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1.
J Microbiol ; 59(2): 124-131, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33527314

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused corona virus disease 2019 (COVID-19) pandemic and led to mass casualty. Even though much effort has been put into development of vaccine and treatment methods to combat COVID-19, no safe and efficient cure has been discovered. Drug repurposing or drug repositioning which is a process of investigating pre-existing drug candidates for novel applications outside their original medical indication can speed up the drug development process. Raloxifene is a selective estrogen receptor modulator (SERM) that has been approved by FDA in 1997 for treatment and prevention of postmenopausal osteoporosis and cancer. Recently, raloxifene demonstrates efficacy in treating viral infections by Ebola, influenza A, and hepatitis C viruses and shows potential for drug repurposing for the treatment of SARS-CoV-2 infection. This review will provide an overview of raloxifene's mechanism of action as a SERM and present proposed mechanisms of action in treatment of viral infections.


Assuntos
Antivirais/uso terapêutico , Reposicionamento de Medicamentos , Cloridrato de Raloxifeno/uso terapêutico , /efeitos dos fármacos , Antagonistas de Estrogênios/uso terapêutico , Estrogênios/agonistas , Humanos , Simulação de Acoplamento Molecular , Osteoporose Pós-Menopausa/tratamento farmacológico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico
2.
J Urol ; 205(1): 44-51, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33295258

RESUMO

PURPOSE: The summary presented herein represents Part II of the two-part series dedicated to the Diagnosis and Treatment of Infertility in Men: AUA/ASRM Guideline. Part II outlines the appropriate management of the male in an infertile couple. Medical therapies, surgical techniques, as well as use of intrauterine insemination (IUI)/in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) are covered to allow for optimal patient management. Please refer to Part I for discussion on evaluation of the infertile male and discussion of relevant health conditions that are associated with male infertility. MATERIALS/METHODS: The Emergency Care Research Institute Evidence-based Practice Center team searched PubMed®, Embase®, and Medline from January 2000 through May 2019. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions (table[Table: see text]). This summary is being simultaneously published in Fertility and Sterility and The Journal of Urology. RESULTS: This Guideline provides updated, evidence-based recommendations regarding management of male infertility. Such recommendations are summarized in the associated algorithm (figure[Figure: see text]). CONCLUSION: Male contributions to infertility are prevalent, and specific treatment as well as assisted reproductive techniques are effective at managing male infertility. This document will undergo additional literature reviews and updating as the knowledge regarding current treatments and future treatment options continues to expand.


Assuntos
Infertilidade Masculina/terapia , Medicina Reprodutiva/normas , Urologia/normas , Varicocele/terapia , Aconselhamento/normas , Suplementos Nutricionais , Medicina Baseada em Evidências/métodos , Medicina Baseada em Evidências/normas , Fertilização In Vitro/métodos , Fertilização In Vitro/normas , Humanos , Infertilidade Masculina/diagnóstico , Infertilidade Masculina/etiologia , Masculino , Medicina Reprodutiva/métodos , Escroto/diagnóstico por imagem , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Análise do Sêmen , Sociedades Médicas/normas , Recuperação Espermática/normas , Resultado do Tratamento , Estados Unidos , Urologia/métodos , Varicocele/complicações , Varicocele/diagnóstico
3.
Int J Mol Sci ; 22(1)2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33375030

RESUMO

Central hypogonadism is a clinical condition, characterized by sexual symptoms and low serum testosterone levels, due to an impaired function of the hypothalamus or pituitary gland. Testosterone replacement therapy (TRT) is the standard treatment for hypogonadism, but it has some disadvantages. TRT is not a good option in men wishing to preserve fertility, nor in men with (a high risk of) prostate cancer, polycythemia, thrombophilia and severe cardiovascular disease. In this review, we discuss alternative treatments for central hypogonadism. If reversible causes are present, non-pharmacological interventions can be therapeutic. Gonadotropins are a good alternative to TRT when fertility is desired in the near future though they require frequent injections. Clomiphene citrate and tamoxifen seem to be a safe alternative for the treatment of functional central hypogonadism in men, as several studies reported a significant increase in testosterone levels with these drugs. However, their use is off-label and data supporting the efficacy of clomiphene citrate and tamoxifen on hypogonadal symptoms are insufficient. For this reason, clomiphene citrate and tamoxifen should not be used in routine clinical practice to treat sexual symptoms in men with central hypogonadism.


Assuntos
Terapia de Reposição Hormonal/métodos , Hipogonadismo/tratamento farmacológico , Testosterona/uso terapêutico , Androgênios/sangue , Androgênios/uso terapêutico , Clomifeno/uso terapêutico , Fertilidade/efeitos dos fármacos , Humanos , Masculino , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Testosterona/sangue , Resultado do Tratamento
5.
Bull Cancer ; 107(11): 1171-1185, 2020 Nov.
Artigo em Francês | MEDLINE | ID: mdl-32988609

RESUMO

Breast cancer is the most frequently diagnosed cancer in women and the first cause of cancer death in France. Among the different subtypes of breast cancer, the predominant form is characterized by positive hormone receptors (more than 70% of breast cancers). Hormone therapy thus plays a key role in the strategy of management of these cancers both in adjuvant and metastatic situations. The two types of adjuvant hormone therapy used are selective estrogen receptor modulators and aromatase inhibitors. Fulvestrant, an anti-estrogen, is used alone or in combination with other molecules in metastatic situations. Hot flashes are one of the symptoms most frequently reported by patients under hormone therapy. Hormone replacement therapy, which is currently the most effective treatment for hot flashes, is contraindicated in patients with a personal history of breast cancer. Various therapeutic classes of drugs have been tested in this indication but without real efficacy in the various studies carried out to date, and moreover associated with non-negligible side effects. The recent discovery of the implication of the kisspeptin system located at the hypothalamic level in the mechanism of genesis of hot flashes opens the way to possible new symptomatic treatments for hot flashes. Neurokinin 3 receptor antagonists have shown encouraging preliminary results in postmenopausal cancer-free patients and could be considered in patients in hormonal therapy for breast cancer. Broader additional studies are needed to confirm these initial results.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/química , Neoplasias da Mama/tratamento farmacológico , Fogachos/etiologia , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Contraindicações de Medicamentos , Terapia de Reposição de Estrogênios/efeitos adversos , Feminino , Fulvestranto/uso terapêutico , Humanos , Kisspeptinas/fisiologia , Ovário/efeitos dos fármacos , Ovário/cirurgia , Receptores da Neurocinina-3/antagonistas & inibidores , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Tamoxifeno/administração & dosagem , Tamoxifeno/uso terapêutico
6.
Endocrinology ; 161(9)2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32730568

RESUMO

Severe outcomes and death from the novel coronavirus disease 2019 (COVID-19) appear to be characterized by an exaggerated immune response with hypercytokinemia leading to inflammatory infiltration of the lungs and acute respiratory distress syndrome. Risk of severe COVID-19 outcomes is consistently lower in women than men worldwide, suggesting that female biological sex is instrumental in protection. This mini-review discusses the immunomodulatory and anti-inflammatory actions of high physiological concentrations of the steroids 17ß-estradiol (E2) and progesterone (P4). We review how E2 and P4 favor a state of decreased innate immune inflammatory response while enhancing immune tolerance and antibody production. We discuss how the combination of E2 and P4 may improve the immune dysregulation that leads to the COVID-19 cytokine storm. It is intended to stimulate novel consideration of the biological forces that are protective in women compared to men, and to therapeutically harness these factors to mitigate COVID-19 morbidity and mortality.


Assuntos
Infecções por Coronavirus/imunologia , Estradiol/imunologia , Imunomodulação/imunologia , Pneumonia Viral/imunologia , Progesterona/imunologia , Formação de Anticorpos/imunologia , Betacoronavirus , Anticoncepcionais Orais Hormonais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/fisiopatologia , Síndrome da Liberação de Citocina/imunologia , Reposicionamento de Medicamentos , Estradiol/uso terapêutico , Terapia de Reposição de Estrogênios , Estrogênios/uso terapêutico , Feminino , Humanos , Tolerância Imunológica/imunologia , Imunidade Inata/imunologia , Masculino , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/mortalidade , Pneumonia Viral/fisiopatologia , Gravidez , Complicações Infecciosas na Gravidez/imunologia , Progesterona/uso terapêutico , Progestinas/uso terapêutico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Índice de Gravidade de Doença , Fatores Sexuais
10.
J Steroid Biochem Mol Biol ; 202: 105697, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32461092

RESUMO

Treatment of hormone sensitive breast cancer tumors with endocrine therapy such as antiestrogens or aromatase inhibitors has improved the outcome significantly. Studies including our own have shown that downregulation of ERα with pure antiestrogen fulvestrant in combination with aromatase inhibitors may prolong responsiveness of the tumors to endocrine therapy. Fulvestrant has been studied as second line or first line treatment for post-menopausal hormone receptor positive breast cancers as a single agent or in combination with AIs. Studies have also suggested that further escalation of dose may improve benefit. However, dose escalation of fulvestrant, which is administered via intramuscular injection, is difficult due to its poor solubility. To overcome this shortcoming of an injectable drug, a novel orally active antiestrogen, AZD9496 was developed. In addition to being orally active, AZD9496 is designed as a selective ERα downregulator (SERD). In the current study, we compared the effect of AZD9496 and fulvestrant on the growth of MCF-7Ca (human estrogen receptor positive MCF-7 cells stably transfected with human placental aromatase gene) xenografts grown in ovariectomized athymic nude mice. AZD9496 was also compared to fulvestrant in vitro as a single agent or in combination with anastrozole. Our current study shows that AZD9496 is equally effective as fulvestrant at controlling the growth of hormone sensitive human breast cancer tumors. Similar to fulvestrant, AZD9496 inhibits cellular aromatase activity through ERα mediated signaling. However, unlike fulvestrant, combination of AZD9496 with anastrozole did not produce increased tumor inhibition. Our results show that AZD9496 was significantly better at inhibiting cellular aromatase which contributed to its anticancer activity. Next, we measured the effect of AZD9496 on the mouse uterus. Uterine weight of mice treated with AZD9496 was significantly lower than that for mice treated with androstenedione. This reduction in uterine weight was due to AZD9496 mediated inhibition of aromatase activity and not a direct effect on uterine ERα expression. We also observed that anti-cancer efficacy of AZD9496 depended on its ability to inhibit cellular aromatase. These results suggest that AZD9496 may be a better alternative to fulvestrant due to its selectivity for mammary ER and ability to inhibit aromatase in addition of downregulating ERα that can be obtained upon oral administration. As such, AZD9496 may prove to be a better option than fulvestrant for the treatment of hormone sensitive human breast cancer.


Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Cinamatos/uso terapêutico , Indóis/uso terapêutico , Neoplasias Mamárias Experimentais/tratamento farmacológico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Anastrozol/farmacologia , Anastrozol/uso terapêutico , Animais , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Hormonais/uso terapêutico , Aromatase/metabolismo , Inibidores da Aromatase/farmacologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Cinamatos/farmacologia , Antagonistas do Receptor de Estrogênio/farmacologia , Antagonistas do Receptor de Estrogênio/uso terapêutico , Receptor alfa de Estrogênio , Feminino , Fulvestranto/farmacologia , Fulvestranto/uso terapêutico , Humanos , Indóis/farmacologia , Neoplasias Mamárias Experimentais/metabolismo , Camundongos Nus , Pós-Menopausa , Moduladores Seletivos de Receptor Estrogênico/farmacologia
12.
Toxicol Appl Pharmacol ; 393: 114928, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32092384

RESUMO

The female gender is protected against immunological complications of endotoxemia. Here we investigated whether gonadal hormone depletion by ovariectomy (OVX) uncovers inflammatory and cardiovascular effects of endotoxemia and whether these effects are reversed by hormone replacement therapies. Changes in inflammatory cytokines, blood pressure (BP), left ventricular (LV) function, and cardiac autonomic activity caused by lipopolysaccharide (LPS) in conscious female rats with different hormonal states were determined. In contrast to no effects in sham-operated females, treatment of OVX rats with LPS (i) decreased BP, (ii) increased spectral low-frequency/high-frequency ratio of HRV, denoting enhanced cardiac sympathetic dominance, (iii) attenuated reflex tachycardic responses to sodium nitroprusside, and (iv) increased systolic contractility (dP/dtmax). The developed hypotension was (i) fully eliminated in estrogen (E2)-pretreated OVX rats, (ii) partially counteracted after selective activation of estrogen receptor-α (PPT) or ß (DPN). All estrogenic compounds abrogated LPS enhancement of cardiac sympathetic drive. However, PPT was more successful than E2 or DPN in compromising LPS depression in baroreflex activity and elevation in dP/dtmax. Molecular studies showed that PPT was most effective in attenuating the upregulated myocardial expressions of NF-κB and iNOS in endotoxic OVX rats. Myocardial expression of the defensive HSP70 was comparably increased by all estrogenic products. Except for improved cardiac spectral activity, none of these functional or molecular entities was affected by medroxyprogesterone acetate (MPA). Overall, our data suggest diverse therapeutic advantages for gonadal hormones in the worsened endotoxic complications in rats with surgical menopause, with probably more favorable role for ERα agonism within this context.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/etiologia , Endotoxemia/complicações , Endotoxemia/tratamento farmacológico , Terapia de Reposição de Estrogênios/métodos , Inflamação/tratamento farmacológico , Inflamação/etiologia , Ovariectomia/efeitos adversos , Animais , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea , Citocinas , Endotoxemia/induzido quimicamente , Estradiol/uso terapêutico , Receptor alfa de Estrogênio/agonistas , Terapia de Reposição de Estrogênios/efeitos adversos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Lipopolissacarídeos , Acetato de Medroxiprogesterona/uso terapêutico , Ratos , Ratos Wistar , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos
13.
Breast J ; 26(1): 86-91, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31971344

RESUMO

Millions of women in the United States are at increased risk of breast cancer. Multiple prospective, randomized clinical trials have demonstrated both the efficacy and safety of selective estrogen receptor modulators and aromatase inhibitors in reducing substantially the risk of invasive breast cancer in women at increased risk. Published tables are available to aid clinicians in shared decision-making regarding drug interventions with their patients who are at increased risk of breast cancer. Both professional and governmental agencies have advised that these interventions should be offered to women at increased risk of breast cancer. Doing so would reduce breast cancer morbidity substantially.


Assuntos
Neoplasias da Mama/prevenção & controle , Inibidores da Aromatase/uso terapêutico , Feminino , Humanos , Comportamento de Redução do Risco , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Estados Unidos
14.
Pediatrics ; 145(2)2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31974217

RESUMO

Many transgender and gender-diverse people have a gender identity that does not conform to the binary categories of male or female; they have a nonbinary gender. Some nonbinary individuals are most comfortable with an androgynous gender expression. For those who have not yet fully progressed through puberty, puberty suppression with gonadotrophin-releasing hormone agonists can support an androgynous appearance. Although such treatment is shown to ameliorate the gender dysphoria and serious mental health issues commonly seen in transgender and gender-diverse young people, long-term use of puberty-suppressing medications carries physical health risks and raises various ethical dilemmas. In this Ethics Rounds, we analyze a case that raised issues about prolonged pubertal suppression for a patient with a nonbinary gender.


Assuntos
Disforia de Gênero/tratamento farmacológico , Consentimento Informado por Menores/ética , Consentimento dos Pais/ética , Puberdade/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Minorias Sexuais e de Gênero/psicologia , Adolescente , Ansiedade/tratamento farmacológico , Temas Bioéticos , Densidade Óssea/efeitos dos fármacos , Tomada de Decisão Clínica/ética , Esquema de Medicação , Ética Médica , Disforia de Gênero/psicologia , Fraturas do Quadril/etiologia , Humanos , Autonomia Pessoal
15.
Biochim Biophys Acta Rev Cancer ; 1873(1): 188339, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31917206

RESUMO

Increasing emphasis has been given to prevention as a feasible approach to reduce the cancer burden. However, for its clinical success, further advances are required to identify effective chemopreventive agents. This review affords a critical and up-to-date discussion of issues related to cancer prevention, including an in-depth knowledge on BRCA1 and p53 tumor suppressor proteins as key molecular players. Indeed, it compiles the most recent advances on the topic, highlighting the unique potential of BRCA1 and p53 germline mutations as molecular biomarkers for risk assessment and targets for chemoprevention. Relevant evidences are herein provided supporting the effectiveness of distinct pharmacological agents in cancer prevention, by targeting BRCA1 and p53. Moreover, the rationale for using germline mutant BRCA1- or p53-related cancer syndromes as model systems to investigate effective chemopreventive agents is also addressed. Altogether, this work provides an innovative conception about the dependence on p53 and BRCA1 co-inactivation in tumor formation and development, emphasizing the relationship between these two proteins as an encouraging direction for future personalized pharmacological interventions in cancer prevention.


Assuntos
Proteína BRCA1/genética , Quimioprevenção/métodos , Mutação em Linhagem Germinativa , Neoplasias Ovarianas/prevenção & controle , Tamoxifeno/uso terapêutico , Proteína Supressora de Tumor p53/genética , Proteína BRCA1/metabolismo , Feminino , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo
16.
J Med Chem ; 63(2): 512-528, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31721572

RESUMO

More than 75% of breast cancers are estrogen receptor alpha (ERα) positive (ER+), and resistance to current hormone therapies occurs in one-third of ER+ patients. Tumor resistance is still ERα-dependent, but mutations usually confer constitutive activation to the hormone receptor, rendering ERα modulator drugs such as tamoxifen and aromatase inhibitors ineffective. Fulvestrant is a potent selective estrogen receptor degrader (SERD), which degrades the ERα receptor in drug-resistant tumors and has been approved for the treatment of hormone-receptor-positive metastatic breast cancer following antiestrogen therapy. However, fulvestrant shows poor pharmacokinetic properties in human, low solubility, weak permeation, and high metabolism, limiting its administration to inconvenient intramuscular injections. This Drug Annotation describes the identification and optimization of a new series of potent orally available SERDs, which led to the discovery of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (43d), showing promising antitumor activity in breast cancer mice xenograft models and whose properties warranted clinical evaluation.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Descoberta de Drogas/métodos , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Receptores Estrogênicos/metabolismo , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Animais , Neoplasias da Mama/metabolismo , Cristalografia por Raios X , Cães , Resistencia a Medicamentos Antineoplásicos , Feminino , Meia-Vida , Ensaios de Triagem em Larga Escala , Humanos , Ligantes , Camundongos , Modelos Moleculares , Ratos , Receptores Estrogênicos/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/farmacocinética , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Pharmacogenomics ; 21(1): 43-53, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31769341

RESUMO

Aim: To assess the cost-effectiveness of CYP2D6*10 genetic testing for the management of Chinese women with hormone receptor-positive (HR+) breast cancer treated with selective estrogen receptor modulator. Methods: A Markov model was developed to evaluate a total expected cost and an incremental cost-effectiveness ratio (ICER). Robustness of the model was addressed in one-way analyses and probabilistic sensitivity analysis. Results: The cost of strategies of tamoxifen, toremifene without genotyping and the strategy base on CYP2D6*10 genotype were $63,879.19, $90,156.60 and $95,021.41, and the quality-adjusted life years gained are 8.1588, 12.89687 and 13.85911, respectively. The incremental cost-effectiveness ratio of the CYP2D6*10 testing versus toremifene were 5,055.74221/quality-adjusted life year, respectively. Conclusion: CYP2D6*10 pharmacogenetic-guided selective estrogen receptor modulator can be a cost-effective strategy in the Chinese patients with hormone receptor-positive breast cancer.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Análise Custo-Benefício , Citocromo P-450 CYP2D6/genética , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Antineoplásicos Hormonais/efeitos adversos , Neoplasias da Mama/economia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Genótipo , Humanos , Cadeias de Markov , Farmacogenética , Testes Farmacogenômicos , Pós-Menopausa/efeitos dos fármacos , Anos de Vida Ajustados por Qualidade de Vida , Receptores Estrogênicos/genética , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Tamoxifeno/efeitos adversos , Tamoxifeno/uso terapêutico , Triazóis/efeitos adversos , Triazóis/uso terapêutico
18.
Cancer Lett ; 469: 78-88, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31629931

RESUMO

Selective estrogen receptor modulators (SERMs) are a class of structurally diverse compounds, which have been extensively used to treat hormone-responsive cancers due to their unique partially agonistic and antagonistic properties toward estrogen receptors. Our previous studies have identified a three-dimensional SERM, oxabicycloheptene sulfonate (OBHS), as an estrogen receptor α (ERα) ligand, which is effective for the prevention and treatment of estrogen-dependent endometriosis in vivo. Here, using genome-wide ChIP-seq and RNA-seq analysis, we report that OBHS rapidly induces genome-wide ERα occupancy and acts as a partial agonist and antagonist for ERα. Interestingly, OBHS downregulates the homologous recombination and repair (HRR) modules, resulting in increased DNA damage, apoptosis and cell cycle arrest, inducing synthetic lethality with poly (ADP-ribose) polymerase (PARP) inhibitor olaparib through ERα antagonism. Mechanistically, OBHS impairs the RNA polymerase II (Pol II) loading at the promoters of estrogen-responsive HRR genes. Furthermore, combination therapy of OBHS with olaparib significantly reduces the tumour burden and delays the progression of breast cancer in vivo. Together, our studies not only characterise a novel SERM which uniquely targets the homologous recombination and repair programmes through ERα antagonism but also propose a synthetic lethal strategy by combining OBHS with PARP inhibitor olaparib for ERα-responsive cancers.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Antagonistas do Receptor de Estrogênio/farmacologia , Reparo de DNA por Recombinação/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Ácidos Sulfônicos/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Chlorocebus aethiops , Sequenciamento de Cromatina por Imunoprecipitação , Antagonistas do Receptor de Estrogênio/uso terapêutico , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Camundongos , Estrutura Molecular , Ftalazinas/farmacologia , Ftalazinas/uso terapêutico , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Regiões Promotoras Genéticas/genética , RNA Polimerase II/antagonistas & inibidores , RNA Polimerase II/metabolismo , RNA-Seq , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Relação Estrutura-Atividade , Ácidos Sulfônicos/uso terapêutico , Mutações Sintéticas Letais/efeitos dos fármacos , Células Vero , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Womens Health (Larchmt) ; 29(1): 46-56, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31560601

RESUMO

Several organizations, including the American Society of Clinical Oncology, the National Comprehensive Cancer Network, and the United States Preventive Services Task Force, recommend incorporation of breast cancer risk-based counseling and chemoprevention into routine well-woman care. However, primary care providers report both discomfort with and a lack of medical knowledge on this topic. In this review we present a practical, evidence-based guide for incorporating breast cancer risk assessment and chemoprevention into routine care. We advocate a stepwise approach consisting of: (1) risk assessment and communication, (2) selection of appropriate chemoprevention based on risk-benefit analysis, (3) shared decision-making regarding chemoprevention, and (4) management of chemoprevention side effects. We encourage providers to identify high-risk women and refer them to genetic counseling or a high-risk breast cancer clinic. For women who are not considered high risk, we suggest using the Gail model to estimate a woman's 5-year risk of invasive breast cancer. Usually, the benefits of chemoprevention outweigh the risks of chemoprevention once a woman's 5-year risk of invasive breast cancer reaches 3%. For these women there are several factors that need to be considered when selecting a chemoprevention agent, including patient preference, thrombotic history, menopausal status, absence or presence of a uterus, and bone mineral density. We advocate an evidence-based shared decision-making approach that reflects the woman's individual preferences when communicating risk and counseling about chemoprevention. After starting a chemoprevention agent, close follow-up is important as side effects of chemoprevention are common, including vasomotor symptoms and arthralgias. We also review evidence-based management of chemoprevention side effects.


Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/prevenção & controle , Quimioprevenção , Atenção Primária à Saúde , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Anastrozol/uso terapêutico , Androstadienos/uso terapêutico , Tomada de Decisão Compartilhada , Feminino , Humanos , Pessoa de Meia-Idade , Relações Médico-Paciente , Cloridrato de Raloxifeno/uso terapêutico , Medição de Risco , Tamoxifeno/uso terapêutico
20.
Zhonghua Fu Chan Ke Za Zhi ; 54(12): 848-853, 2019 Dec 25.
Artigo em Chinês | MEDLINE | ID: mdl-31874475

RESUMO

Objective: To study influencing factors which cause the endometrial diseases in patients with breast cancer after operation. Methods: A retrospective study was performed on 212 breast cancer post-operation patients with endometrial diseases between June 2006 and January 2018 in Women's Hospital School of Medicine Zhejiang University to analyse the factors which influenced the endometrial diseases. Results: The abnormal uterine bleeding and endometrial thickness were related to the severity of endometrial disease in patients with breast cancer, and they were independent risk factors for breast cancer patients to have endometrial cancer (P<0.05) . When the diagnostic cut off value of endometrial thickness was ≥0.49 cm, the sensitivity and specificity to endometrial cancer were 78% and 25%, respectively. The average endometrial thickness was (0.56±0.39) cm in patients who were treated by selective estrogen receptor modulator (SERM) after gynecological surgery, which was significantly thicker than that of aromatase inhibitor (AI) group [ (0.33±0.23) cm] and no treatment group [ (0.44±0.28) cm, P<0.05]. The endometrial disease recurrent rate and reoperation rate in SERM group were (26.2%, 14.3%) slightly higher than that of AI group (9.5%, 4.8%) and no treatment group (21.6%, 4.9%), but there were not significant differences (all P>0.05). Conclusions: The clinical symptom of abnormal uterine bleeding and thickening endometrium are risk factors for breast cancer patients to have endometrial cancer. The endometrial thickness has high predictive value for breast cancer patients to diagnose endometrial cancer. The SERM treatment increases the endometrial thickness, recurrent rate and reoperation rate in post-operation patients.


Assuntos
Antineoplásicos Hormonais/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Hiperplasia Endometrial/induzido quimicamente , Neoplasias do Endométrio/induzido quimicamente , Endométrio/efeitos dos fármacos , Moduladores de Receptor Estrogênico/efeitos adversos , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Hemorragia Uterina/etiologia , Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Terapia Combinada , Hiperplasia Endometrial/epidemiologia , Hiperplasia Endometrial/patologia , Neoplasias do Endométrio/epidemiologia , Neoplasias do Endométrio/patologia , Endométrio/patologia , Moduladores de Receptor Estrogênico/uso terapêutico , Feminino , Humanos , Estudos Retrospectivos , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Índice de Gravidade de Doença , Ultrassonografia
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