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Pesquisa : D06.347.295 [Categoria DeCS]
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[PMID]:29180066
[Au] Autor:Tsai CF; Cheng YK; Lu DY; Wang SL; Chang CN; Chang PC; Yeh WL
[Ad] Endereço:Department of Biotechnology, Asia University, No.500 Lioufeng Road, Taichung 41354, Taiwan. Electronic address: tsaicf@asia.edu.tw.
[Ti] Título:Inhibition of estrogen receptor reduces connexin 43 expression in breast cancers.
[So] Source:Toxicol Appl Pharmacol;338:182-190, 2018 01 01.
[Is] ISSN:1096-0333
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Connexins are widely supported as tumor suppressors due to their downregulation in cancers, nevertheless, more recent evidence suggests roles for connexins in facilitating tumor progression in later stages, including metastasis. One of the key factors regulating the expression, modification, stability, and localization of connexins is hormone receptors in hormone-dependent cancers. It is reasonable to consider that hormones/hormone receptors may modulate connexins expression and play critical roles in the cellular control of connexins during breast cancer progression. In estrogen receptor (ER)-positive breast cancers, tamoxifen and fulvestrant are widely used therapeutic agents and are considered to alter ER signaling. In this present study, we investigated the effects of fulvestrant and tamoxifen in Cx43 expression, and we also explored the role of Cx43 in ER-positive breast cancer migration and the relationship between Cx43 and ER. The involvement of estrogen/ER in Cx43 modulation was further verified by administering tyrosine kinase inhibitors and chemotherapeutic agents. We found that inhibition of ER promoted the binding of E3 ligase Nedd4 to Cx43, leading to Cx43 ubiquitination. Furthermore, inhibition of ER by fulvestrant and tamoxifen phosphorylated p38 MAPK, and inhibition of Rac, MKK3/6, and p38 reversed fulvestrant-reduced Cx43 expression. These findings suggest that Cx43 expression which may positively regulate cell migration is ER-dependent in ER-positive breast cancer cells.
[Mh] Termos MeSH primário: Neoplasias da Mama/patologia
Conexina 43/fisiologia
Antagonistas de Estrogênios/farmacologia
[Mh] Termos MeSH secundário: Neoplasias da Mama/química
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Conexina 43/análise
Feminino
Seres Humanos
Ubiquitina-Proteína Ligases Nedd4/metabolismo
Receptores Estrogênicos/fisiologia
Tamoxifeno/análogos & derivados
Tamoxifeno/farmacologia
Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Connexin 43); 0 (Estrogen Antagonists); 0 (GJA1 protein, human); 0 (Receptors, Estrogen); 094ZI81Y45 (Tamoxifen); 17197F0KYM (afimoxifene); EC 2.3.2.26 (Nedd4 Ubiquitin Protein Ligases); EC 2.3.2.26 (Nedd4 protein, human); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171129
[St] Status:MEDLINE


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[PMID]:29269484
[Au] Autor:Geter PA; Ernlund AW; Bakogianni S; Alard A; Arju R; Giashuddin S; Gadi A; Bromberg J; Schneider RJ
[Ad] Endereço:Department of Microbiology, Alexandria Center for Life Science, New York University School of Medicine, New York, New York 10016, USA.
[Ti] Título:Hyperactive mTOR and MNK1 phosphorylation of eIF4E confer tamoxifen resistance and estrogen independence through selective mRNA translation reprogramming.
[So] Source:Genes Dev;31(22):2235-2249, 2017 11 15.
[Is] ISSN:1549-5477
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The majority of breast cancers expresses the estrogen receptor (ER ) and is treated with anti-estrogen therapies, particularly tamoxifen in premenopausal women. However, tamoxifen resistance is responsible for a large proportion of breast cancer deaths. Using small molecule inhibitors, phospho-mimetic proteins, tamoxifen-sensitive and tamoxifen-resistant breast cancer cells, a tamoxifen-resistant patient-derived xenograft model, patient tumor tissues, and genome-wide transcription and translation studies, we show that tamoxifen resistance involves selective mRNA translational reprogramming to an anti-estrogen state by and other mRNAs. Tamoxifen-resistant translational reprogramming is shown to be mediated by increased expression of eIF4E and its increased availability by hyperactive mTOR and to require phosphorylation of eIF4E at Ser209 by increased MNK activity. Resensitization to tamoxifen is restored only by reducing eIF4E expression or mTOR activity and also blocking MNK1 phosphorylation of eIF4E. mRNAs specifically translationally up-regulated with tamoxifen resistance include , which inhibits ER signaling and estrogen responses and promotes breast cancer metastasis. Silencing significantly restores tamoxifen sensitivity. Tamoxifen-resistant but not tamoxifen-sensitive patient ER breast cancer specimens also demonstrate strongly increased MNK phosphorylation of eIF4E. eIF4E levels, availability, and phosphorylation therefore promote tamoxifen resistance in ER breast cancer through selective mRNA translational reprogramming.
[Mh] Termos MeSH primário: Antineoplásicos Hormonais/farmacologia
Neoplasias da Mama/metabolismo
Antagonistas de Estrogênios/farmacologia
Fator de Iniciação 4E em Eucariotos/metabolismo
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo
Biossíntese de Proteínas
Proteínas Serina-Treonina Quinases/metabolismo
Tamoxifeno/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Resistência a Medicamentos Antineoplásicos
Feminino
Seres Humanos
Fosforilação
RNA Mensageiro/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents, Hormonal); 0 (Estrogen Antagonists); 0 (Eukaryotic Initiation Factor-4E); 0 (Intracellular Signaling Peptides and Proteins); 0 (RNA, Messenger); 094ZI81Y45 (Tamoxifen); EC 2.7.1.- (MKNK1 protein, human); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1); EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180202
[Lr] Data última revisão:
180202
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171223
[St] Status:MEDLINE
[do] DOI:10.1101/gad.305631.117


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[PMID]:29202630
[Au] Autor:Cronin-Fenton D; Lash TL; Ahern TP; Damkier P; Christiansen P; Ejlertsen B; Sørensen HT
[Ad] Endereço:a Department of Clinical Epidemiology , Aarhus University , Aarhus , Denmark.
[Ti] Título:Concurrent new drug prescriptions and prognosis of early breast cancer: studies using the Danish Breast Cancer Group clinical database.
[So] Source:Acta Oncol;57(1):120-128, 2018 Jan.
[Is] ISSN:1651-226X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Myriad reports suggest that frequently used prescription drugs alter the viability of breast cancer cells in pre-clinical studies. Routine use of these drugs, therefore, may impact breast cancer prognosis, and could have important implications for public health. METHODS: The Danish Breast Cancer Group (DBCG) clinical database provides high-quality prospectively collected data on breast cancer diagnosis, treatment, and routine follow-up for breast cancer recurrence. Individual-level linkage of DBCG data to other population-based and medical registries in Denmark, including the Danish National Prescription Registry, has facilitated large population-based pharmacoepidemiology studies. A unique advantage of using DBCG data for such studies is the ability to investigate the association of drugs with breast cancer recurrence rather than breast cancer mortality - which may be misclassified - or all-cause mortality. Here we summarize findings from pharmacoepidemiological studies, based on DBCG data, on the association between routinely used prescription drugs and risk of breast cancer recurrence. RESULTS: Our findings suggest that concurrent use of glucocorticoids, ACE inhibitors, aspirin, NSAIDs, selective COX-2 inhibitors, digoxin, and opioids has little impact on breast cancer recurrence. Similarly, patients who use SSRIs concurrently with tamoxifen treatment are not at increased risk of recurrence. In contrast, post-diagnostic use of simvastatin, a lipophilic statin, correlates with a decreased risk of breast cancer recurrence, providing a rationale for a prospective randomized clinical trial investigating simvastatin as an adjuvant therapy for breast cancer. CONCLUSION: As a whole, findings of pharmacoepidemiological studies based on DBCG data provide reassurance to physicians and healthcare personnel who provide supportive care during and after cancer (including prescriptions for comedications) and to breast cancer survivors for whom the risk of breast cancer recurrence is a major concern.
[Mh] Termos MeSH primário: Neoplasias da Mama/patologia
Progressão da Doença
Recidiva Local de Neoplasia
[Mh] Termos MeSH secundário: Antagonistas Adrenérgicos beta/uso terapêutico
Analgésicos Opioides/uso terapêutico
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico
Anti-Inflamatórios não Esteroides/uso terapêutico
Aspirina/uso terapêutico
Cardiotônicos/uso terapêutico
Inibidores de Ciclo-Oxigenase 2/uso terapêutico
Bases de Dados Factuais
Dinamarca
Digoxina/uso terapêutico
Antagonistas de Estrogênios/uso terapêutico
Feminino
Glucocorticoides/uso terapêutico
Seres Humanos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico
Inibidores da Agregação de Plaquetas/uso terapêutico
Prognóstico
Inibidores da Captação de Serotonina/uso terapêutico
Sinvastatina/uso terapêutico
Tamoxifeno/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adrenergic beta-Antagonists); 0 (Analgesics, Opioid); 0 (Angiotensin-Converting Enzyme Inhibitors); 0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Cardiotonic Agents); 0 (Cyclooxygenase 2 Inhibitors); 0 (Estrogen Antagonists); 0 (Glucocorticoids); 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors); 0 (Platelet Aggregation Inhibitors); 0 (Serotonin Uptake Inhibitors); 094ZI81Y45 (Tamoxifen); 73K4184T59 (Digoxin); AGG2FN16EV (Simvastatin); R16CO5Y76E (Aspirin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180201
[Lr] Data última revisão:
180201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171206
[St] Status:MEDLINE
[do] DOI:10.1080/0284186X.2017.1407040


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[PMID]:28419445
[Au] Autor:Yang H; Ma L; Wang Y; Zuo W; Li B; Yang Y; Chen Y; Chen L; Wang L; Zhu L
[Ad] Endereço:Department of Pathology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China.
[Ti] Título:Activation of ClC-3 chloride channel by 17ß-estradiol relies on the estrogen receptor α expression in breast cancer.
[So] Source:J Cell Physiol;233(2):1071-1081, 2018 Feb.
[Is] ISSN:1097-4652
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Although extensively studied, the mechanisms by which estrogen promotes breast cancer growth remain to be fully elucidated. Tamoxifen, an antiestrogen agent to treat ERα+ breast cancer, is also a high-affinity blocker of the chloride channels. In this study, we explored the involvement of the chloride channels in the action of estrogen in breast cancer. We found that 17ß-estradiol (17ß-E2) concentration-dependently activated the chloride currents in ERα+ breast cancer MCF-7 cells. Extracellular hypertonic challenge and chloride channel blockers, NPPB and DIDS inhibited the 17ß-E2-activated chloride currents. Decreased the ClC-3 protein expression caused the depletion of the 17ß-E2-activated chloride currents. 17ß-E2-activated chloride currents which relied on the ERα expression were demonstrated by the following evidences. Firstly, 17ß-E2-activated chloride currents could not be observed in ERα- breast cancer MDA-MB-231 cells. Secondly, ER antagonists, tamoxifen and ICI 182,780, and downregulation of ERα expression inhibited or abolished the 17ß-E2-activated chloride currents. Thirdly, ERα expression was induced in MDA-MB-231 cells by ESR1 gene transfection, and then 17ß-E2-activated chloride currents could be observed. In MCF-7 cells, ERα and ClC-3 mainly located in nucleus and translocated to cell plasma and membrane with respect to co-localization following treatment of 17ß-E2. Downregulation of ERα expression could decrease the expression of ClC-3 protein. Conversely, downregulation of ClC-3 expression did not influence the ERα expression. Taken together, our findings demonstrated that ClC-3 is a potential target of 17ß-E2 and is modulated by the ERα in breast cancer cell. Pharmacological modulation of ClC-3 may provide a deep understanding in antiestrogen treatment of breast cancer patients.
[Mh] Termos MeSH primário: Neoplasias da Mama/metabolismo
Agonistas dos Canais de Cloreto/farmacologia
Canais de Cloreto/efeitos dos fármacos
Estradiol/farmacologia
Receptor alfa de Estrogênio/agonistas
[Mh] Termos MeSH secundário: Neoplasias da Mama/genética
Neoplasias da Mama/patologia
Canais de Cloreto/genética
Canais de Cloreto/metabolismo
Relação Dose-Resposta a Droga
Antagonistas de Estrogênios/farmacologia
Receptor alfa de Estrogênio/genética
Receptor alfa de Estrogênio/metabolismo
Feminino
Regulação Neoplásica da Expressão Gênica
Seres Humanos
Células MCF-7
Potenciais da Membrana
Interferência de RNA
Transdução de Sinais/efeitos dos fármacos
Fatores de Tempo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chloride Channel Agonists); 0 (Chloride Channels); 0 (ClC-3 channel); 0 (Estrogen Antagonists); 0 (Estrogen Receptor alpha); 0 (estrogen receptor alpha, human); 4TI98Z838E (Estradiol)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170419
[St] Status:MEDLINE
[do] DOI:10.1002/jcp.25963


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[PMID]:28977593
[Au] Autor:Simon V; Avet C; Grange-Messent V; Wargnier R; Denoyelle C; Pierre A; Dairou J; Dupret JM; Cohen-Tannoudji J
[Ad] Endereço:Sorbonne Paris Cité, Université Paris-Diderot, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 8251, Institut National de la Santé et de la Recherche Médicale (INSERM) U1133, Biologie Fonctionnelle et Adaptative, Physiologie de l'axe gonadotrope, Paris 75013, Franc
[Ti] Título:Carbon Black Nanoparticles Inhibit Aromatase Expression and Estradiol Secretion in Human Granulosa Cells Through the ERK1/2 Pathway.
[So] Source:Endocrinology;158(10):3200-3211, 2017 Oct 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Secretion of 17-ß-estradiol (E2) by human granulosa cells can be disrupted by various environmental toxicants. In the current study, we investigated whether carbon black nanoparticles (CB NPs) affect the steroidogenic activity of cultured human granulosa cells. The human granulosa cell line KGN and granulosa cells from patients undergoing in vitro fertilization were treated with increasing concentrations of CB NPs (1 to 100 µg/mL) together or not with follicle-stimulating hormone (FSH). We observed that CB NPs are internalized in KGN cells without affecting cell viability. CB NPs could be localized in the cytoplasm, within mitochondria and in association with the outer face of the endoplasmic reticulum membrane. In both cell types, CB NPs reduced in a dose-dependent manner the activity of aromatase enzyme, as reflected by a decrease in E2 secretion. A significant decrease was observed in response to CB NPs concentrations from 25 and 50 µg/mL in KGN cell line and primary cultures, respectively. Furthermore, CB NPs decreased aromatase protein levels in both cells and reduced aromatase transcript levels in KGN cells. CB NPs rapidly activated extracellular signal-regulated kinase 1 and 2 in KGN cells and pharmacological inhibition of this signaling pathway using PD 98059 significantly attenuated the inhibitory effects of CB NPs on CYP19A1 gene expression and aromatase activity. CB NPs also inhibited the stimulatory effect of FSH on aromatase expression and activity. Altogether, our study on cultured ovarian granulosa cells reveals that CB NPs decrease estrogens production and highlights possible detrimental effect of these common NPs on female reproductive health.
[Mh] Termos MeSH primário: Inibidores da Aromatase/farmacologia
Estradiol/secreção
Células da Granulosa/enzimologia
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Nanopartículas/administração & dosagem
Fuligem/farmacologia
[Mh] Termos MeSH secundário: Aromatase/genética
Aromatase/metabolismo
Linhagem Celular
Relação Dose-Resposta a Droga
Regulação para Baixo/efeitos dos fármacos
Disruptores Endócrinos/farmacologia
Estradiol/biossíntese
Antagonistas de Estrogênios
Feminino
Fertilização In Vitro
Hormônio Foliculoestimulante/administração & dosagem
Células da Granulosa/química
Células da Granulosa/secreção
Seres Humanos
Sistema de Sinalização das MAP Quinases/fisiologia
Nanopartículas/análise
Fuligem/administração & dosagem
Fuligem/análise
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aromatase Inhibitors); 0 (Endocrine Disruptors); 0 (Estrogen Antagonists); 0 (Soot); 4TI98Z838E (Estradiol); 9002-68-0 (Follicle Stimulating Hormone); EC 1.14.14.1 (Aromatase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171005
[St] Status:MEDLINE
[do] DOI:10.1210/en.2017-00374


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[PMID]:28882502
[Au] Autor:Torikai K; Koga R; Liu X; Umehara K; Kitano T; Watanabe K; Oishi T; Noguchi H; Shimohigashi Y
[Ad] Endereço:Department of Chemistry, Faculty and Graduate School of Science, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan. Electronic address: torikai@chem.kyushu-univ.jp.
[Ti] Título:Design and synthesis of benzoacridines as estrogenic and anti-estrogenic agents.
[So] Source:Bioorg Med Chem;25(20):5216-5237, 2017 Oct 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Estrogens play undisputedly important physiological roles, but lifetime exposure to estrogens has also been linked to the development of breast cancer. Moreover, imbalanced estrogen levels have been associated with various symptoms such as osteoporosis and menopausal disorders. For the improvement of such estrogen imbalances, estrogenic reagents with regulatory properties have shown promising potential. Herein, we report the construction of a 12-arylbenzoacridine library via a diversity-oriented strategy that furnished non-toxic estrogenic and anti-estrogenic agents. Derivatives with a hydroxy group at the molecular edge exhibit potent binding affinity to the estrogen receptor α (ERα) and ERß (IC < µM), while binding to the estrogen-related receptor γ (ERRγ), i.e., an orphan nuclear receptor on which estrogens often trigger unfavorable events, was not observed. These findings offer valuable insights into 12-arylbenzoacridines as a novel platform for the development of selective estrogen-receptor modulators (SERMs).
[Mh] Termos MeSH primário: Acridinas/farmacologia
Antineoplásicos/farmacologia
Desenho de Drogas
Antagonistas de Estrogênios/farmacologia
Estrogênios/metabolismo
[Mh] Termos MeSH secundário: Acridinas/síntese química
Acridinas/química
Antineoplásicos/síntese química
Antineoplásicos/química
Ligação Competitiva/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Antagonistas de Estrogênios/síntese química
Antagonistas de Estrogênios/química
Células HeLa
Seres Humanos
Células MCF-7
Estrutura Molecular
Receptores Estrogênicos/antagonistas & inibidores
Receptores Estrogênicos/metabolismo
Relação Estrutura-Atividade
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acridines); 0 (Antineoplastic Agents); 0 (Estrogen Antagonists); 0 (Estrogens); 0 (Receptors, Estrogen)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170909
[St] Status:MEDLINE


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[PMID]:28854070
[Au] Autor:Goetz MP; Suman VJ; Reid JM; Northfelt DW; Mahr MA; Ralya AT; Kuffel M; Buhrow SA; Safgren SL; McGovern RM; Black J; Dockter T; Haddad T; Erlichman C; Adjei AA; Visscher D; Chalmers ZR; Frampton G; Kipp BR; Liu MC; Hawse JR; Doroshow JH; Collins JM; Streicher H; Ames MM; Ingle JN
[Ad] Endereço:Matthew P. Goetz, Vera J. Suman, Joel M. Reid, Don W. Northfelt, Michael A. Mahr, Andrew T. Ralya, Mary Kuffel, Sarah A. Buhrow, Stephanie L. Safgren, Renee M. McGovern, John Black, Travis Dockter, Tufia Haddad, Charles Erlichman, Alex A. Adjei, Dan Visscher, Benjamin R. Kipp, Minetta C. Liu, John R
[Ti] Título:First-in-Human Phase I Study of the Tamoxifen Metabolite Z-Endoxifen in Women With Endocrine-Refractory Metastatic Breast Cancer.
[So] Source:J Clin Oncol;35(30):3391-3400, 2017 Oct 20.
[Is] ISSN:1527-7755
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose Endoxifen is a tamoxifen metabolite with potent antiestrogenic activity. Patients and Methods We performed a phase I study of oral Z-endoxifen to determine its toxicities, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity. Eligibility included endocrine-refractory, estrogen receptor-positive metastatic breast cancer. An accelerated titration schedule was applied until moderate or dose-limiting toxicity occurred, followed by a 3+3 design and expansion at 40, 80, and 100 mg per day. Tumor DNA from serum (circulating cell free [cf); all patients] and biopsies [160 mg/day and expansion]) was sequenced. Results Of 41 enrolled patients, 38 were evaluable for MTD determination. Prior endocrine regimens during which progression occurred included aromatase inhibitor (n = 36), fulvestrant (n = 21), and tamoxifen (n = 15). Patients received endoxifen once daily at seven dose levels (20 to 160 mg). Dose escalation ceased at 160 mg per day given lack of MTD and endoxifen concentrations > 1,900 ng/mL. Endoxifen clearance was unaffected by CYP2D6 genotype. One patient (60 mg) had cycle 1 dose-limiting toxicity (pulmonary embolus). Overall clinical benefit rate (stable > 6 months [n = 7] or partial response by RECIST criteria [n = 3]) was 26.3% (95% CI, 13.4% to 43.1%) including prior tamoxifen progression (n = 3). cfDNA mutations were observed in 13 patients ( PIK3CA [n = 8], ESR1 [n = 5], TP53 [n = 4], and AKT [n = 1]) with shorter progression-free survival ( v those without cfDNA mutations; median, 61 v 132 days; log-rank P = .046). Clinical benefit was observed in those with ESR1 amplification (tumor; 80 mg/day) and ESR1 mutation (cfDNA; 160 mg/day). Comparing tumor biopsies and cfDNA, some mutations ( PIK3CA, TP53, and AKT) were undetected by cfDNA, whereas cfDNA mutations ( ESR1, TP53, and AKT) were undetected by biopsy. Conclusion In endocrine-refractory metastatic breast cancer, Z-endoxifen provides substantial drug exposure unaffected by CYP2D6 metabolism, acceptable toxicity, and promising antitumor activity.
[Mh] Termos MeSH primário: Neoplasias da Mama/tratamento farmacológico
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Tamoxifeno/análogos & derivados
[Mh] Termos MeSH secundário: Administração Oral
Adulto
Idoso
Idoso de 80 Anos ou mais
Área Sob a Curva
Inibidores da Aromatase/uso terapêutico
Neoplasias da Mama/genética
Neoplasias da Mama/metabolismo
Classe I de Fosfatidilinositol 3-Quinases/genética
Citocromo P-450 CYP2D6/genética
Citocromo P-450 CYP2D6/metabolismo
DNA de Neoplasias/sangue
DNA de Neoplasias/genética
Intervalo Livre de Doença
Relação Dose-Resposta a Droga
Estradiol/análogos & derivados
Estradiol/uso terapêutico
Antagonistas de Estrogênios/efeitos adversos
Antagonistas de Estrogênios/metabolismo
Antagonistas de Estrogênios/uso terapêutico
Feminino
Seres Humanos
Meia-Idade
Mutação
Metástase Neoplásica
Tamoxifeno/metabolismo
Tamoxifeno/farmacocinética
Tamoxifeno/uso terapêutico
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aromatase Inhibitors); 0 (DNA, Neoplasm); 0 (Estrogen Antagonists); 094ZI81Y45 (Tamoxifen); 22X328QOC4 (fulvestrant); 46AF8680RC (4-hydroxy-N-desmethyltamoxifen); 4TI98Z838E (Estradiol); EC 1.14.14.1 (Cytochrome P-450 CYP2D6); EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases); EC 2.7.1.137 (PIK3CA protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170831
[St] Status:MEDLINE
[do] DOI:10.1200/JCO.2017.73.3246


  8 / 7739 MEDLINE  
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[PMID]:28780879
[Au] Autor:Kohalmi KV; Veszeli N; Luczay A; Varga L; Farkas H
[Ad] Endereço:III. Belgyógyászati Klinika, Országos Angiooedema Központ, Semmelweis Egyetem, Általános Orvostudományi Kar Budapest, Kútvölgyi út 4., 1125.
[Ti] Título:[Effect of danazol treatment on growth in pediatric patients with hereditary angioedema due to C1-inhibitor deficiency].
[Ti] Título:A danazolkezelés hatása C1-inhibitor-hiány okozta hereditaer angiooedemás gyermekek növekedésére..
[So] Source:Orv Hetil;158(32):1269-1276, 2017 Aug.
[Is] ISSN:0030-6002
[Cp] País de publicação:Hungary
[La] Idioma:hun
[Ab] Resumo:INTRODUCTION: Attenuated androgens are used for the prevention of angioedema attacks of hereditary angioedema with C1-inhibitor deficiency. After prepuberty, their use can lead to growth retardation. AIM: We assessed the effect of danazol on the growth of pediatric patients with hereditary angioedema. METHOD: In the retrospective study on 42 patients diagnosed with hereditary angioedema, we calculated the deviation from the mid-parental target height, and analyzed it against the gender, the dose and duration of danazol treatment administered before the age of 21 years and before the age of 16 years. RESULTS: Regarding the deviation from the mid-parental target height, we did not find any significant difference between patients taking vs. not taking danazol, males vs. females taking danazol. The dose and the duration of danazol treatment did not influence that value neither before 21, nor before 16 years of age. CONCLUSIONS: Our findings suggest that treatment with the lowest effective doses of danazol does not influence growth. Orv Hetil. 2017; 158(32): 1269-1276.
[Mh] Termos MeSH primário: Angioedemas Hereditários/tratamento farmacológico
Síndrome Linfoproliferativa Autoimune/tratamento farmacológico
Danazol/uso terapêutico
Antagonistas de Estrogênios/uso terapêutico
Transtornos do Crescimento/induzido quimicamente
[Mh] Termos MeSH secundário: Adolescente
Angioedemas Hereditários/genética
Síndrome Linfoproliferativa Autoimune/genética
Criança
Proteína Inibidora do Complemento C1/genética
Danazol/efeitos adversos
Antagonistas de Estrogênios/efeitos adversos
Feminino
Seres Humanos
Masculino
Estudos Retrospectivos
Fatores de Risco
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Complement C1 Inhibitor Protein); 0 (Estrogen Antagonists); N29QWW3BUO (Danazol)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170928
[Lr] Data última revisão:
170928
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170808
[St] Status:MEDLINE
[do] DOI:10.1556/650.2017.30806


  9 / 7739 MEDLINE  
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[PMID]:28768532
[Au] Autor:Zingue S; Michel T; Nde CBM; Njuh AN; Cisilotto J; Ndinteh DT; Clyne C; Fernandez X; Creczynski-Pasa TB; Njamen D
[Ad] Endereço:Department of Life and Earth Sciences, Higher Teachers' Training College, University of Maroua, P.O. Box 55, Maroua, Cameroon. stephanezingue@gmail.com.
[Ti] Título:Estrogen-like and tissue-selective effects of 7-methoxycoumarin from Ficus umbellata (Moraceae): an in vitro and in vivo study.
[So] Source:BMC Complement Altern Med;17(1):383, 2017 Aug 02.
[Is] ISSN:1472-6882
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Ficus umbellata is a medicinal plant previously shown to endow estrogenic properties. Its major component was isolated and characterized as 7-methoxycoumarin (MC). Noteworthy, coumarins and the respective active metabolite 7-hydroxycoumarin analogs have shown aromatase inhibitory activity, which is of particular interest in the treatment of estrogen-dependent cancers. The present work aimed at evaluating the estrogenic/antiestrogenic effects of MC in vitro and in vivo. METHODS: To do so, in vitro assays using E-screen and reporter gene were done. In vivo, a 3-day uterotrophic assay followed by a postmenopausal-like rat model to characterize MC as well as F. umbellata aqueous extract in ovariectomized Wistar rats was performed. The investigations focused on histological (vaginal and uterine epithelial height) and morphological (uterine wet weight, vagina stratification and cornification) endpoints, bone mass, biochemical parameters and lipid profile. RESULTS: MC induced a significant (p < 0.05) MCF-7 cell proliferation at a concentration of 0.1 µM, but did not inhibit the effect induced by estradiol in both E-screen and reporter gene assays. In vivo, MC treatment did not show an uterotrophic effect in both rat models used. However, MC (1 mg/kg) induced a significant increase (p < 0.01) of vaginal epithelial height. No significant change was observed with MC in abdominal fat weight, serum lipid levels and bone weight. CONCLUSION: These results suggest that MC has a weak estrogenic activity in vitro and in vivo that accounts only in part to the estrogenicity of the whole plant extract. MC could be beneficial with regard to vagina dryness as it showed a tissue specific effect without exposing the uterus to a potential tumorigenic growth.
[Mh] Termos MeSH primário: Estrogênios/metabolismo
Ficus/química
Fitoestrógenos/farmacologia
Extratos Vegetais/farmacologia
Umbeliferonas/farmacologia
Útero/efeitos dos fármacos
Vagina/efeitos dos fármacos
[Mh] Termos MeSH secundário: Tecido Adiposo/metabolismo
Animais
Inibidores da Aromatase/farmacologia
Osso e Ossos/efeitos dos fármacos
Epitélio/efeitos dos fármacos
Estradiol/metabolismo
Estradiol/farmacologia
Antagonistas de Estrogênios/farmacologia
Feminino
Células HEK293
Seres Humanos
Lipídeos/sangue
Células MCF-7
Ovariectomia
Pós-Menopausa
Ratos Wistar
Útero/metabolismo
Vagina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aromatase Inhibitors); 0 (Estrogen Antagonists); 0 (Estrogens); 0 (Lipids); 0 (Phytoestrogens); 0 (Plant Extracts); 0 (Umbelliferones); 4TI98Z838E (Estradiol)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170901
[Lr] Data última revisão:
170901
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170804
[St] Status:MEDLINE
[do] DOI:10.1186/s12906-017-1895-9


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[PMID]:28759386
[Au] Autor:Cuzick J
[Ad] Endereço:Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK. Electronic address: j.cuzick@qmul.ac.uk.
[Ti] Título:Preventive therapy for cancer.
[So] Source:Lancet Oncol;18(8):e472-e482, 2017 Aug.
[Is] ISSN:1474-5488
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Therapeutic cancer prevention is a developing area that can gain a lot from the successes in the prevention of cardiovascular diseases. Although weight control and physical activity are important in the prevention of both diseases, several other preventive measures exist. Low-dose aspirin for cancer prevention is often cited as the most important approach in terms of population benefit, and should be offered to those older than 50 years of age without hypertension or risk factors for gastrointestinal bleeding. Universal vaccination against the human papillomavirus, ideally with the nine-valent vaccine, also offers substantial benefits for the whole population if given before infection occurs (ie, typically at age 12-14 years). Other therapies, such as anti-oestrogen drugs for breast cancer prevention, should be targeted to high-risk groups to maintain a favourable benefit-risk ratio. Better algorithms for identification and improved platforms to reach these groups, such as during a screening visit, remain a key priority to allow existing knowledge to inform public health. Many other promising compounds have been identified, often as components of food, but results suggesting increased disease incidence with ß carotene and vitamin E administration indicate that such treatments need rigorous evaluation before acceptance.
[Mh] Termos MeSH primário: Anti-Inflamatórios não Esteroides/uso terapêutico
Anticarcinógenos/uso terapêutico
Aspirina/uso terapêutico
Quimioprevenção
Neoplasias/prevenção & controle
[Mh] Termos MeSH secundário: Inibidores da Aromatase/uso terapêutico
Colectomia
Anticoncepcionais Orais/uso terapêutico
Dieta
Antagonistas de Estrogênios/uso terapêutico
Vacinas contra Hepatite B/uso terapêutico
Seres Humanos
Neoplasias/genética
Ovariectomia
Vacinas contra Papillomavirus/uso terapêutico
Mastectomia Profilática
Tamoxifeno/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Anticarcinogenic Agents); 0 (Aromatase Inhibitors); 0 (Contraceptives, Oral); 0 (Estrogen Antagonists); 0 (Hepatitis B Vaccines); 0 (Papillomavirus Vaccines); 094ZI81Y45 (Tamoxifen); R16CO5Y76E (Aspirin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170801
[St] Status:MEDLINE



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