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[PMID]:29330466
[Au] Autor:Carney B; Kossatz S; Lok BH; Schneeberger V; Gangangari KK; Pillarsetty NVK; Weber WA; Rudin CM; Poirier JT; Reiner T
[Ad] Endereço:Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
[Ti] Título:Target engagement imaging of PARP inhibitors in small-cell lung cancer.
[So] Source:Nat Commun;9(1):176, 2018 01 12.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Insufficient chemotherapy response and rapid disease progression remain concerns for small-cell lung cancer (SCLC). Oncologists rely on serial CT scanning to guide treatment decisions, but this cannot assess in vivo target engagement of therapeutic agents. Biomarker assessments in biopsy material do not assess contemporaneous target expression, intratumoral drug exposure, or drug-target engagement. Here, we report the use of PARP1/2-targeted imaging to measure target engagement of PARP inhibitors in vivo. Using a panel of clinical PARP inhibitors, we show that PARP imaging can quantify target engagement of chemically diverse small molecule inhibitors in vitro and in vivo. We measure PARP1/2 inhibition over time to calculate effective doses for individual drugs. Using patient-derived xenografts, we demonstrate that different therapeutics achieve similar integrated inhibition efficiencies under different dosing regimens. This imaging approach to non-invasive, quantitative assessment of dynamic intratumoral target inhibition may improve patient care through real-time monitoring of drug delivery.
[Mh] Termos MeSH primário: Neoplasias Pulmonares/tratamento farmacológico
Terapia de Alvo Molecular/métodos
Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico
Ensaios Antitumorais Modelo de Xenoenxerto
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Relação Dose-Resposta a Droga
Seres Humanos
Neoplasias Pulmonares/diagnóstico por imagem
Neoplasias Pulmonares/enzimologia
Camundongos Endogâmicos NOD
Camundongos Knockout
Camundongos SCID
Ftalazinas/farmacologia
Piperazinas/farmacologia
Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores
Poli(ADP-Ribose) Polimerase-1/metabolismo
Tomografia Computadorizada com Tomografia por Emissão de Pósitrons
Carcinoma de Pequenas Células do Pulmão/diagnóstico por imagem
Carcinoma de Pequenas Células do Pulmão/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Phthalazines); 0 (Piperazines); 0 (Poly(ADP-ribose) Polymerase Inhibitors); 9QHX048FRV (talazoparib); EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1); WOH1JD9AR8 (olaparib)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180114
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02096-w


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[PMID]:29335205
[Au] Autor:Chen X; Huan X; Liu Q; Wang Y; He Q; Tan C; Chen Y; Ding J; Xu Y; Miao Z; Yang C
[Ad] Endereço:Synthetic Organic & Medicinal Chemistry Laboratory, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
[Ti] Título:Design and synthesis of 2-(4,5,6,7-tetrahydrothienopyridin-2-yl)-benzoimidazole carboxamides as novel orally efficacious Poly(ADP-ribose)polymerase (PARP) inhibitors.
[So] Source:Eur J Med Chem;145:389-403, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:The nuclear protein poly(ADP-ribose) polymerases-1/2 (PARP-1/2) are involved in DNA repair damaged by endogenous or exogenous process. And PARP-1/2 inhibitors have been proved to be clinically efficacious for DNA repair deficient tumors in the past decade. We have developed a series of 4,5,6,7-tetrahydrothienopyridin-2-yl benzimidazole carboxamides as novel and potent PARP-1/2 inhibitors. The best compound resulted from this series is compound 27 which displays excellent PARP-1 and PARP-2 inhibitory activity with IC of 18 nM and 42 nM, respectively. Furthermore, it can selectively kill BRCA2 deficient V-C8 cells with a CC of 920 nM. In the MDA-MB-436 (BRCA-1 mutant) xenograft model, this compound was well tolerated and showed single-agent activity. Based on the results above, compound 27 has been selected as a lead candidate targeting PARP-1/2 and its preclinical characterization is also underway.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Benzimidazóis/farmacologia
Desenho de Drogas
Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
Poli(ADP-Ribose) Polimerases/metabolismo
[Mh] Termos MeSH secundário: Administração Oral
Animais
Antineoplásicos/administração & dosagem
Antineoplásicos/química
Benzimidazóis/administração & dosagem
Benzimidazóis/química
Peso Corporal/efeitos dos fármacos
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Cricetulus
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Camundongos
Modelos Moleculares
Estrutura Molecular
Neoplasias Experimentais/tratamento farmacológico
Neoplasias Experimentais/patologia
Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem
Inibidores de Poli(ADP-Ribose) Polimerases/química
Relação Estrutura-Atividade
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Benzimidazoles); 0 (Poly(ADP-ribose) Polymerase Inhibitors); EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180117
[St] Status:MEDLINE


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[PMID]:29248130
[Au] Autor:Capoluongo E; Ellison G; López-Guerrero JA; Penault-Llorca F; Ligtenberg MJL; Banerjee S; Singer C; Friedman E; Markiefka B; Schirmacher P; Büttner R; van Asperen CJ; Ray-Coquard I; Endris V; Kamel-Reid S; Percival N; Bryce J; Röthlisberger B; Soong R; de Castro DG
[Ad] Endereço:Catholic University of the Sacred Heart and A. Gemelli Teaching Hospital Foundation, Rome, Italy.
[Ti] Título:Guidance Statement On BRCA1/2 Tumor Testing in Ovarian Cancer Patients.
[So] Source:Semin Oncol;44(3):187-197, 2017 06.
[Is] ISSN:1532-8708
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The approval, in 2015, of the first poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi; olaparib, Lynparza) for platinum-sensitive relapsed high-grade ovarian cancer with either germline or somatic BRCA1/2 deleterious mutations is changing the way that BRCA1/2 testing services are offered to patients with ovarian cancer. Ovarian cancer patients are now being referred for BRCA1/2 genetic testing for treatment decisions, in addition to familial risk estimation, and irrespective of a family history of breast or ovarian cancer. Furthermore, testing of tumor samples to identify the estimated 3%-9% of patients with somatic BRCA1/2 mutations who, in addition to germline carriers, could benefit from PARPi therapy is also now being considered. This new testing paradigm poses some challenges, in particular the technical and analytical difficulties of analyzing chemically challenged DNA derived from formalin-fixed, paraffin-embedded specimens. The current manuscript reviews some of these challenges and technical recommendations to consider when undertaking BRCA1/2 testing in tumor tissue samples to detect both germline and somatic BRCA1/2 mutations. Also provided are considerations for incorporating genetic analysis of ovarian tumor samples into the patient pathway and ethical requirements.
[Mh] Termos MeSH primário: Proteína BRCA1/genética
Proteína BRCA2/genética
Testes Genéticos
Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico
Neoplasias Ovarianas/genética
[Mh] Termos MeSH secundário: Feminino
Mutação em Linhagem Germinativa
Síndrome Hereditária de Câncer de Mama e Ovário/genética
Seres Humanos
Neoplasias Ovarianas/tratamento farmacológico
Ftalazinas/uso terapêutico
Piperazinas/uso terapêutico
Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
Guias de Prática Clínica como Assunto
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (BRCA1 Protein); 0 (BRCA1 protein, human); 0 (BRCA2 Protein); 0 (BRCA2 protein, human); 0 (Phthalazines); 0 (Piperazines); 0 (Poly(ADP-ribose) Polymerase Inhibitors); WOH1JD9AR8 (olaparib)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171218
[St] Status:MEDLINE


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[PMID]:29269176
[Au] Autor:Vignot S; André T; Caux C; Bouleuc C; Evrard S; Gonçalves A; Lacroix M; Magné N; Massard C; Mazeron JJ; Orbach D; Rodrigues M; Thariat J; Wislez M; L'Allemain G; Bay JO
[Ad] Endereço:Institut de cancérologie Jean-Godinot, département d'oncologie médicale, 1, rue du Général-Koenig, 51100 Reims, France. Electronic address: Stephane.VIGNOT@reims.unicancer.fr.
[Ti] Título:[Hot topics in 2017 in oncology and hematology. A selection by the editorial board of Bulletin du Cancer].
[Ti] Título:Les points chauds de l'actualité en 2017. Une sélection du comité de rédaction du Bulletin du Cancer..
[So] Source:Bull Cancer;105(1):6-14, 2018 Jan.
[Is] ISSN:1769-6917
[Cp] País de publicação:France
[La] Idioma:fre
[Ab] Resumo:Actuality was dense in 2017 for oncology and hematology. The editorial board of the Bulletin du Cancer proposes a selection of key data distinguishing four trends: precision medicine, immunotherapy, focus on early stages and global management of metastatic disease. A summary of results which have been published or presented in congresses is proposed and the impact on daily practices is discussed.
[Mh] Termos MeSH primário: Imunoterapia/tendências
Oncologia/tendências
Metástase Neoplásica/terapia
Neoplasias/terapia
Medicina de Precisão/tendências
[Mh] Termos MeSH secundário: Radioterapia com Íons Pesados/tendências
Seres Humanos
Neoplasias/patologia
Inibidores de Poli(ADP-Ribose) Polimerases
Terapia com Prótons/tendências
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Poly(ADP-ribose) Polymerase Inhibitors)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171223
[St] Status:MEDLINE


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[PMID]:29173760
[Au] Autor:Foy V; Schenk MW; Baker K; Gomes F; Lallo A; Frese KK; Forster M; Dive C; Blackhall F
[Ad] Endereço:Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, UK.
[Ti] Título:Targeting DNA damage in SCLC.
[So] Source:Lung Cancer;114:12-22, 2017 Dec.
[Is] ISSN:1872-8332
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:SCLC accounts for 15% of lung cancer worldwide. Characterised by early dissemination and rapid development of chemo-resistant disease, less than 5% of patients survive 5 years. Despite 3 decades of clinical trials there has been no change to the standard platinum and etoposide regimen for first line treatment developed in the 1970's. The exceptionally high number of genomic aberrations observed in SCLC combined with the characteristic rapid cellular proliferation results in accumulation of DNA damage and genomic instability. To flourish in this precarious genomic context, SCLC cells are reliant on functional DNA damage repair pathways and cell cycle checkpoints. Current cytotoxic drugs and radiotherapy treatments for SCLC have long been known to act by induction of DNA damage and the response of cancer cells to such damage determines treatment efficacy. Recent years have witnessed improved understanding of strategies to exploit DNA damage and repair mechanisms in order to increase treatment efficacy. This review will summarise the rationale to target DNA damage response in SCLC, the progress made in evaluating novel DDR inhibitors and highlight various ongoing challenges for their clinical development in this disease.
[Mh] Termos MeSH primário: Dano ao DNA/genética
Neoplasias Pulmonares/tratamento farmacológico
Rad51 Recombinase/antagonistas & inibidores
Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico
[Mh] Termos MeSH secundário: Aurora Quinases/uso terapêutico
Azepinas/uso terapêutico
Benzimidazóis/uso terapêutico
Carbolinas/uso terapêutico
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Pontos de Checagem do Ciclo Celular/genética
Proliferação Celular/efeitos dos fármacos
Proliferação Celular/genética
Citotoxinas/uso terapêutico
Dano ao DNA/efeitos dos fármacos
Reparo do DNA
Etoposídeo/uso terapêutico
Instabilidade Genômica/efeitos dos fármacos
Instabilidade Genômica/genética
Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico
Seres Humanos
Neoplasias Pulmonares/genética
Terapia de Alvo Molecular/métodos
Ftalazinas/uso terapêutico
Piperazinas/uso terapêutico
Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
Inibidores de Proteínas Quinases/uso terapêutico
Pirimidinas/uso terapêutico
Rad51 Recombinase/uso terapêutico
Carcinoma de Pequenas Células do Pulmão/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Azepines); 0 (Benzimidazoles); 0 (Carbolines); 0 (Cytotoxins); 0 (Heterocyclic Compounds, 4 or More Rings); 0 (MLN 8237); 0 (PM 01183); 0 (Phthalazines); 0 (Piperazines); 0 (Poly(ADP-ribose) Polymerase Inhibitors); 0 (Protein Kinase Inhibitors); 0 (Pyrimidines); 01O4K0631N (veliparib); 6PLQ3CP4P3 (Etoposide); 9QHX048FRV (talazoparib); EC 2.7.11.1 (Aurora Kinases); EC 2.7.7.- (Rad51 Recombinase); WOH1JD9AR8 (olaparib)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180131
[Lr] Data última revisão:
180131
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE


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[PMID]:28454587
[Au] Autor:Hu X; Huang W; Fan M
[Ad] Endereço:Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. huxicun@gmail.com.
[Ti] Título:Emerging therapies for breast cancer.
[So] Source:J Hematol Oncol;10(1):98, 2017 Apr 28.
[Is] ISSN:1756-8722
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:HER2 and CDK4/6 are undoubted two most important biological targets for breast cancer. Anti-HER2 treatments enhance objective response and progression-free survival/disease-free survival as well as overall survival. Three CDK4/6 inhibitors consistently improve objective response and progression-free survival; however, overall survival data are waited. Optimization of chemotherapy and endocrine strategies remains an unmet need. Check point inhibitor-based immunotherapy combined with chemotherapy is a promising field, especially for triple-negative breast cancer.
[Mh] Termos MeSH primário: Neoplasias da Mama/terapia
Terapias em Estudo
[Mh] Termos MeSH secundário: Anticorpos Monoclonais/uso terapêutico
Antineoplásicos Hormonais/uso terapêutico
Antineoplásicos Imunológicos/uso terapêutico
Neoplasias da Mama/tratamento farmacológico
Ensaios Clínicos como Assunto
Portadores de Fármacos
Estradiol/análogos & derivados
Estradiol/uso terapêutico
Feminino
Seres Humanos
Imunoconjugados/uso terapêutico
Imunoterapia/tendências
Imunoterapia Adotiva
Terapia de Alvo Molecular/tendências
Estudos Multicêntricos como Assunto
Proteínas de Neoplasias/antagonistas & inibidores
Piperazinas/uso terapêutico
Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
Inibidores de Proteínas Quinases/uso terapêutico
Piridinas/uso terapêutico
Moduladores de Tubulina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Antineoplastic Agents, Hormonal); 0 (Antineoplastic Agents, Immunological); 0 (Drug Carriers); 0 (Immunoconjugates); 0 (Neoplasm Proteins); 0 (Piperazines); 0 (Poly(ADP-ribose) Polymerase Inhibitors); 0 (Protein Kinase Inhibitors); 0 (Pyridines); 0 (Tubulin Modulators); 22X328QOC4 (fulvestrant); 4TI98Z838E (Estradiol); G9ZF61LE7G (palbociclib)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180112
[Lr] Data última revisão:
180112
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE
[do] DOI:10.1186/s13045-017-0466-3


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[PMID]:29207339
[Au] Autor:Saleeb M; Sundin C; Aglar Ö; Pinto AF; Ebrahimi M; Forsberg Å; Schüler H; Elofsson M
[Ad] Endereço:Department of Chemistry, Umeå University, 90187, Umeå, Sweden.
[Ti] Título:Structure-activity relationships for inhibitors of Pseudomonas aeruginosa exoenzyme S ADP-ribosyltransferase activity.
[So] Source:Eur J Med Chem;143:568-576, 2018 Jan 01.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:During infection, the Gram-negative opportunistic pathogen Pseudomonas aeruginosa employs its type III secretion system to translocate the toxin exoenzyme S (ExoS) into the eukaryotic host cell cytoplasm. ExoS is an essential in vivo virulence factor that enables P. aeruginosa to avoid phagocytosis and eventually kill the host cell. ExoS elicits its pathogenicity mainly via ADP-ribosyltransferase (ADPRT) activity. We recently identified a new class of ExoS ADPRT inhibitors with in vitro IC of around 20 µM in an enzymatic assay using a recombinant ExoS ADPRT domain. Herein, we report structure-activity relationships of this compound class by comparing a total of 51 compounds based on a thieno [2,3-d]pyrimidin-4(3H)-one and 4-oxo-3,4-dihydroquinazoline scaffolds. Improved inhibitors with in vitro IC values of 6 µM were identified. Importantly, we demonstrated that the most potent inhibitors block ADPRT activity of native full-length ExoS secreted by viable P. aeruginosa with an IC value of 1.3 µM in an enzymatic assay. This compound class holds promise as starting point for development of novel antibacterial agents.
[Mh] Termos MeSH primário: ADP Ribose Transferases/antagonistas & inibidores
Toxinas Bacterianas/antagonistas & inibidores
Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
Pseudomonas aeruginosa/enzimologia
Pirimidinonas/farmacologia
Quinazolinas/farmacologia
[Mh] Termos MeSH secundário: ADP Ribose Transferases/metabolismo
Toxinas Bacterianas/metabolismo
Relação Dose-Resposta a Droga
Estrutura Molecular
Inibidores de Poli(ADP-Ribose) Polimerases/síntese química
Inibidores de Poli(ADP-Ribose) Polimerases/química
Pirimidinonas/síntese química
Pirimidinonas/química
Quinazolinas/síntese química
Quinazolinas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (4-oxo-3,4-dihydroquinazoline); 0 (Bacterial Toxins); 0 (Poly(ADP-ribose) Polymerase Inhibitors); 0 (Pyrimidinones); 0 (Quinazolines); 0 (thieno(2,3-d)pyrimidin-4(3H)-one); EC 2.4.2.- (ADP Ribose Transferases); EC 2.4.2.31 (exoenzyme S)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180110
[Lr] Data última revisão:
180110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171206
[St] Status:MEDLINE


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[PMID]:29202431
[Au] Autor:Lee A; Djamgoz MBA
[Ad] Endereço:Faculty of Medicine, Imperial College London, South Kensington Campus, London SW7 2AZ, UK.
[Ti] Título:Triple negative breast cancer: Emerging therapeutic modalities and novel combination therapies.
[So] Source:Cancer Treat Rev;62:110-122, 2018 Jan.
[Is] ISSN:1532-1967
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Triple negative breast cancer (TNBC) is a complex and aggressive subtype of breast cancer which lacks oestrogen receptors, progesterone receptors and HER2 amplification, thereby making it difficult to target therapeutically. In addition, TNBC has the highest rates of metastatic disease and the poorest overall survival of all breast cancer subtypes. Resultantly, development of targeted therapies for TNBC is urgently needed. Recent efforts aimed at molecular characterisation of TNBCs have revealed various emerging therapeutic targets including PARP1, receptor and non-receptor tyrosine kinases, immune-checkpoints, androgen receptor and epigenetic proteins. Key successes include that of the PARP inhibitor, olaparib, which prolonged progression-free survival in a trial of BRCA-mutated breast cancer and for which clinical approval (in this setting) appears imminent. Nevertheless, the heterogeneity of TNBC has limited the clinical benefits of many trialled therapies in 'unselected' patients. Further, drug resistance develops following use of many targeted monotherapies due to upregulation of compensatory signalling pathways. In this review, we evaluate the current status of investigational targeted treatments and present evidence for the role of novel biomarkers and combination therapies in increasing response rates and circumventing drug-induced resistance. Additionally, we discuss promising novel targets in metastatic TNBC identified through preclinical and/or epidemiological studies.
[Mh] Termos MeSH primário: Antagonistas Adrenérgicos beta/uso terapêutico
Antagonistas de Receptores de Andrógenos/uso terapêutico
Inibidores da Angiogênese/uso terapêutico
Antineoplásicos Imunológicos/uso terapêutico
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Carcinoma/tratamento farmacológico
Inibidores de Histona Desacetilases/uso terapêutico
Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
Inibidores de Proteínas Quinases/uso terapêutico
Neoplasias de Mama Triplo Negativas/tratamento farmacológico
[Mh] Termos MeSH secundário: Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Adrenergic beta-Antagonists); 0 (Androgen Receptor Antagonists); 0 (Angiogenesis Inhibitors); 0 (Antineoplastic Agents, Immunological); 0 (Histone Deacetylase Inhibitors); 0 (Poly(ADP-ribose) Polymerase Inhibitors); 0 (Protein Kinase Inhibitors)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180102
[Lr] Data última revisão:
180102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE


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[PMID]:29087384
[Au] Autor:Schlacher K
[Ad] Endereço:Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
[Ti] Título:PARPi focus the spotlight on replication fork protection in cancer.
[So] Source:Nat Cell Biol;19(11):1309-1310, 2017 Oct 31.
[Is] ISSN:1476-4679
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:PARP inhibitors (PARPi) kill BRCA1/2-mutated cancers, which become resistant when DNA repair functions are restored. Now, MUS81 nuclease inhibition due to EZH2 downregulation is found to restore DNA replication fork protection but not repair, leading to PARPi-resistance in mutant BRCA2 cells and patients. This challenges the DNA repair dominance in synthetic lethality.
[Mh] Termos MeSH primário: Replicação do DNA/efeitos dos fármacos
Neoplasias/tratamento farmacológico
Neoplasias/genética
Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
Poli(ADP-Ribose) Polimerases/metabolismo
[Mh] Termos MeSH secundário: Proteína BRCA1/genética
Proteína BRCA2/genética
Dano ao DNA/efeitos dos fármacos
Dano ao DNA/genética
Reparo do DNA/efeitos dos fármacos
Reparo do DNA/genética
Replicação do DNA/genética
Regulação para Baixo/efeitos dos fármacos
Regulação para Baixo/genética
Proteína Potenciadora do Homólogo 2 de Zeste/genética
Seres Humanos
Neoplasias/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BRCA1 Protein); 0 (BRCA1 protein, human); 0 (BRCA2 Protein); 0 (BRCA2 protein, human); 0 (Poly(ADP-ribose) Polymerase Inhibitors); EC 2.1.1.43 (EZH2 protein, human); EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein); EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
[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:171101
[St] Status:MEDLINE
[do] DOI:10.1038/ncb3638


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[PMID]:29064327
[Au] Autor:Chen T; Liu C; Lu H; Yin M; Shao C; Hu X; Wu J; Wang Y
[Ad] Endereço:1 Department of Oncology, Changhai Hospital, The Second Military Medical University, Shanghai, China.
[Ti] Título:The expression of APE1 in triple-negative breast cancer and its effect on drug sensitivity of olaparib.
[So] Source:Tumour Biol;39(10):1010428317713390, 2017 Oct.
[Is] ISSN:1423-0380
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Triple-negative breast cancer is a kind of breast cancer with poor prognosis and special biological behavior, which lacked endocrine therapy and targeted therapy. We investigate the effect of human APE1 (apurinic/apyrimidyl endonuclease 1), a rate-limiting enzyme of base excision repair, on the prognosis in triple-negative breast cancer and drug sensitivity of olaparib. The expression of APE1 was detected by immunohistochemistry in the triple-negative breast cancer tissues and its effect on survival of triple-negative breast cancer patients was followed. To find whether APE1 effect the drug sensitivity in triple-negative breast cancer cells, the APE1-knockout HCC1937 cell line (triple-negative breast cancer cell line) was established by CRISPR/Cas9 system. Then, we use the wild-type and knockout one to test the drug sensitivity of olaparib. The expression of APE1 in triple-negative breast cancer tissues was significantly higher than that in the adjacent tissues (85.6% vs 14.4%) and its expression was related to tumor size (p < 0.05). We also found that it is an independent prognostic factor in patients with triple-negative breast cancer (overall survival, p = 0.01). In vitro assay, the half maximal inhibitory concentration of olaparib in HCC1937-APE1-KO was significantly increased (17.22 vs 91.85 µM) compared to the wild type. The growth curve showed that olaparib had a stronger lethality on HCC1937 compared to HCC1937- APE1-KO (p < 0.05 on day 3). HCC1937 resulted in more mitotic G2/M arrest and increased apoptosis rate after treatment with 40 µM of olaparib, while HCC1937-APE1-KO did not change significantly. When HCC1937 was treated with different concentrations of olaparib, it was found that APE1 expression decreased more significantly at 15 µM of olaparib was. In HCC1937-APE1-KO, the expression of endogenous poly (ADP-ribose) polymerase 1 was also less than that of HCC1937. These results suggested that the expression of APE1 was an important basis for the maintenance of poly (ADP-ribose) polymerase 1, and the deletion of APE1 may be related to the resistance of olaparib.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo
Resistência a Medicamentos Antineoplásicos/fisiologia
Ftalazinas/farmacologia
Piperazinas/farmacologia
Neoplasias de Mama Triplo Negativas/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Apoptose/efeitos dos fármacos
Apoptose/fisiologia
Linhagem Celular Tumoral
Feminino
Citometria de Fluxo
Técnicas de Inativação de Genes
Seres Humanos
Imuno-Histoquímica
Concentração Inibidora 50
Estimativa de Kaplan-Meier
Meia-Idade
Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
Poli(ADP-Ribose) Polimerases/metabolismo
Prognóstico
Modelos de Riscos Proporcionais
Análise Serial de Tecidos
Neoplasias de Mama Triplo Negativas/tratamento farmacológico
Neoplasias de Mama Triplo Negativas/mortalidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Phthalazines); 0 (Piperazines); 0 (Poly(ADP-ribose) Polymerase Inhibitors); EC 2.4.2.30 (Poly(ADP-ribose) Polymerases); EC 4.2.99.18 (APEX1 protein, human); EC 4.2.99.18 (DNA-(Apurinic or Apyrimidinic Site) Lyase); WOH1JD9AR8 (olaparib)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171025
[St] Status:MEDLINE
[do] DOI:10.1177/1010428317713390



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