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Benita S. Katzenellenbogen - One of the best experts on this subject based on the ideXlab platform.
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selective estrogen Receptor Modulators discrimination of agonistic versus antagonistic activities by gene expression profiling in breast cancer cells
Cancer Research, 2004Co-Authors: Jonna Frasor, Barry S. Komm, Fabio Stossi, Jeanne M Danes, Richard C Lyttle, Benita S. KatzenellenbogenAbstract:Selective estrogen Receptor Modulators (SERMs) such as tamoxifen are effective in the treatment of many estrogen Receptor-positive breast cancers and have also proven to be effective in the prevention of breast cancer in women at high risk for the disease. The comparative abilities of tamoxifen versus raloxifene in breast cancer prevention are currently being compared in the Study of Tamoxifen and Raloxifene trial. To better understand the actions of these compounds in breast cancer, we have examined their effects on the expression of ∼12,000 genes, using Affymetrix GeneChip microarrays, with quantitative PCR verification in many cases, categorizing their actions as agonist, antagonist, or partial agonist/antagonist. Analysis of gene stimulation and inhibition by the SERMs trans-hydroxytamoxifen (TOT) and raloxifene (Ral) or ICI 182,780 (ICI) and by estradiol (E2) in estrogen Receptor-containing MCF-7 human breast cancer cells revealed that (a) TOT was the most E2-like of the three compounds, (b) all three compounds either partially or fully antagonized the action of E2 on most genes, with the order of antagonist activity being ICI > Ral > TOT, (c) TOT and Ral, but not ICI, displayed partial agonist/partial antagonist activity on a number of E2-regulated genes, (d) several stimulatory cell cycle-related genes were down-regulated exclusively by ICI, (e) the estrogen-like activity of Ral nearly always overlapped with that of TOT, indicating that Ral has little unique agonist activity different from that of TOT, and (f) some genes were specifically up-regulated by TOT but not Ral, ICI, or E2. Hence, gene expression profiling can discern fundamental differences among SERMs and provides insight into the distinct biologies of TOT, Ral, and ICI in breast cancer.
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selective estrogen Receptor Modulators discrimination of agonistic versus antagonistic activities by gene expression profiling in breast cancer cells
Cancer Research, 2004Co-Authors: Jonna Frasor, Barry S. Komm, Fabio Stossi, Jeanne M Danes, Richard C Lyttle, Benita S. KatzenellenbogenAbstract:Selective estrogen Receptor Modulators (SERMs) such as tamoxifen are effective in the treatment of many estrogen Receptor-positive breast cancers and have also proven to be effective in the prevention of breast cancer in women at high risk for the disease. The comparative abilities of tamoxifen versus raloxifene in breast cancer prevention are currently being compared in the Study of Tamoxifen and Raloxifene trial. To better understand the actions of these compounds in breast cancer, we have examined their effects on the expression of approximately 12,000 genes, using Affymetrix GeneChip microarrays, with quantitative PCR verification in many cases, categorizing their actions as agonist, antagonist, or partial agonist/antagonist. Analysis of gene stimulation and inhibition by the SERMs trans-hydroxytamoxifen (TOT) and raloxifene (Ral) or ICI 182,780 (ICI) and by estradiol (E2) in estrogen Receptor-containing MCF-7 human breast cancer cells revealed that (a) TOT was the most E2-like of the three compounds, (b) all three compounds either partially or fully antagonized the action of E2 on most genes, with the order of antagonist activity being ICI > Ral > TOT, (c) TOT and Ral, but not ICI, displayed partial agonist/partial antagonist activity on a number of E2-regulated genes, (d) several stimulatory cell cycle-related genes were down-regulated exclusively by ICI, (e) the estrogen-like activity of Ral nearly always overlapped with that of TOT, indicating that Ral has little unique agonist activity different from that of TOT, and (f) some genes were specifically up-regulated by TOT but not Ral, ICI, or E2. Hence, gene expression profiling can discern fundamental differences among SERMs and provides insight into the distinct biologies of TOT, Ral, and ICI in breast cancer.
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Estrogen Receptor transcription and transactivation Estrogen Receptor alpha and estrogen Receptor beta: regulation by selective estrogen Receptor Modulators and importance in breast cancer
Breast Cancer Research, 2000Co-Authors: Benita S. Katzenellenbogen, John A KatzenellenbogenAbstract:Estrogens display intriguing tissue-selective action that is of great biomedical importance in the development of optimal therapeutics for the prevention and treatment of breast cancer, for menopausal hormone replacement, and for fertility regulation. Certain compounds that act through the estrogen Receptor (ER), now referred to as selective estrogen Receptor Modulators (SERMs), can demonstrate remarkable differences in activity in the various estrogen target tissues, functioning as agonists in some tissues but as antagonists in others. Recent advances elucidating the tripartite nature of the biochemical and molecular actions of estrogens provide a good basis for understanding these tissue-selective actions. As discussed in this thematic review, the development of optimal SERMs should now be viewed in the context of two estrogen Receptor subtypes, ERα and ERβ, that have differing affinities and responsiveness to various SERMs, and differing tissue distribution and effectiveness at various gene regulatory sites. Cellular, biochemical, and structural approaches have also shown that the nature of the ligand affects the conformation assumed by the ER-ligand complex, thereby regulating its state of phosphorylation and the recruitment of different coregulator proteins. Growth factors and protein kinases that control the phosphorylation state of the complex also regulate the bioactivity of the ER. These interactions and changes determine the magnitude of the transcriptional response and the potency of different SERMs. As these critical components are becoming increasingly well defined, they provide a sound basis for the development of novel SERMs with optimal profiles of tissue selectivity as medical therapeutic agents.
Francesco Botrè - One of the best experts on this subject based on the ideXlab platform.
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relevance of the selective oestrogen Receptor Modulators tamoxifen toremifene and clomiphene in doping field endogenous steroids urinary profile after multiple oral doses
Steroids, 2011Co-Authors: Monica Mazzarino, Xavier Torre, Maria Cristina Bragano, Francesco Molaioni, Francesco BotrèAbstract:Abstract The present study was performed to investigate the influence of the intake of selective oestrogen Receptor Modulators on the urinary endogenous steroids profile. For this purpose the circadian variability of luteinizing hormone, follicle-stimulating hormone, testosterone, 5α-androstan-3α,17β-diol, 5β-androstan-3α,17β-diol, epitestosterone, 4-androstenedione, androsterone and etiocholanolone were measured on eight subjects (four males and four females) by gas chromatography–mass spectrometry and chemiluminescent immunometric assay techniques before and after oral administration of multiple doses of either tamoxifen (80 mg for 2 days) or toremifene (120 mg for 2 days) or clomiphene (100 mg for 2 days). The individual baseline variability of the steroids studied was set up by collecting the urine samples every 3 h, for 3 days prior to the treatment; whereas the evaluation of the effects of the oral administration of multiple doses of selective oestrogen Receptor Modulators on the steroid urinary profile was assessed by collecting urine samples every three hours for at least five days from the first administration. The results of our measurements showed that, only in male subjects, the relative urinary concentrations of testosterone, epitestosterone and 4-androstenedione were significantly altered generally after the second day of drug administration. While no significant effects were recorded in both sexes on the luteinizing hormone, follicle-stimulating hormone, androsterone, etiocholanolone, 5α-androstan-3α,17β-diol and 5β-androstan-3α,17β-diol urinary levels and on testosterone/epitestosterone, 5α-androstan-3α,17β-diol/5β-androstan-3α,17β-diol and androsterone/etiocholanolone ratios.
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Relevance of the selective oestrogen Receptor Modulators tamoxifen, toremifene and clomiphene in doping field: Endogenous steroids urinary profile after multiple oral doses
'Elsevier BV', 2011Co-Authors: Monica Mazzarino, Xavier Torre, Maria Cristina Bragano, Francesco Molaioni, Francesco BotrèAbstract:The present study was performed to investigate the influence of the intake of selective oestrogen Receptor Modulators on the urinary endogenous steroids profile. For this purpose the circadian variability of luteinizing hormone, follicle-stimulating hormone, testosterone, 5 alpha-androstan-3 alpha,17 beta-diol, 5 beta-androstan-3 alpha,17 beta-diol, epitestosterone, 4-androstenedione, androsterone and etiocholanolone were measured on eight subjects (four males and four females) by gas chromatography-mass spectrometry and chemiluminescent immunometric assay techniques before and after oral administration of multiple doses of either tamoxifen (80 mg for 2 days) or toremifene (120 mg for 2 days) or clomiphene (100 mg for 2 days). The individual baseline variability of the steroids studied was set up by collecting the urine samples every 3 h, for 3 days prior to the treatment: whereas the evaluation of the effects of the oral administration of multiple doses of selective oestrogen Receptor Modulators on the steroid urinary profile was assessed by collecting urine samples every three hours for at least five days from the first administration. The results of our measurements showed that, only in male subjects, the relative urinary concentrations of testosterone, epitestosterone and 4-androstenedione were significantly altered generally after the second day of drug administration. While no significant effects were recorded in both sexes on the luteinizing hormone, follicle-stimulating hormone, androsterone, etiocholanolone, 5 alpha-androstan-3 alpha,17 beta-diol and 5 beta-androstan-3 alpha,17 beta-diol urinary levels and on testosterone/epitestosterone, 5 alpha-androstan-3 alpha,17 beta-diol/5 beta-androstan-3 alpha,17 beta-diol and androsterone/etiocholanolone ratios. (C) 2011 Elsevier Inc. All rights reserved
Dalibor Sames - One of the best experts on this subject based on the ideXlab platform.
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synthetic and Receptor signaling explorations of the mitragyna alkaloids mitragynine as an atypical molecular framework for opioid Receptor Modulators
Journal of the American Chemical Society, 2016Co-Authors: Andrew C Kruegel, Madalee M Gassaway, Andras Varadi, Susruta Majumdar, Abhijeet Kapoor, Marta Filizola, Jonathan A Javitch, Dalibor SamesAbstract:Mu-opioid Receptor agonists represent mainstays of pain management. However, the therapeutic use of these agents is associated with serious side effects, including potentially lethal respiratory depression. Accordingly, there is a longstanding interest in the development of new opioid analgesics with improved therapeutic profiles. The alkaloids of the Southeast Asian plant Mitragyna speciosa, represented by the prototypical member mitragynine, are an unusual class of opioid Receptor Modulators with distinct pharmacological properties. Here we describe the first Receptor-level functional characterization of mitragynine and related natural alkaloids at the human mu-, kappa-, and delta-opioid Receptors. These results show that mitragynine and the oxidized analogue 7-hydroxymitragynine, are partial agonists of the human mu-opioid Receptor and competitive antagonists at the kappa- and delta-opioid Receptors. We also show that mitragynine and 7-hydroxymitragynine are G-protein-biased agonists of the mu-opioid r...
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Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators
2016Co-Authors: Andrew C Kruegel, Madalee M Gassaway, Susruta Majumdar, Abhijeet Kapoor, Marta Filizola, Jonathan A Javitch, András Váradi, Dalibor SamesAbstract:Mu-opioid Receptor agonists represent mainstays of pain management. However, the therapeutic use of these agents is associated with serious side effects, including potentially lethal respiratory depression. Accordingly, there is a longstanding interest in the development of new opioid analgesics with improved therapeutic profiles. The alkaloids of the Southeast Asian plant Mitragyna speciosa, represented by the prototypical member mitragynine, are an unusual class of opioid Receptor Modulators with distinct pharmacological properties. Here we describe the first Receptor-level functional characterization of mitragynine and related natural alkaloids at the human mu-, kappa-, and delta-opioid Receptors. These results show that mitragynine and the oxidized analogue 7-hydroxymitragynine, are partial agonists of the human mu-opioid Receptor and competitive antagonists at the kappa- and delta-opioid Receptors. We also show that mitragynine and 7-hydroxymitragynine are G-protein-biased agonists of the mu-opioid Receptor, which do not recruit β-arrestin following Receptor activation. Therefore, the Mitragyna alkaloid scaffold represents a novel framework for the development of functionally biased opioid Modulators, which may exhibit improved therapeutic profiles. Also presented is an enantioselective total synthesis of both (−)-mitragynine and its unnatural enantiomer, (+)-mitragynine, employing a proline-catalyzed Mannich–Michael reaction sequence as the key transformation. Pharmacological evaluation of (+)-mitragynine revealed its much weaker opioid activity. Likewise, the intermediates and chemical transformations developed in the total synthesis allowed the elucidation of previously unexplored structure–activity relationships (SAR) within the Mitragyna scaffold. Molecular docking studies, in combination with the observed chemical SAR, suggest that Mitragyna alkaloids adopt a binding pose at the mu-opioid Receptor that is distinct from that of classical opioids
Monica Mazzarino - One of the best experts on this subject based on the ideXlab platform.
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relevance of the selective oestrogen Receptor Modulators tamoxifen toremifene and clomiphene in doping field endogenous steroids urinary profile after multiple oral doses
Steroids, 2011Co-Authors: Monica Mazzarino, Xavier Torre, Maria Cristina Bragano, Francesco Molaioni, Francesco BotrèAbstract:Abstract The present study was performed to investigate the influence of the intake of selective oestrogen Receptor Modulators on the urinary endogenous steroids profile. For this purpose the circadian variability of luteinizing hormone, follicle-stimulating hormone, testosterone, 5α-androstan-3α,17β-diol, 5β-androstan-3α,17β-diol, epitestosterone, 4-androstenedione, androsterone and etiocholanolone were measured on eight subjects (four males and four females) by gas chromatography–mass spectrometry and chemiluminescent immunometric assay techniques before and after oral administration of multiple doses of either tamoxifen (80 mg for 2 days) or toremifene (120 mg for 2 days) or clomiphene (100 mg for 2 days). The individual baseline variability of the steroids studied was set up by collecting the urine samples every 3 h, for 3 days prior to the treatment; whereas the evaluation of the effects of the oral administration of multiple doses of selective oestrogen Receptor Modulators on the steroid urinary profile was assessed by collecting urine samples every three hours for at least five days from the first administration. The results of our measurements showed that, only in male subjects, the relative urinary concentrations of testosterone, epitestosterone and 4-androstenedione were significantly altered generally after the second day of drug administration. While no significant effects were recorded in both sexes on the luteinizing hormone, follicle-stimulating hormone, androsterone, etiocholanolone, 5α-androstan-3α,17β-diol and 5β-androstan-3α,17β-diol urinary levels and on testosterone/epitestosterone, 5α-androstan-3α,17β-diol/5β-androstan-3α,17β-diol and androsterone/etiocholanolone ratios.
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Relevance of the selective oestrogen Receptor Modulators tamoxifen, toremifene and clomiphene in doping field: Endogenous steroids urinary profile after multiple oral doses
'Elsevier BV', 2011Co-Authors: Monica Mazzarino, Xavier Torre, Maria Cristina Bragano, Francesco Molaioni, Francesco BotrèAbstract:The present study was performed to investigate the influence of the intake of selective oestrogen Receptor Modulators on the urinary endogenous steroids profile. For this purpose the circadian variability of luteinizing hormone, follicle-stimulating hormone, testosterone, 5 alpha-androstan-3 alpha,17 beta-diol, 5 beta-androstan-3 alpha,17 beta-diol, epitestosterone, 4-androstenedione, androsterone and etiocholanolone were measured on eight subjects (four males and four females) by gas chromatography-mass spectrometry and chemiluminescent immunometric assay techniques before and after oral administration of multiple doses of either tamoxifen (80 mg for 2 days) or toremifene (120 mg for 2 days) or clomiphene (100 mg for 2 days). The individual baseline variability of the steroids studied was set up by collecting the urine samples every 3 h, for 3 days prior to the treatment: whereas the evaluation of the effects of the oral administration of multiple doses of selective oestrogen Receptor Modulators on the steroid urinary profile was assessed by collecting urine samples every three hours for at least five days from the first administration. The results of our measurements showed that, only in male subjects, the relative urinary concentrations of testosterone, epitestosterone and 4-androstenedione were significantly altered generally after the second day of drug administration. While no significant effects were recorded in both sexes on the luteinizing hormone, follicle-stimulating hormone, androsterone, etiocholanolone, 5 alpha-androstan-3 alpha,17 beta-diol and 5 beta-androstan-3 alpha,17 beta-diol urinary levels and on testosterone/epitestosterone, 5 alpha-androstan-3 alpha,17 beta-diol/5 beta-androstan-3 alpha,17 beta-diol and androsterone/etiocholanolone ratios. (C) 2011 Elsevier Inc. All rights reserved
Barry S. Komm - One of the best experts on this subject based on the ideXlab platform.
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selective estrogen Receptor Modulators and the combination therapy conjugated estrogens bazedoxifene a review of effects on the breast
Post Reproductive Health: The Journal of The British Menopause Society, 2015Co-Authors: James H Pickar, Barry S. KommAbstract:Traditional menopausal hormone therapy containing estrogens/progestin has been associated with an increased risk of breast cancer, and estrogen exposure is known to promote growth and proliferation of a majority of breast cancers. Therefore, it is important for clinicians to consider the breast safety profile of any hormone-based therapy used in postmenopausal women. This review provides an overview of the breast safety and tolerability profiles of currently marketed selective estrogen Receptor Modulators, antiestrogens, and the first tissue selective estrogen complex combining conjugated estrogens with the selective estrogen Receptor modulator bazedoxifene in postmenopausal women. Selective estrogen Receptor Modulators and antiestrogens act as estrogen Receptor antagonists in the breast. Tamoxifen, toremifene, and the selective estrogen Receptor degrader fulvestrant are used to treat breast cancer, and tamoxifen and raloxifene protect against breast cancer in high-risk women. Postmenopausal women using selective estrogen Receptor Modulators for prevention or treatment of osteoporosis (raloxifene, bazedoxifene) can be reassured that these hormonal treatments do not adversely affect their risk of breast cancer and may, in the case of raloxifene, even be protective. There are limited data on breast cancer in women who use ospemifene for dyspareunia. Conjugated estrogens/bazedoxifene use for up to two years did not increase mammographic breast density or breast pain/tenderness, and there was no evidence of an increased risk of breast cancer, suggesting that conjugated estrogens/bazedoxifene has an improved breast safety profile compared with traditional menopausal hormone therapies. Future research will continue to focus on development of selective estrogen Receptor Modulators and selective estrogen Receptor modulator combinations capable of achieving the ideal balance of estrogen Receptor agonist and antagonist effects.
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effects of various selective estrogen Receptor Modulators with or without conjugated estrogens on mouse mammary gland
Endocrinology, 2009Co-Authors: Bryan J Peano, Barry S. Komm, Judy S Crabtree, Richard C Winneker, Heather A HarrisAbstract:Selective estrogen Receptor Modulators (SERMs) are small molecules that, depending on the end point measured, may either function as estrogen Receptor (ER) agonists or antagonize estrogens’ agonist activity. A key feature of SERMs is the inhibition of ER agonist action on the uterus and mammary gland, but the degree of antagonism varies among compounds and end points. Bazedoxifene is a SERM that is being clinically evaluated both as a monotherapy for the prevention and treatment of osteoporosis and in combination with conjugated estrogens (CEs) for the treatment of menopausal symptoms and prevention of osteoporosis. The studies reported here compare the relative ER agonist and antagonist effects of three pharmacologically distinct SERMs (bazedoxifene, raloxifene, and lasofoxifene) on the ovariectomized mouse when administered alone or as a tissue-selective estrogen complex, a term used to describe the partnering of a SERM and one or more estrogens. At the minimum dose required to maximally reduce CE-stimu...
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selective estrogen Receptor Modulators discrimination of agonistic versus antagonistic activities by gene expression profiling in breast cancer cells
Cancer Research, 2004Co-Authors: Jonna Frasor, Barry S. Komm, Fabio Stossi, Jeanne M Danes, Richard C Lyttle, Benita S. KatzenellenbogenAbstract:Selective estrogen Receptor Modulators (SERMs) such as tamoxifen are effective in the treatment of many estrogen Receptor-positive breast cancers and have also proven to be effective in the prevention of breast cancer in women at high risk for the disease. The comparative abilities of tamoxifen versus raloxifene in breast cancer prevention are currently being compared in the Study of Tamoxifen and Raloxifene trial. To better understand the actions of these compounds in breast cancer, we have examined their effects on the expression of approximately 12,000 genes, using Affymetrix GeneChip microarrays, with quantitative PCR verification in many cases, categorizing their actions as agonist, antagonist, or partial agonist/antagonist. Analysis of gene stimulation and inhibition by the SERMs trans-hydroxytamoxifen (TOT) and raloxifene (Ral) or ICI 182,780 (ICI) and by estradiol (E2) in estrogen Receptor-containing MCF-7 human breast cancer cells revealed that (a) TOT was the most E2-like of the three compounds, (b) all three compounds either partially or fully antagonized the action of E2 on most genes, with the order of antagonist activity being ICI > Ral > TOT, (c) TOT and Ral, but not ICI, displayed partial agonist/partial antagonist activity on a number of E2-regulated genes, (d) several stimulatory cell cycle-related genes were down-regulated exclusively by ICI, (e) the estrogen-like activity of Ral nearly always overlapped with that of TOT, indicating that Ral has little unique agonist activity different from that of TOT, and (f) some genes were specifically up-regulated by TOT but not Ral, ICI, or E2. Hence, gene expression profiling can discern fundamental differences among SERMs and provides insight into the distinct biologies of TOT, Ral, and ICI in breast cancer.
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selective estrogen Receptor Modulators discrimination of agonistic versus antagonistic activities by gene expression profiling in breast cancer cells
Cancer Research, 2004Co-Authors: Jonna Frasor, Barry S. Komm, Fabio Stossi, Jeanne M Danes, Richard C Lyttle, Benita S. KatzenellenbogenAbstract:Selective estrogen Receptor Modulators (SERMs) such as tamoxifen are effective in the treatment of many estrogen Receptor-positive breast cancers and have also proven to be effective in the prevention of breast cancer in women at high risk for the disease. The comparative abilities of tamoxifen versus raloxifene in breast cancer prevention are currently being compared in the Study of Tamoxifen and Raloxifene trial. To better understand the actions of these compounds in breast cancer, we have examined their effects on the expression of ∼12,000 genes, using Affymetrix GeneChip microarrays, with quantitative PCR verification in many cases, categorizing their actions as agonist, antagonist, or partial agonist/antagonist. Analysis of gene stimulation and inhibition by the SERMs trans-hydroxytamoxifen (TOT) and raloxifene (Ral) or ICI 182,780 (ICI) and by estradiol (E2) in estrogen Receptor-containing MCF-7 human breast cancer cells revealed that (a) TOT was the most E2-like of the three compounds, (b) all three compounds either partially or fully antagonized the action of E2 on most genes, with the order of antagonist activity being ICI > Ral > TOT, (c) TOT and Ral, but not ICI, displayed partial agonist/partial antagonist activity on a number of E2-regulated genes, (d) several stimulatory cell cycle-related genes were down-regulated exclusively by ICI, (e) the estrogen-like activity of Ral nearly always overlapped with that of TOT, indicating that Ral has little unique agonist activity different from that of TOT, and (f) some genes were specifically up-regulated by TOT but not Ral, ICI, or E2. Hence, gene expression profiling can discern fundamental differences among SERMs and provides insight into the distinct biologies of TOT, Ral, and ICI in breast cancer.
