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[PMID]:29431540
[Au] Autor:Hong JH
[Ad] Endereço:a Department of Urology , Dankook University College of Medicine , Cheonan , Republic of Korea.
[Ti] Título:Pharmacokinetic/pharmacodynamic drug evaluation of enzalutamide for treating prostate cancer.
[So] Source:Expert Opin Drug Metab Toxicol;14(3):361-369, 2018 Mar.
[Is] ISSN:1744-7607
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Enzalutamide is the first approved second-generation androgen receptor (AR) antagonist in the treatment of metastatic castration-resistant prostate cancer (mCRPC) with or without docetaxel-based chemotherapy. Over the past 5 years, a number of attempts were made to determine the efficacy of enzalutamide in the different clinical settings. Areas covered: A literature search was performed at the PubMed, Embase, and Web of Science database to collect the most relevant and impactful studies, including basic science investigations, clinical trials, and reviews. This article focuses on the pharmacology, efficacy, tolerability, and future perspective of enzalutamide. Expert opinion: The treatment paradigm of CRPC has been dramatically challenged of late. Enzalutamide are in wide use because of its favorable efficacy and safety, but primary or acquired resistance to the drug will eventually develop. Further studies are thus necessary to identify appropriate patients who can achieve apparent benefits from enzalutamide alone or in combination with other drugs.
[Mh] Termos MeSH primário: Antagonistas de Receptores de Andrógenos/administração & dosagem
Feniltioidantoína/análogos & derivados
Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico
[Mh] Termos MeSH secundário: Antagonistas de Receptores de Andrógenos/farmacocinética
Antagonistas de Receptores de Andrógenos/farmacologia
Animais
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Resistência a Medicamentos Antineoplásicos
Seres Humanos
Masculino
Metástase Neoplásica
Feniltioidantoína/administração & dosagem
Feniltioidantoína/farmacocinética
Feniltioidantoína/farmacologia
Neoplasias de Próstata Resistentes à Castração/patologia
Taxoides/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Androgen Receptor Antagonists); 0 (MDV 3100); 0 (Taxoids); 15H5577CQD (docetaxel); 2010-15-3 (Phenylthiohydantoin)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180213
[St] Status:MEDLINE
[do] DOI:10.1080/17425255.2018.1440288


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[PMID]:29292905
[Au] Autor:Henriksson R; Falkenius J; Norin S; Öhman D; Abrahamsson M; Lindquist M; Lööv SÅ
[Ad] Endereço:Onkologi & Patologi - Regionalt Cancercentrum STOCKHOLM, Sweden Onkologi & Patologi - Regionalt Cancercentrum STOCKHOLM, Sweden.
[Ti] Título:Register för nya läkemedel i cancervården ger värdefull hjälp - Visar en bra bild av hur läkemedlen används ­ patienten kan följas i den kliniska vardagen..
[So] Source:Lakartidningen;114, 2017 Nov 06.
[Is] ISSN:1652-7518
[Cp] País de publicação:Sweden
[La] Idioma:swe
[Ab] Resumo:Register for new drugs in cancer care provides a picture of how the drugs are used in the daily clinical practice Today, an increasing number of cancer drugs are approved before traditional well-controlled phase 3 studies have been conducted and in many registration studies there is no participation of Swedish departments. This article describes the general experience of a caregiver initiated systematic follow-up of new cancer drugs that shows the possibility of obtaining a picture of the drug's use in routine care. From the register "New Pharmaceuticals in Cancer care", registrations from Stockholm-Gotland region are reported. The structure of the registry can be used with advantage in other therapeutic areas than cancer and can be supplemented with data from national and regional registers as well as quality registers including patient experiences. The knowledge is important to many actors in health care and can contribute to an evidence based, patient-safe and equal healthcare in accordance with current guidelines.
[Mh] Termos MeSH primário: Antineoplásicos
Neoplasias/tratamento farmacológico
Sistema de Registros
[Mh] Termos MeSH secundário: Androstenos/uso terapêutico
Antineoplásicos/administração & dosagem
Antineoplásicos/uso terapêutico
Bevacizumab/uso terapêutico
Neoplasias da Mama/tratamento farmacológico
Neoplasias da Mama/mortalidade
Neoplasias Colorretais/tratamento farmacológico
Neoplasias Colorretais/mortalidade
Uso de Medicamentos
Seres Humanos
Ipilimumab/uso terapêutico
Masculino
Melanoma/tratamento farmacológico
Melanoma/mortalidade
Neoplasias/mortalidade
Cuidados Paliativos/métodos
Feniltioidantoína/análogos & derivados
Feniltioidantoína/uso terapêutico
Projetos Piloto
Neoplasias da Próstata/tratamento farmacológico
Neoplasias da Próstata/mortalidade
Rádio (Elemento)/uso terapêutico
Taxa de Sobrevida
Suécia/epidemiologia
Suspensão de Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Androstenes); 0 (Antineoplastic Agents); 0 (Ipilimumab); 0 (MDV 3100); 0 (Radium-223); 2010-15-3 (Phenylthiohydantoin); 2S9ZZM9Q9V (Bevacizumab); G819A456D0 (abiraterone); W90AYD6R3Q (Radium)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180103
[St] Status:MEDLINE


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[PMID]:29261702
[Au] Autor:Liu CY; Lau KY; Hsu CC; Chen JL; Lee CH; Huang TT; Chen YT; Huang CT; Lin PH; Tseng LM
[Ad] Endereço:Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, Taiwan.
[Ti] Título:Combination of palbociclib with enzalutamide shows in vitro activity in RB proficient and androgen receptor positive triple negative breast cancer cells.
[So] Source:PLoS One;12(12):e0189007, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: Triple negative breast cancer (TNBC) lacks specific drug targets and remains challenging. Palbociclib, a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor is approved for metastatic estrogen receptor (ER)-positive and human epithermal growth factor 2 (HER2)-negative breast cancer. The nature of cell cycle inhibition by palbociclib suggests its potential in TNBC cells. Retinoblastoma (RB, a known substrate of CDK4/6) pathway deregulation is a frequent occurrence in TNBC and studies have revealed that pharmacological CDK4/6 inhibition induces a cooperative cytostatic effect with doxorubicin in RB-proficient TNBC models. In addition, recent studies reported that anti-androgen therapy shows preclinical efficacy in androgen-receptor (AR)-positive TNBC cells. Here we examined the effect of palbociclib in combination with an anti-androgen enzalutamide in TNBC cells. METHOD: MDA-MB-453, BT-549, MDA-MB-231 and MDA-MB-468 TNBC cell lines were used for in vitro studies. Protein expressions were assessed by Western blot analysis. Cytostatic effect was examined by MTT assay. Cell cycle and apoptosis were examined by flow cytometry. RESULTS: Palbociclib showed inhibitory effect in RB-proficient TNBC cells, and enzalutamide inhibited cell viability in AR-positive TNBC cells. Enzalutamide treatment could enhance the palbociclib-induced cytostatic effect in AR-positive/RB-proficient TNBC cells. In addition, palbociclib-mediated G1 arrest in AR-positive/RB-proficient TNBC cells was attenuated by RB knockdown. CONCLUSION: Our study provided a preclinical rationale in selecting patients who might have therapeutic benefit from combining CDK4/6 inhibitors with AR antagonists.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Receptores Androgênicos/metabolismo
Proteína do Retinoblastoma/metabolismo
Neoplasias de Mama Triplo Negativas/patologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Ensaios de Seleção de Medicamentos Antitumorais
Feminino
Fase G1/efeitos dos fármacos
Seres Humanos
Feniltioidantoína/análogos & derivados
Feniltioidantoína/análise
Piperazinas/análise
Piridinas/análise
Receptores Androgênicos/genética
Proteína do Retinoblastoma/genética
Neoplasias de Mama Triplo Negativas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MDV 3100); 0 (Piperazines); 0 (Pyridines); 0 (Receptors, Androgen); 0 (Retinoblastoma Protein); 2010-15-3 (Phenylthiohydantoin); G9ZF61LE7G (palbociclib)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171221
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189007


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[PMID]:28749536
[Au] Autor:Bandari J; Ayyash OM; Turner RM; Jacobs BL; Davies BJ
[Ad] Endereço:Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
[Ti] Título:The lack of a relationship between physician payments from drug manufacturers and Medicare claims for abiraterone and enzalutamide.
[So] Source:Cancer;123(22):4356-4362, 2017 Nov 15.
[Is] ISSN:1097-0142
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Interactions between industry and prescribers have raised concerns regarding conflicts of interest. To the best of the authors' knowledge, quantitative data measuring these interactions have been limited until recently. In the current study, the authors sought to determine whether an association exists between industry payments and prescriber behavior with regard to abiraterone and enzalutamide. METHODS: Two Centers for Medicare and Medicaid Services databases were combined to analyze oncologists and urologists who received industry payments and/or prescribed abiraterone and enzalutamide. Correlation analysis was constructed on prescription count and industry payments. Multivariable median regression examined predictors of change in prescription count per dollar of industry payment. Stratifying prescribers by quantile evaluated threshold effects on prescribers. RESULTS: The number of prescriptions was similar between prescribers who did and those who did not receive industry payment for both drugs. The median industry payment amount to prescribers differed between prescribers and nonprescribers for abiraterone ($72 vs $56) and enzalutamide ($59 vs $31). Although no statistical association was found to exist between industry payment amount and prescription count for abiraterone prescribers, an association was found to exist for enzalutamide prescribers (rho = 0.31). A small change was found with regard to prescription count per dollar of industry payment for abiraterone (0.0007 prescriptions) and enzalutamide (0.0006 prescriptions). The amount of industry payment needed to predict one additional prescription was found to be lower in the fourth and fifth quantiles compared with the first through third quantiles. CONCLUSIONS: No difference in prescription count was found to exist between prescribers who received industry payments and those who did not. A positive correlation was noted between industry payments and prescription count for enzalutamide. Ease of adoption may affect differences between the 2 drugs. Cancer 2017;123:4356-62. © 2017 American Cancer Society.
[Mh] Termos MeSH primário: Androstenos/economia
Androstenos/uso terapêutico
Indústria Farmacêutica/economia
Medicare/economia
Feniltioidantoína/análogos & derivados
Padrões de Prática Médica/economia
[Mh] Termos MeSH secundário: Conflito de Interesses
Custos de Medicamentos
Indústria Farmacêutica/ética
Ética Médica
Gastos em Saúde/estatística & dados numéricos
Seres Humanos
Revisão da Utilização de Seguros
Medicare/estatística & dados numéricos
Feniltioidantoína/economia
Feniltioidantoína/uso terapêutico
Médicos/economia
Médicos/ética
Padrões de Prática Médica/ética
Estados Unidos/epidemiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Androstenes); 0 (MDV 3100); 2010-15-3 (Phenylthiohydantoin); G819A456D0 (abiraterone)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170728
[St] Status:MEDLINE
[do] DOI:10.1002/cncr.30914


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[PMID]:29061806
[Au] Autor:Yang Y; Li X; Mamouni K; Kucuk O; Wu D
[Ad] Endereço:Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
[Ti] Título:Mifepristone Has Limited Activity to Enhance the Efficacy of Docetaxel and Enzalutamide Against Bone Metastatic and Castration-Resistant Prostate Cancer.
[So] Source:Anticancer Res;37(11):6235-6243, 2017 11.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Mifepristone has gained great interest in its potential as a novel agent against human cancers, including prostate cancer (PCa). However, recent clinical trials using mifepristone in PCa and other cancers have been disappointing. We evaluated the in vitro and in vivo activities of mifepristone, in combination with docetaxel and enzalutamide, against bone metastatic castration-resistant PCa. MATERIALS AND METHODS: The effects of mifepristone, alone or in combination with docetaxel or enzalutamide, on PCa cell viability, in vitro, were determined by the colorimetric assay. Intratibial model of C4-2-Luc tumors in athymic nude mice was used to evaluate the in vivo efficacy of mifepristone alone or in combination with docetaxel or enzalutamide. Tumor growth in mouse bone was assessed by serum prostate-specific antigen (PSA) levels and radiography. RESULTS: Although mifepristone exhibits a certain degree of synergism with docetaxel or enzalutamide in cell culture, statistical analyses showed that combination regimens fail to demonstrate effectiveness in suppressing the skeletal growth of PCa and enhancing the in vivo efficacy of docetaxel or enzalutamide in athymic nude mice (p>0.05). CONCLUSION: These results provide the first pre-clinical evidence suggesting that mifepristone may not effectively inhibit bone metastatic PCa, either as a single agent or combined with standard chemotherapy and androgen-deprivation therapy. This report may raise concerns over the clinical use of mifepristone in the management of advanced PCa.
[Mh] Termos MeSH primário: Neoplasias Ósseas/tratamento farmacológico
Mifepristona/farmacologia
Feniltioidantoína/análogos & derivados
Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico
Taxoides/farmacologia
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/farmacologia
Apoptose/efeitos dos fármacos
Neoplasias Ósseas/secundário
Proliferação Celular/efeitos dos fármacos
Antagonistas de Hormônios/farmacologia
Seres Humanos
Masculino
Camundongos
Feniltioidantoína/farmacologia
Neoplasias de Próstata Resistentes à Castração/patologia
Células Tumorais Cultivadas
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Hormone Antagonists); 0 (MDV 3100); 0 (Taxoids); 15H5577CQD (docetaxel); 2010-15-3 (Phenylthiohydantoin); 320T6RNW1F (Mifepristone)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171025
[St] Status:MEDLINE


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[PMID]:28977599
[Au] Autor:Masoodi KZ; Eisermann K; Yang Z; Dar JA; Pascal LE; Nguyen M; O'Malley K; Parrinello E; Feturi FG; Kenefake AN; Nelson JB; Johnston PA; Wipf P; Wang Z
[Ad] Endereço:Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15232.
[Ti] Título:Inhibition of Androgen Receptor Function and Level in Castration-Resistant Prostate Cancer Cells by 2-[(isoxazol-4-ylmethyl)thio]-1-(4-phenylpiperazin-1-yl)ethanone.
[So] Source:Endocrinology;158(10):3152-3161, 2017 Oct 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The androgen receptor (AR) plays a critical role in the development of castration-resistant prostate cancer (CRPC) as well as in the resistance to the second-generation AR antagonist enzalutamide and the selective inhibitor of cytochrome P450 17A1 (CYP17A1) abiraterone. Novel agents targeting AR may inhibit the growth of prostate cancer cells resistant to enzalutamide and/or abiraterone. Through a high-throughput/high-content screening of a 220,000-member small molecule library, we have previously identified 2-[(isoxazol-4-ylmethyl)thio]-1-(4-phenylpiperazin-1-yl)ethanone (IMTPPE) (SID 3712502) as a novel small molecule capable of inhibiting AR transcriptional activity and protein level in C4-2 prostate cancer cells. In this study, we show that IMTPPE inhibits AR-target gene expression using real-time polymerase chain reaction, Western blot, and luciferase assays. IMTPPE inhibited proliferation of AR-positive, but not AR-negative, prostate cancer cells in culture. IMTPPE inhibited the transcriptional activity of a mutant AR lacking the ligand-binding domain (LBD), indicating that IMTPPE inhibition of AR is independent of the LBD. Furthermore, animal studies showed that IMTPPE inhibited the growth of 22Rv1 xenograft tumor, a model for enzalutamide-resistant prostate cancer. These findings suggest that IMTPPE is a potential lead compound for developing clinical candidates for the treatment of CRPC, including those resistant to enzalutamide.
[Mh] Termos MeSH primário: Antagonistas de Receptores de Andrógenos/farmacologia
Isoxazóis/farmacologia
Piperazinas/farmacologia
Neoplasias de Próstata Resistentes à Castração/química
Receptores Androgênicos/fisiologia
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação/genética
Sítios de Ligação/fisiologia
Linhagem Celular Tumoral
Resistência a Medicamentos Antineoplásicos
Expressão Gênica/efeitos dos fármacos
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos BALB C
Camundongos SCID
Feniltioidantoína/análogos & derivados
Regiões Promotoras Genéticas/efeitos dos fármacos
Isoformas de Proteínas/genética
Reação em Cadeia da Polimerase em Tempo Real
Receptores Androgênicos/análise
Receptores Androgênicos/genética
Tetra-Hidronaftalenos
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-((isoxazol-4-ylmethyl)thio)-1-(4-phenylpiperazin-1-yl)ethanone); 0 (Androgen Receptor Antagonists); 0 (Isoxazoles); 0 (MDV 3100); 0 (Piperazines); 0 (Protein Isoforms); 0 (Receptors, Androgen); 0 (Tetrahydronaphthalenes); 2010-15-3 (Phenylthiohydantoin); A61RXM4375 (bexarotene)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171005
[St] Status:MEDLINE
[do] DOI:10.1210/en.2017-00408


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[PMID]:28826721
[Au] Autor:Chen J; Li L; Yang Z; Luo J; Yeh S; Chang C
[Ad] Endereço:Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061, China; George Whipple Lab for Cancer Research, Departments of Pathology and Urology, The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, 14642, US
[Ti] Título:Androgen-deprivation therapy with enzalutamide enhances prostate cancer metastasis via decreasing the EPHB6 suppressor expression.
[So] Source:Cancer Lett;408:155-163, 2017 Nov 01.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Early studies suggested that using ADT with the recently developed anti-androgen Enzalutamide (Enz, also named as MDV3100 could extent castration resistant prostate cancer (CRPC) patients' survival an extra 4.8 months. Yet the therapy in most patients might eventually fail due to development of Enz-resistance. Here we found Enz might also increase some unwanted side-effects via increasing the CRPC cell invasion that might involve altering the Enz-mediated androgen receptor (AR)/EPHB6 suppressor/JNK signaling. Results from multiple clinical surveys also indicated that EPHP6 might function as a suppressor of PCa metastasis. Mechanism dissection revealed that Enz-mediated AR might function via binding to the androgen-response-element (ARE) on the EPHB6 promoter to decrease EPHB6 suppressor expression, which might then activate the phosphorylation of JNK signals to increase the CRPC cell invasion. Targeting this newly identified AR/EPHB6/JNK signaling with JNK inhibitor (SP600125) may then block/reverse the Enz-increased CRPC cell invasion. Collectively, our results suggest that Enz may increase CRPC cell invasion via altering the AR/EPHB6/JNK/MMP9 signaling and targeting this newly identified signaling may help us to increase the Enz efficacy to better suppress the CRPC at the later metastatic stage.
[Mh] Termos MeSH primário: Antagonistas de Androgênios/farmacologia
Feniltioidantoína/análogos & derivados
Neoplasias de Próstata Resistentes à Castração/secundário
Receptores da Família Eph/metabolismo
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Movimento Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Resistência a Medicamentos Antineoplásicos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Masculino
Invasividade Neoplásica
Metástase Neoplásica
Feniltioidantoína/farmacologia
Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico
Neoplasias de Próstata Resistentes à Castração/metabolismo
Receptores Androgênicos/química
Receptores Androgênicos/metabolismo
Receptores da Família Eph/genética
Transdução de Sinais
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Androgen Antagonists); 0 (MDV 3100); 0 (Receptors, Androgen); 2010-15-3 (Phenylthiohydantoin); EC 2.7.10.1 (EPHB6 protein, human); EC 2.7.10.1 (Receptors, Eph Family)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170823
[St] Status:MEDLINE


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[PMID]:28762529
[Au] Autor:Harshman LC; Werner L; Tripathi A; Wang X; Maughan BL; Antonarakis ES; Nakabayashi M; McKay R; Pomerantz M; Mucci LA; Taplin ME; Sweeney CJ; Lee GM; Kantoff PW
[Ad] Endereço:Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
[Ti] Título:The impact of statin use on the efficacy of abiraterone acetate in patients with castration-resistant prostate cancer.
[So] Source:Prostate;77(13):1303-1311, 2017 May.
[Is] ISSN:1097-0045
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Statins compete with DHEAS for influx through the SLCO2B1 transporter, which may prolong time to progression (TTP) on androgen deprivation therapy. Abiraterone acetate (AA) may also undergo SLCO-mediated transport. Based on preclinical findings showing antagonism, we hypothesized that statins may compete with AA for influx via SLCO2B1 and could negatively impact drug efficacy. METHODS: We queried two institutional clinical databases (Dana-Farber Cancer Institute [DFCI], Johns Hopkins University [JHU]) for CRPC patients treated with AA. Treatment duration was a surrogate for TTP. Associations between statin use and AA duration were estimated using the Kaplan-Meier method. Multivariable Cox regression modeling adjusted for known prognostic factors. RESULTS: Of the 224 DFCI and 270 JHU patients included, the majority (96%) had metastatic disease. Nearly half (41% and 45%) were statin users. In the DFCI cohort, there was a trend toward longer AA duration in statin users: 14.2 versus 9.2 months (HR 0.79, 95%CI: 0.57-1.09, P = 0.14). There was no association between statin use and AA duration in the JHU cohort: 8.3 versus 8.0 months (HR 0.89, 95%CI: 0.69-1.16, P = 0.38) in the statin users versus non-users, except for a trend in patients that had not previously received docetaxel or enzalutamide (HR 0.79; 95%CI: 0.57-1.10). CONCLUSIONS: Contrary to our initial hypothesis, there was a trend toward longer (rather than shorter) AA duration in statin users in the entire DFCI cohort and in the enzalutamide- and docetaxel-naïve JHU patients. Together, these results do not support the hypothesis that statins interfere with AA efficacy.
[Mh] Termos MeSH primário: Acetato de Abiraterona
Transporte Biológico/efeitos dos fármacos
Inibidores de Hidroximetilglutaril-CoA Redutases
Transportadores de Ânions Orgânicos/metabolismo
Neoplasias de Próstata Resistentes à Castração
[Mh] Termos MeSH secundário: Acetato de Abiraterona/administração & dosagem
Acetato de Abiraterona/farmacocinética
Idoso
Antineoplásicos/administração & dosagem
Antineoplásicos/farmacocinética
Antineoplásicos/uso terapêutico
Linhagem Celular
Progressão da Doença
Sinergismo Farmacológico
Registros Eletrônicos de Saúde/estatística & dados numéricos
Seres Humanos
Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética
Masculino
Meia-Idade
Feniltioidantoína/análogos & derivados
Feniltioidantoína/uso terapêutico
Antígeno Prostático Específico/análise
Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico
Neoplasias de Próstata Resistentes à Castração/metabolismo
Neoplasias de Próstata Resistentes à Castração/patologia
Estudos Retrospectivos
Taxoides/uso terapêutico
Fatores de Tempo
Estados Unidos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors); 0 (MDV 3100); 0 (Organic Anion Transporters); 0 (SLCO2B1 protein, human); 0 (Taxoids); 15H5577CQD (docetaxel); 2010-15-3 (Phenylthiohydantoin); EC 3.4.21.77 (Prostate-Specific Antigen); EM5OCB9YJ6 (Abiraterone Acetate)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171111
[Lr] Data última revisão:
171111
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170802
[St] Status:MEDLINE
[do] DOI:10.1002/pros.23390


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[PMID]:28754673
[Au] Autor:Yin Y; Li R; Xu K; Ding S; Li J; Baek G; Ramanand SG; Ding S; Liu Z; Gao Y; Kanchwala MS; Li X; Hutchinson R; Liu X; Woldu SL; Xing C; Desai NB; Feng FY; Burma S; de Bono JS; Dehm SM; Mani RS; Chen BPC; Raj GV
[Ad] Endereço:Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas. Yi.Yin@utsouthwestern.edu Ganesh.Raj@utsouthwestern.edu.
[Ti] Título:Androgen Receptor Variants Mediate DNA Repair after Prostate Cancer Irradiation.
[So] Source:Cancer Res;77(18):4745-4754, 2017 Sep 15.
[Is] ISSN:1538-7445
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In prostate cancer, androgen deprivation therapy (ADT) enhances the cytotoxic effects of radiotherapy. This effect is associated with weakening of the DNA damage response (DDR) normally supported by the androgen receptor. As a significant number of patients will fail combined ADT and radiotherapy, we hypothesized that DDR may be driven by androgen receptor splice variants (ARV) induced by ADT. Investigating this hypothesis, we found that ARVs increase the clonogenic survival of prostate cancer cells after irradiation in an ADT-independent manner. Notably, prostate cancer cell irradiation triggers binding of ARV to the catalytic subunit of the critical DNA repair kinase DNA-PK. Pharmacologic inhibition of DNA-PKc blocked this interaction, increased DNA damage, and elevated prostate cancer cell death after irradiation. Our findings provide a mechanistic rationale for therapeutic targeting of DNA-PK in the context of combined ADT and radiotherapy as a strategy to radiosensitize clinically localized prostate cancer. .
[Mh] Termos MeSH primário: Antagonistas de Androgênios/farmacologia
Reparo do DNA/genética
Proteína Quinase Ativada por DNA/antagonistas & inibidores
Neoplasias da Próstata/genética
Inibidores de Proteínas Quinases/farmacologia
Receptores Androgênicos/genética
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/farmacologia
Reparo do DNA/efeitos da radiação
Proteína Quinase Ativada por DNA/metabolismo
Seres Humanos
Masculino
Camundongos
Camundongos Nus
Feniltioidantoína/análogos & derivados
Feniltioidantoína/farmacologia
Neoplasias da Próstata/tratamento farmacológico
Neoplasias da Próstata/radioterapia
Radiação Ionizante
Receptores Androgênicos/química
Receptores Androgênicos/metabolismo
Células Tumorais Cultivadas
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AR protein, human); 0 (Androgen Antagonists); 0 (Antineoplastic Agents); 0 (MDV 3100); 0 (Protein Kinase Inhibitors); 0 (Receptors, Androgen); 2010-15-3 (Phenylthiohydantoin); EC 2.7.11.1 (DNA-Activated Protein Kinase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170730
[St] Status:MEDLINE
[do] DOI:10.1158/0008-5472.CAN-17-0164


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[PMID]:28682871
[Au] Autor:Kim CS; Choi YD; Lee SE; Lee HM; Ueda T; Yonese J; Fukagai T; Chiong E; Lau W; Abhyankar S; Theeuwes A; Tombal B; Beer TM; Kimura G
[Ad] Endereço:aDepartment of Urology, Asan Medical Center, University of Ulsan College of Medicine bDepartment of Urology, Yonsei University College of Medicine cDepartment of Urology, Seoul National University Bundang Hospital dDepartment of Urology, Samsung Medical Center, Seoul, Korea eProstate Center and Division of Urology, Chiba Cancer Center, Chiba fDepartment of Urology, Cancer Institute Hospital of Japanese Foundation for Cancer Research gDepartment of Urology, Showa University Koto Toyosu Hospital, Tokyo, Japan hDepartment of Urology, National University Health System iUrology Centre, Singapore General Hospital, Singapore jMedical Affairs, Medivation, Inc., San Francisco, CA [Medivation was acquired by Pfizer Inc in September 2016] kBiostatistics, Astellas Pharma Europe B.V., Leiden, The Netherlands lDivision of Urology, Cliniques universitaires Saint-Luc, Brussels, Belgium mOHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR nDepartment of Urology, Nippon Medical School, Tokyo, Japan.
[Ti] Título:Post hoc analyses of East Asian patients from the randomized placebo-controlled PREVAIL trial of enzalutamide in patients with chemotherapy-naïve, metastatic castration-resistant prostate cancer.
[So] Source:Medicine (Baltimore);96(27):e7223, 2017 Jul.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Enzalutamide is an androgen receptor (AR) inhibitor that acts on different steps in the AR signaling pathway. In PREVAIL, an international, phase III, double-blind, placebo-controlled trial, enzalutamide significantly reduced the risk of radiographic progression by 81% (hazard ratio [HR], 0.19; P < .0001) and reduced the risk of death by 29% (HR, 0.71; P < .0001) compared with placebo in chemotherapy-naïve men with metastatic castration-resistant prostate cancer. METHODS: To evaluate treatment effects, safety, and pharmacokinetics of enzalutamide in East Asian patients from the PREVAIL trial, we performed a post hoc analysis of the Japanese, Korean, and Singaporean patients. PREVAIL enrolled patients with asymptomatic or mildly symptomatic chemotherapy-naïve metastatic castration-resistant prostate cancer who had progressed on androgen deprivation therapy. During the study, patients received enzalutamide (160 mg/d) or placebo (1:1) until death or discontinuation because of radiographic progression or skeletal-related event and initiation of subsequent therapy. Centrally assessed radiographic progression-free survival (rPFS) and overall survival (OS) were coprimary endpoints. The secondary endpoints of the PREVAIL trial were investigator-assessed rPFS, time to initiation of chemotherapy, time to prostate-specific antigen (PSA) progression, and PSA response (≥50% decline). RESULTS: Of 1717 patients, 148 patients were enrolled at sites in East Asia (enzalutamide 73, placebo 75). Treatment effect of enzalutamide versus placebo was consistent with that for the overall population as indicated by the HRs (95% confidence interval) of 0.38 (0.10-1.44) for centrally assessed rPFS, 0.59 (0.29-1.23) for OS, 0.33 (0.19-0.60) for time to chemotherapy, and 0.32 (0.20-0.50) for time to PSA progression. In East Asian patients, PSA responses were observed in 68.5% and 14.7% of enzalutamide- and placebo-treated patients, respectively. The enzalutamide plasma concentration ratio (East Asian:non-Asian patients) was 1.12 (90% confidence interval, 1.05-1.20) at 13 weeks. Treatment-related adverse events grade ≥ 3 occurred in 1.4% and 2.7% of enzalutamide- and placebo-treated East Asian patients, respectively. CONCLUSIONS: Treatment effects and safety of enzalutamide in East Asian patients were generally consistent with those observed in the overall study population from PREVAIL. CLINICALTRIALS. GOV NUMBER: NCT01212991.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Feniltioidantoína/análogos & derivados
Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Antineoplásicos/efeitos adversos
Antineoplásicos/sangue
Biomarcadores Tumorais/metabolismo
Intervalo Livre de Doença
Método Duplo-Cego
Seguimentos
Seres Humanos
Japão
Masculino
Meia-Idade
Feniltioidantoína/efeitos adversos
Feniltioidantoína/sangue
Feniltioidantoína/uso terapêutico
Modelos de Riscos Proporcionais
Antígeno Prostático Específico
Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem
Neoplasias de Próstata Resistentes à Castração/metabolismo
República da Coreia
Risco
Singapura
Fatores de Tempo
Resultado do Tratamento
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE III; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Biomarkers, Tumor); 0 (MDV 3100); 2010-15-3 (Phenylthiohydantoin); EC 3.4.21.77 (Prostate-Specific Antigen)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170724
[Lr] Data última revisão:
170724
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170707
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000007223



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