bone mass support this idea, demonstrating clinically relevant additive improvements in BMD after treatment with HRT (or a selective estrogen receptor modulator) plus a bisphosphonate. Data regarding fracture rates after HRT and bisphosphonate combination therapy are unavailable, however. A newer osteoporosis treatment is subcutaneously injected parathyroid hormone (PTH). Treatment with PTH stimulates new bone formation, and recent studies have shown that PTH monotherapy reduces fracture rates. Initial data from studies of HRT and PTH combination therapy have shown impressive gains in BMD, but fracture rate data have not been published. Use of HRT for osteoporosis, either alone or in combination with a bisphosphonate or PTH, has become problematic since the recent report of a small number of serious adverse effects associated with HRT in the Women's Health Initiative.

Aged↗

PubMed2005

Interaction between estrogen receptor alpha, ionizing radiation and (anti-) estrogens in breast cancer cells.

PURPOSE: Estrogen receptor alpha (ERalpha) plays a major role in breast cancer development. It acts as ligand-inducible transcription factor which determines growth, survival and differentiation of breast cancer cells. The aim of this study is to evaluate the potential interference between radiotherapy and estrogen receptor responsiveness. Materials and methods. The effect of ionizing radiation was assessed on the estrogen receptor alpha status, growth (proliferation and apoptosis) and sensitivity of MCF-7 breast cancer cells to estrogenic (17beta-estradiol (E2)), selective estrogen receptor modulator (SERM) and anti-estrogenic compounds. Results. We have observed a ligand-independent decrease in ERalpha expression after radiation, resulting from a specific reduction in mRNA level and protein synthesis. This ERalpha disappearance occurred 72 h post-irradiation at 8 Gy and decreased the transcriptional activity in ERalpha of these cells. On the other hand, E2 impedes the growth inhibitory effects (essentially on proliferation) of ionizing radiation in MCF-7 cells, which potentially decreases radiosensitivity of these cells. This effect was totally blocked by SERM and anti-estrogenic treatments. Moreover, this growth effect of concurrent anti-estrogenic drugs and ionizing radiation appeared to be strongly synergistic. CONCLUSIONS: This study may increase general comprehension of ERalpha modulation by radiotherapy and improve adjuvant therapeutic approaches based on co-administration of radiation and endocrine therapy.

Analysis of Variance↗

PubMed2004

Bazedoxifene (Wyeth).

Bazedoxifene is a tissue-specific selective estrogen receptor modulator being developed by Wyeth Pharmaceuticals (formerly Wyeth-Ayerst Laboratories) to be used alone for the prevention and treatment of osteoporosis in postmenopausal women and in combination with Premarin for menopausal symptoms. As of March and June 2004, worldwide phase III trials for bazedoxifene, and bazedoxifene in combination with Premarin, were ongoing.

Animals↗

PubMed2001

Developing a SERM: stringent preclinical selection criteria leading to an acceptable candidate (WAY-140424) for clinical evaluation.

Estrogens are represented by a diverse group of compounds. Within this large family of molecules are tissue-selective estrogens that have been classified as selective estrogen receptor modulators (SERMs). These compounds are characterized by the fact that they exhibit both estrogen agonist and antagonist activity dependent upon the gene promoter and target tissue being examined. SERMs have been intensively studied over the past decade, especially since one, raloxifene, has been approved for the prevention and treatment of postmenopausal osteoporosis. While not a replacement for hormone replacement therapy (HRT), raloxifene can be an alternative to it and other treatments for osteoporosis. The ideal SERM would provide the positive benefits associated with HRT without the uterine and breast stimulation. Raloxifene does achieve some of the benefits of HRT, specifically on the skeleton and lipid metabolism with no apparent uterine effects, and a potential decreased risk of developing breast cancer associated with raloxifene therapy. However, there are a number of parameters that can be improved. A number of SERMs have been evaluated only to fail in development due to, for the most part, uterine safety issues. In order to develop an improved SERM, a stringent screening process was designed to select compounds that did not stimulate the uterus or breast. At the same time, these new compounds would have a positive impact on the skeleton and lipid metabolism with the additional improvement (over raloxifene) of a neutral effect on hot flashes. Under these strict conditions, WAY-140424 was developed and, to date, the preclinical pharmacology data have accurately predicted the clinical response demonstrated in phase I and II trials.

Animals↗

PubMed2001

Rationale and overview of the Raloxifene Use for the Heart (RUTH) trial.

Raloxifene is a selective estrogen receptor modulator (SERM) that has beneficial effects on several cardiovascular risk factors and has also been associated with a reduced risk of breast cancer in osteoporosis prevention trials. The Raloxifene Use for the Heart (RUTH) study was designed to test the hypothesis that, compared to placebo, raloxifene at 60 mg/day (1) lowers the risk of the combined end point of coronary death, nonfatal myocardial infarction (MI), and hospitalized acute coronary syndromes other than MI and (2) reduces the risk of invasive breast cancer (coprimary end point) in women at high risk for major coronary events based on established cardiovascular disease (CVD) or multiple risk factors. RUTH is a double-blind, placebo-controlled, randomized, clinical trial of 10,101 women aged 55 years or older from 26 countries and is expected to be completed in approximately 5 years.

Adenocarcinoma↗

PubMed2005

Cyclooxygenase-2 protein reduces tamoxifen and N-(4-hydroxyphenyl)retinamide inhibitory effects in breast cancer cells.

Approximately 30-40% of estrogen receptor alpha (ERalpha)-positive breast tumors express high levels of the cyclooxygenase-2 (COX-2) protein, and these high levels have been associated with a poorer prognosis in breast cancer patients. We speculate that high levels of COX-2 induce drug resistance in ERalpha-positive breast tumors, thus reducing the survival rate of patients with such tumors. Human breast cancer cell lines that express high levels of COX-2 are generally ERalpha negative. To determine whether COX-2 induces drug resistance, plasmids encoding the COX-2 gene were stably transfected into ERalpha-positive MCF-7 human breast cancer cells (MCF-7/COX-2). MCF-7/COX-2 cells were resistant to the selective estrogen receptor modulator tamoxifen but not to its analog, raloxifene. MCF-7/COX-2 cells were also resistant to the retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) but not to its analog, all-trans retinoic acid. In contrast, the sensitivities of MCF-7/COX-2 cells to doxorubicin and paclitaxel were similar to those of the parental MCF-7 cells. We then determined which COX-2 product, prostaglandin E2 (PGE2) or prostaglandin F2alpha is involved in the COX-2-mediated drug resistance. PGE2, but not PGF2alpha, blocked the antiproliferative effects of tamoxifen and 4-HPR. Agonists that activate PGE2 receptors and their downstream kinase effectors, protein kinases A and C, also blocked the growth inhibitory effects of these drugs. Increased levels of Bcl-2 and Bcl-XL proteins have been reported in mammary tumors of COX-2 transgenic mice and in human colon cancer cell lines that have high levels of COX-2. However, we did not observe any changes in Bcl-2, Bcl-XL, or Bax expression induced by COX-2 or PGE2. Here we report the novel findings that COX-2 uses PGE2 to stimulate the activities of protein kinases A and C to induce selectively tamoxifen and 4-HPR resistance in ERalpha-positive breast cancer cells.

Antineoplastic Agents↗

PubMed2001

Beyond tamoxifen new endpoints for breast cancer chemoprevention, new drugs for breast cancer prevention.

Although tamoxifen appears to markedly reduce breast cancer risk in women with a prior diagnosis of atypical hyperplasia or in situ carcinoma, it is not clear what other groups of women receive substantial benefit. Major breast chemoprevention priorities are to (1) develop new agents that (a) have fewer side effects, (b) are effective in ER--as well as tamoxifen-resistant precancerous tissue, and (c) are compatible with hormone therapy; and (2) develop efficient clinical strategies including prognostic and predictive morphologic and molecular biomarkers. Breast tissue may be repeatedly sampled for evidence of intraepithelial neoplasia by fine needle aspiration, ductal lavage, or needle biopsy to select candidates at highest short-term risk as well as to monitor response in small proof of principle studies prior to a large cancer incidence trial. Molecular marker expression may also be used to select a cohort most likely to respond to a particular agent. A large number of new agents are attractive as potential prevention agents and some are already in clinical prevention testing. Compounds which should be effective in ER + precancerous tissue but may have a better side-effect profile include new selective estrogen receptor modulators which lack uterine estrogen agonist activity, isoflavones, aromatase inactivators/inhibitors for postmenopausal women, and gonadotropin-releasing hormone regimens for premenopausal women. Retinoids, rexinoids, and deltanoids may be efficacious in ER+ tissue resistant to tamoxifen. Agents which should theoretically have activity in ER- or ER+ precancerous tissue include polyamine synthesis inhibitors, tyrosine kinase inhibitors, combined demethylating agents and histone deacetylase inhibitors, as well as metalloprotease and angiogenesis inhibitors. Sample Phase I and Phase II clinical trial designs are reviewed using modulation of molecular markers and breast intraepithelial neoplasia as the major endpoints.

Aneuploidy↗

PubMed2006

[SERM].

SERM is the abbreviation of the selective estrogen receptor modulator which is the synthetic ligands of estrogen receptor (ER) acting estrogenically or anti-estrogenically among various tissues through modifying the ER function. Clomifene, tamoxifen, toremifene and raloxifene are generally classified as SERM in the clinical use. The main cause of postmenopausal osteoporosis is estrogen deficiency and it was revealed that the continuous combined use of conjugated estrogen and medroxyprogesterone acetate reduced the relative risk of femoral neck fracture to 0.66, however increased the relative risk of cardiovascular event and breast cancer to 1.29 or 1.26, respectively. From the standpoint of safe and clinical compliance for the breast and uterine tissue, raloxifene is recommendable for middle aged postmenopausal osteoporosis.

Female↗