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Results for “Estrogen Receptor Modulators”

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PubMed2001

Stepwise estrogen suppression manipulating the estrostat.

Estrogen suppression is an effective endocrine treatment option in pre- as well as postmenopausal breast cancer patients. The fact that it produces clinical benefits not only in these two groups of patients that differ significantly with respect to plasma estrogen levels but also among patients with very low plasma estrogen levels due to previous hypophysectomy, adrenalectomy or treatment with first/second generation aromatase inhibitors, suggests estrogen deprivation to work independent of pretreatment plasma estrogen levels. Interestingly, in vitro studies have revealed MCF-7 cells to respond to estrogen deprivation by sensitization, causing maximum estradiol stimulation at a concentration 10(-5) to 10(-4) the concentration needed in wild-type cells. While results from recent phase III studies comparing novel aromatase inhibitors and inactivators to conventional therapy have suggested that a more effective hormone ablation may be translated into an improved clinical efficacy, the biochemical rationale for lack of complete cross-resistance between aromatase inhibitors and inactivators or aromatase inhibitors and megestrol acetate remains to be explained. Interestingly, patients becoming resistant to estrogen deprivation may still respond to estrogens administered in pharmacological doses. Future studies are warranted to explore alterations in gene expression and signaling mechanisms in response to different therapies in tumor tissue in vivo.

Adaptation, Physiological↗
PubMed1999

19-oxygenations of 3-deoxy androgens, potent competitive inhibitors of estrogen biosynthesis, with human placental aromatase.

Aromatase is a cytochrome P450 enzyme complex that catalyzes the conversion of androst-4-ene-3,17-dione (AD) to estrone through three sequential oxygenations of the 19-methyl group. To gain insight into the ability of 3-deoxy derivative of AD, compound 1, and its 5-ene isomer 4, which are potent competitive inhibitors of aromatase, to serve as a substrate, we studied their 19-oxygenation by human placental aromatase and the metabolites isolated were analyzed by gas chromatography-mass spectrometry. Inhibitors 1 and 4 were found to be oxygenated with aromatase to produce the corresponding 19-hydroxy derivatives 2 and 5 and 19-oxo derivatives 3 and 6 as well as the 17beta-reduced 19-hydroxy compounds 7 and 8. Kinetic studies indicated that the 5-ene steroid 4 was surprisingly a good substrate for the aromatase-catalyzing 19-oxygenation with the V(max) value of 45 pmol/min per mg prot which was approx. four times higher than that of the other. The relative K(m) value for steroids 1 and 4 obtained in this study is opposite from the relative K(i) value obtained previously in the inhibition study. The results reveal that there is a difference between a binding suitable for serving as an inhibitor of aromatase and a binding suitable for serving as a substrate of the enzyme in the 3-deoxy steroid series and the C-3 carbonyl group of AD is essential for a proper binding as a substrate to the active site of aromatase.

Androgens↗
PubMed2000

Synthesis and estrogenic activities of novel 7-thiosubstituted estratriene derivatives.

A diastereomerically pure series of 7alpha-thioestratrienes was prepared and evaluated for its affinity for both the human estrogen receptor alpha and the more recently discovered estrogen receptor beta. The functional estrogenic activities of the compounds were measured in a MCF-7 ERE-tk-luciferase assay. The activities and selectivities of the compounds were sensitive to the nature of the thioether side chain.

Binding, Competitive↗
PubMed1999

Targeted Antiestrogens to Prevent Breast Cancer.

Tamoxifen, the first selective estrogen receptor modulator (SERM), has provided invaluable laboratory and clinical evidence that such drugs can reduce the risk of breast cancer and increase bone density. Raloxifene is available for the prevention of osteoporosis, and preliminary studies show a decrease in breast cancer risk. On the basis of current information about the pharmacology of SERMs, a large breast cancer prevention trial called study of tamoxifen and raloxifene (STAR) has started in the USA. Results should be available in the next seven years.

Journal Article↗
PubMed2000

The prognostic value and clinical utility of estrogen and progesterone receptors in endometrial carcinoma.

In the United States, endometrial carcinoma is the most common gynecologic malignancy, and accounts for 4,900 deaths per year in the United States. While this disease has relatively good cure rates, there is motivation to describe other determinants, which may help in the treatment of this disease. Attempts have been made to correlate hormone receptor status with disease-free intervals and survival in patients with endometrial carcinoma. The weight of evidence seems to support that of the two hormone receptors, progesterone is the more significant predictor of patient outcome. If hormone receptors are to be used in the management of endometrial carcinoma, they should be determined by immunohistochemistry. In the adjuvant setting, patients with progesterone positive tumors are more amenable to treatment with progestational agents than are patients with receptor negative tumors. Future areas of research include the use of tamoxifen and selective estrogen receptor modulators in the chemoprevention and treatment of endometrial carcinoma.

Journal Article↗
PubMed2000

Inherited coagulopathies in OB/GYN.

There is an increased risk of venous thrombosis in women with inherited plasma protein coagulopathies (thrombophilias). Although a general screening for thrombophilia is impractical, risk assessment based on identification of other hypercoagulable states-such as a personal or family history of venous thrombosis-can identify patients who may benefit from testing. Those patients testing positive for thrombophilia need to be counseled regarding the implications of oral contraceptive use, hormone replacement therapy, use of selective estrogen receptor modulators, and pregnancy.

Journal Article↗
PubMed2003

The homeopathic approach to the treatment of symptoms of oestrogen withdrawal in breast cancer patients. A prospective observational study.

This paper reports on an investigation of the homeopathic approach to the management of symptoms of oestrogen withdrawal in women with breast cancer. Forty-five patients entered the study. The most common presenting symptoms were hot flushes (HF) (n=38), mood disturbance (n=23), joint pain (n=12), and fatigue (n=16). Other symptoms included sleeplessness, reduced libido, weight gain, cystitis, vaginal dryness and skin eruptions. The active intervention was an individualised homeopathic medicine. Forty women (89%) completed the study. Significant improvements in mean symptom scores were seen over the study period and for the primary end-point 'the effect on daily living' scores. Symptoms other than HF such as fatigue and mood disturbance appear to be helped. Significant improvements in anxiety, depression and quality of life were demonstrated over the study period. The homeopathic approach appears to be clinically useful in the management of oestrogen withdrawal symptoms in women with breast cancer whether on or off Tamoxifen and improves mood disturbance. A placebo-controlled trial would be the next stage in this line of inquiry.

Adult↗
PubMedDate not supplied

FLAME: a program to flexibly align molecules.

Herein, we describe a method to flexibly align molecules (FLAME = FLexibly Align MolEcules). FLAME aligns two molecules by first finding maximum common pharmacophores between them using a genetic algorithm. The resulting alignments are then subjected to simultaneous optimizations of their internal energies and an alignment score. The utility of the method in pairwise alignment, multiple molecule flexible alignment, and database searching was examined. For pairwise alignment, two carboxypeptidase ligands (Protein Data Bank codes and ), two estrogen receptor ligands ( and ), and two thrombin ligands ( and ) were used as test sets. Alignments generated by FLAME starting from CONCORD structures compared very well to the X-ray structures (average root-mean-square deviation = 0.36 A) even without further minimization in the presence of the protein. For multiple flexible alignments, five structurally diverse D3 receptor ligands were used as a test set. The FLAME alignment automatically identified three common pharmacophores: a base, a hydrogen-bond acceptor, and a hydrophobe/aromatic ring. The best alignment was then used to search the MDDR database. The search results were compared to the results using atom pair and Daylight fingerprint similarity. A similar database search comparison was also performed using estrogen receptor modulators. In both cases, hits identified by FLAME were structurally more diverse compared to those from the atom pair and Daylight fingerprint methods.

Journal Article↗
PubMed2006

Quantitative profiling of drug-associated proteomic alterations by combined 2-nitrobenzenesulfenyl chloride (NBS) isotope labeling and 2DE/MS identification.

The identification of drug-responsive biomarkers in complex protein mixtures is an important goal of quantitative proteomics. Here, we describe a novel approach for identifying such drug-induced protein alterations, which combines 2-nitrobenzenesulfenyl chloride (NBS) tryptophan labeling with two-dimensional gel electrophoresis (2DE)/mass spectrometry (MS). Lysates from drug-treated and control samples are labeled with light or heavy NBS moiety and separated on a common 2DE gel, and protein alterations are identified by MS through the differential intensity of paired NBS peptide peaks. Using NBS/2DE/MS, we profiled the proteomic alterations induced by tamoxifen (TAM) in the estrogen receptor (ER) positive MCF-7 breast cancer cell line. Of 88 protein spots that significantly changed upon TAM treatment, 44 spots representing 23 distinct protein species were successfully identified with NBS-paired peptides. Of these 23 TAM-altered proteins, 16 (70%) have not been previously associated with TAM or ER activity. We found the NBS labeling procedure to be both technically and biologically reproducible, and the NBS/2DE/MS alterations exhibited good concordance with conventional 2DE differential protein quantitation, with discrepancies largely due to the comigration of distinct proteins in the regular 2DE gels. To validate the NBS/2DE/MS results, we used immunoblotting to confirm GRP78, CK19, and PA2G4 as bona fide TAM-regulated proteins. Furthermore, we demonstrate that PA2G4 expression can serve as a novel prognostic factor for disease-free survival in two independent breast cancer patient cohorts. To our knowledge, this is the first report describing the proteomic changes in breast cancer cells induced by TAM, the most commonly used selective estrogen receptor modulator (SERM). Our results indicate that NBS/2DE/MS may represent a more reliable approach for cellular protein quantitation than conventional 2DE approaches.

Cell Line, Tumor↗
PubMed2005

Analysis of protein covalent modification by xenobiotics using a covert oxidatively activated tag: raloxifene proof-of-principle study.

Numerous xenobiotics, including therapeutics agents, are substrates for bioactivation to electrophilic reactive intermediates that may covalently modify biomolecules. Selective estrogen receptor modulators (SERMs) are in clinical use for long-term therapy of postmenopausal syndromes and chemoprevention and provide a potential alternative for hormone replacement therapy (HRT). Raloxifene, in common with many SERMs and other xenobiotics, is a polyaromatic phenol that has been shown to be metabolically bioactivated to electrophilic and redox active quinoids. Nucleic acid and glutathione adduct formation have been reported, but little is known about protein covalent modification. A novel COATag (covert oxidatively activated tag) was synthesized in which raloxifene was linked to biotin. The COATag was reactive toward a model protein, human glutathione-S-transferase P1-1, in the presence but not the absence of monooxygenase. The covalent modification of proteins in rat liver microsomal incubations was NADPH-dependent implicating cytochrome P450 oxidase. The COATag facilitated isolation and identification of covalently modified microsomal proteins: cytosolic glucose regulated protein (GRP78/BiP), three protein disulfide isomerases, and microsomal glutathione S-transferase 1. Oxidative metabolism of raloxifene produces reactive intermediates of sufficient lifetimes to covalently modify proteins in tissue microsomes, behavior anticipated for other polyaromatic phenol xenobiotics that can be tested by the COATag methodology. The combined use of a COATag with a simple biotin-linked electrophile (such as an iodoacetamide tag) is a new technique that allows quantification of protein covalent modification via alkylation vs oxidation in response to xenobiotic reactive intermediates. The identification of modified proteins is important for defining pathways that might lead alternatively to either cytotoxicity or cytoprotection.

Animals↗
PubMed2003

Dopamine resistance of prolactinomas.

Resistance to dopamine agonists can be defined with respect to failure to normalize PRL levels and failure to decrease tumor size by > or = 50%. Using these definitions, failure to normalize PRL levels is seen in 24% of those treated with bromocriptine, 13% of those treated with pergolide and 11% of those treated with cabergoline. Failure to achieve at least a 50% reduction in tumor size occurs in about one-third of those treated with bromocriptine and 10-15% of those treated with pergolide or cabergoline. Studies of in vitro cell preparations show that the D2 receptors of resistant tumors are decreased in number but have normal affinity. Treatment approaches for resistant patients include switching to another dopamine agonist and raising the dose of the drug as long as there is continued response to the dose increases and no adverse effects. Transsphenoidal surgery can also be done. If fertility is desired, clomiphene, gonadotropins, and GnRH are also options. If fertility is not desired, estrogen replacement may be used unless there is a macroadenoma, in which case control of tumor growth is also an issue and dopamine agonists are generally necessary. However, in many cases modest or even no reduction may be acceptable long-term as long as there is not tumor growth. Hormone replacement (estrogen or testosterone) may cause a decrease in efficacy of the dopamine agonist so that it must be carried out cautiously. Reduction of endogenous estrogen, use of selective estrogen receptor modulators, and aromatase inhibitors are potential experimental approaches.

Bromocriptine↗
PubMed2004

[Aromatase inhibitors in the adjuvant therapy of breast carcinomas].

Hormonal therapies have been used in the adjuvant therapy of breast cancer for decades. Tamoxifen, a selective estrogen receptor modulator, is the current standard therapy. It reduces the risk of recurrence by about one half Only recently, new aromatase inhibitors (anastrozole, letrozole, exemestane) have been competing with tamoxifen; these drugs are superior to tamoxifen in advanced breast cancer. Two recent trials are discussed: Anastrozole reduced the short-term risk of recurrent disease more efficiently than tamoxifen. The use of letrozole after five years of adjuvant tamoxifen treatment further reduced the risk of recurrence. Numerous side-effects, notably endometrial cancer and thromboembolic disease, were less frequent with aromatase inhibitors whereas the risk of osteoporotic fractures increased substantially. The positive preliminary results of these and other trials are discussed: At present, the use of aromatase inhibitors is not yet recommended on a routine basis. Future trial results will allow a more complete assessment of the efficacy and toxicity of aromatase inhibitors.

Anastrozole↗
PubMed2001

Estrogen synthesis in the male brain triggers development of the avian song control pathway in vitro.

Sexual differentiation of the brain is determined in part by steroids such as estrogen, which are generally assumed to arise from the gonads. Here we show that estrogens are produced autonomously in cultured juvenile male zebra finch brain slices, and this brain-derived estrogen is both necessary and sufficient to trigger formation in vitro of a key male-specific synaptic connection in the telencephalic song control circuit. Male-like development was stimulated in female slices cultured with male slices or exposed to estrogen, and estrogen antagonists inhibited song circuit development in slices of either sex. These results reveal a new mode of sex-specific neural development, induced not by differential exposure to gonadal steroids, but rather by differential synthesis of steroids in the brain.

Animals↗
PubMed2005

Therapy Insight: osteoporosis during hormone therapy for prostate cancer.

The intended therapeutic effect of gonadotropin-releasing-hormone (GnRH) agonists is hypogonadism, which is a leading cause of osteoporosis in men. Observations are consistent with this effect: GnRH agonists decrease bone mineral density and increase fracture risk in men with prostate cancer. Estrogens play a central role in homeostasis of the normal male skeleton and evidence suggests that estrogen deficiency is primarily responsible for the adverse skeletal effects of GnRH agonists. The mechanism of treatment-related bone loss involves acceleration of physiologic bone turnover. In small, randomized, controlled trials, bisphosphonates (pamidronate, zoledronic acid) and selective estrogen-receptor modulators (raloxifene, toremifene) increased bone mineral density in GnRH-agonist-treated men. Two ongoing large, randomized, placebo-controlled studies will prospectively define fracture outcomes in men with prostate cancer and assess the efficacy of novel pharmacologic interventions (AMG 162, toremifene) in GnRH-agonist-treated men.

Bone Density↗
PubMed2004

Effect of red clover-derived isoflavone supplementation on insulin-like growth factor, lipid and antioxidant status in healthy female volunteers: a pilot study.

BACKGROUND: Isoflavones are estrogen-like plant compounds that may protect against cardiovascular disease and endocrine-responsive cancer. Isoflavones may, because of their ability to act as selective estrogen receptor modulators, alter insulin-like growth factor (IGF) status. OBJECTIVE: The aim of this study was to assess the effect of 1-month isoflavone supplementation (86 mg/day red clover-derived isoflavones) on IGF status. DESIGN AND SUBJECTS: Healthy pre- (n=16) and postmenopausal (n=7) women were invited to take part in a randomised, placebo-controlled crossover study with a minimum 2-month washout period. RESULTS: : For premenopausal subjects, the change in IGF-1, IGF-BP1 and IGF-BP3 assessed at different points of the menstrual cycle did not differ between isoflavone and placebo phase. However, the change in IGF-1, when examined pre- and post-supplementation, was nonsignificantly reduced (P=0.06) on the isoflavone supplement compared to placebo. For postmenopausal subjects, the change in IGF-1, IGF-BP1 and IGFBP-3 concentrations over the supplementation period did not differ between isoflavone or placebo phase. Isoflavones increased HDL in postmenopausal women compared to placebo (P=0.02) but did not alter either cholesterol or triacylglycerol concentrations, and had no effect on antioxidant status. CONCLUSIONS: This study shows that 1-month supplementation with red clover isoflavones has a positive effect on HDL cholesterol, but at most a small effect on IGF status in premenopausal and no effect in postmenopausal subjects. Further studies are required to ascertain the role these dietary compounds may have to play in breast cancer prevention.

Adult↗
PubMed2000

Reversal of an antiestrogen-mediated cell cycle arrest of MCF-7 cells by viral tumor antigens requires the retinoblastoma protein-binding domain.

Proliferation of MCF-7 cells is estrogen dependent and antiestrogen sensitive. In the absence of estrogens or presence of antiestrogens MCF-7 cells arrest in the G1 phase of the cell cycle, and this arrest is associated with an accumulation of the active, hypophosphorylated form of the retinoblastoma protein (pRb). Because active pRb negatively regulates passage from G1 to S phase, this suggests that pRb is a crucial target of estrogen action, and that its inactivation might lead to antiestrogen resistance. We tested this hypothesis by expressing viral tumor antigens (T antigens), which bind and inactivate pRb, in MCF-7 cells, and determining the effects on cell proliferation in the presence of antiestrogens. The results of these experiments demonstrate that T antigen expression confers antiestrogen resistance to MCF-7 cells. Using a panel of mutant T antigens, we further demonstrate that the pRb-binding, but not the p53 binding domain is required to confer antiestrogen resistance. Thus, pRb is an important target of estrogen action, and its inactivation can contribute to the development of antiestrogen resistance.

Adenocarcinoma↗
PubMed2002

Ectopic expression of cyclin E in estrogen responsive cells abrogates antiestrogen mediated growth arrest.

Estrogens stimulate proliferation of estrogen receptor positive MCF7 breast cancer cells while antiestrogens signal a G0/G1 growth arrest. In MCF7 cells, arrest is mediated through the CDK inhibitors p21 and p27 and through a decrease in cyclin E/CDK2 kinase activity. We found that in MCF7 cells, overexpression of cyclin E partially abrogates a tamoxifen mediated growth arrest. Overexpression of cyclin E is accompanied by a decrease in the levels of RB and CDK inhibitor p21 but an increase in CDK inhibitor p27. Cyclin E overexpression also alters the composition of E2F transcription factor complexes. The E2F4/p107/cyclin E/CDK2 complex, a minor component in proliferating control cells that is absent in growth-arrested cells, is more abundant in both proliferating and tamoxifen treated cyclin E overexpressing cells. Conversely, levels of the quiescence associated E2F/p130 complex is not detected in these cells. Expression from the E2F dependant promoter is elevated in proliferating and tamoxifen treated cyclin E overexpressing cells. This study suggests that a modest overexpression of cyclin E abrogates the tamoxifen mediated growth arrest through modification of the RB/E2F pathway. Moreover, these results provide one explanation of why some cells that express the estrogen receptor may be unresponsive to antiestrogens.

CDC2-CDC28 Kinases↗
PubMed2001

Role of extra-ovarian oestrogens in the regulation of gonadotropin releasing hormone mRNA expression in the rat brain.

To further understand the role of oestrogens in the regulation of gonadotropin releasing hormone (GnRH) mRNA expression in the female rat brain, the effect of EM-652.HCl, a pure anti-oestrogen, was studied in intact and ovariectomized rats as well as in rats chronically treated with a GnRH agonist D-trp6, des-Gly-NH210 GnRH ethylamide (GnRH-A), a treatment which blocks ovarian steroidogenesis. Quantitative in situ hybridization was used to measure GnRH mRNA at the cellular level in the preoptic-anterior hypothalamic area. It was found that, 49 weeks after ovariectomy (OVX), the number of silver grains per cell corresponding to GnRH mRNA was increased by 34%. Long-term administration (49 weeks) of EM-652.HCl to OVX rats resulted in a further increase (11% over the levels measured in OVX rats) in the hybridization signal. By contrast, in intact female rats, treated during 52 weeks with EM-652.HCl, a 49% increase in the GnRH hybridization signal was detected. In rats treated with GnRH-A during the same period, a 20% decrease in GnRH mRNA was observed. When EM-652.HCl was administered concomitantly with GnRH-A, a further 63% increase over the mRNA levels recorded in GnRH-A treated rats was found. Thus, long-term treatment with the anti-oestrogen EM-652.HCl can upregulate GnRH mRNA expression in intact female rats, OVX rats and female rats chronically treated with a GnRH-A. It is suggested that the pure anti-oestrogen EM-652.HCl can exert an influence on the oestrogen feedback mechanism involved in the regulation of GnRH neuronal activity by neutralizing the action of locally produced or low circulating levels of oestrogens remaining after OVX or GnRH-A treatment.

Animals↗