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[PMID]:27233754
[Au] Autor:Kirby MA; Heuerman AC; Custer M; Dobyns AE; Strilaeff R; Stutz KN; Cooperrider J; Elsissy JG; Yellon SM
[Ad] Endereço:Center for Perinatal Biology, School of Medicine, Loma Linda University, Loma Linda, CA, USA Departments of Pathology and Human anatomy, and Pediatrics, School of Medicine, Loma Linda University, Loma Linda, CA, USA.
[Ti] Título:Progesterone Receptor-Mediated Actions Regulate Remodeling of the Cervix in Preparation for Preterm Parturition.
[So] Source:Reprod Sci;23(11):1473-1483, 2016 Nov.
[Is] ISSN:1933-7205
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:This study determined whether a progesterone (P) receptor (PR)-mediated mechanism regulates morphological characteristics associated with prepartum cervix remodeling at term and with preterm birth. With focus on the transition from a soft to ripe cervix, the cervix stroma of untreated controls had reduced cell nuclei density/area and less organized extracellular collagen, while the density of macrophages/area, but not neutrophils, increased just 2 days before birth (day 17 vs day 15 or 16.5 postbreeding). Preterm birth was induced within 24 hours of treatment on day 16 postbreeding with PR antagonist or ovariectomy (Ovx). Pure or mixed PR antagonists increased the density of macrophages in the cervix within 8 hours (day 16.5 postbreeding), in advance of preterm birth. However, neither PR antagonists nor P withdrawal after Ovx affected the densities of cell nuclei and neutrophils or extracellular collagen compared to the same day controls-an indication that the cervix was sufficiently remodeled for birth to occur. To block the effect of systemic P withdrawal, Ovx pregnant mice were given a PR agonist, either pure or mixed. These treatments forestalled preterm birth and prevented further morphological remodeling of the cervix. The resulting increase in macrophage density in cervix stroma following Ovx was only blocked by a pure PR agonist. These findings support the hypothesis that inflammatory processes in the prepartum cervix that include residency of macrophages, cellular hypertrophy, and extracellular collagen structure are regulated by genomic actions of PR in a final common mechanism both at term and with induced preterm birth.
[Mh] Termos MeSH primário: Maturidade Cervical
Colo do Útero/fisiologia
Nascimento Prematuro/fisiopatologia
Receptores de Progesterona/fisiologia
[Mh] Termos MeSH secundário: Animais
Contagem de Células
Maturidade Cervical/efeitos dos fármacos
Colo do Útero/citologia
Colo do Útero/efeitos dos fármacos
Feminino
Gonanos/administração & dosagem
Macrófagos/citologia
Macrófagos/efeitos dos fármacos
Camundongos
Mifepristona/administração & dosagem
Neutrófilos/citologia
Neutrófilos/efeitos dos fármacos
Ovariectomia
Gravidez
Nascimento Prematuro/induzido quimicamente
Nascimento Prematuro/patologia
Receptores de Progesterona/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Gonanes); 0 (Receptors, Progesterone); 320T6RNW1F (Mifepristone); H6H7G23O3N (onapristone)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160529
[St] Status:MEDLINE


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[PMID]:27118441
[Au] Autor:Bowles DW; Kochenderfer M; Cohn A; Sideris L; Nguyen N; Cline-Burkhardt V; Schnadig I; Choi M; Nabell L; Chaudhry A; Ruxer R; Ucar A; Hausman D; Walker L; Spira A; Jimeno A
[Ad] Endereço:Denver Veterans Affairs Medical Center, Denver, CO; Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO. Electronic address: daniel.bowles@ucdenver.edu.
[Ti] Título:A Randomized, Phase II Trial of Cetuximab With or Without PX-866, an Irreversible Oral Phosphatidylinositol 3-Kinase Inhibitor, in Patients With Metastatic Colorectal Carcinoma.
[So] Source:Clin Colorectal Cancer;15(4):337-344.e2, 2016 Dec.
[Is] ISSN:1938-0674
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase/mammalian target of rapamycin signaling pathway is frequently altered in colorectal cancer (CRC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. This randomized phase II study evaluated cetuximab with or without PX-866 in patients with metastatic, anti-epidermal growth factor receptor-naive, KRAS codon 12 and 13 wild-type CRC. PATIENTS AND METHODS: Patients with metastatic CRC who had received both oxaliplatin and irinotecan were randomized (1:1) to cetuximab (400 mg/m loading then 250 mg/m weekly) with or without PX-866 (8 mg orally daily; arms A and B, respectively). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate, overall survival (OS), toxicity, and correlation of relevant biomarkers with efficacy outcomes. RESULTS: A total of 85 patients were enrolled. The median PFS was 59 days versus 104 days for arms A (cetuximab + PX-866) and B (cetuximab alone), respectively (P = .77). OS between the 2 arms (266 vs. 333 days for arm A vs. B) were similar (P = .83). Overall toxicity, including treatment-related toxicity, was higher in arm A compared with arm B, especially in terms of all-grade nausea (66% vs. 37%), vomiting (50% vs. 29%), diarrhea (64% vs. 18%), and rash (66% vs. 37%). Grade 3 diarrhea occurred in 19% of patients in Arm A and 0% in Arm B. PIK3CA mutations and PTEN loss by immunohistochemistry were infrequently seen. CONCLUSION: The addition of PX-866 to cetuximab did not improve PFS, objective response rate, or OS in patients with metastatic CRC. The combination arm had greater toxicity and may have been harmful in this study.
[Mh] Termos MeSH primário: Adenocarcinoma/tratamento farmacológico
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Cetuximab/administração & dosagem
Neoplasias Colorretais/tratamento farmacológico
Gonanos/administração & dosagem
[Mh] Termos MeSH secundário: Adenocarcinoma/mortalidade
Adulto
Idoso
Idoso de 80 Anos ou mais
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
Cetuximab/efeitos adversos
Neoplasias Colorretais/mortalidade
Intervalo Livre de Doença
Feminino
Gonanos/efeitos adversos
Seres Humanos
Estimativa de Kaplan-Meier
Masculino
Meia-Idade
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Gonanes); 0 (PX-866); PQX0D8J21J (Cetuximab)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160428
[St] Status:MEDLINE


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[PMID]:27017931
[Au] Autor:Peek GW; Tollefsbol TO
[Ad] Endereço:Department of Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
[Ti] Título:Down-regulation of hTERT and Cyclin D1 transcription via PI3K/Akt and TGF-ß pathways in MCF-7 Cancer cells with PX-866 and Raloxifene.
[So] Source:Exp Cell Res;344(1):95-102, 2016 May 15.
[Is] ISSN:1090-2422
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human telomerase reverse transcriptase (hTERT) is the catalytic and limiting component of telomerase and also a transcription factor. It is critical to the integrity of the ends of linear chromosomes and to the regulation, extent and rate of cell cycle progression in multicellular eukaryotes. The level of hTERT expression is essential to a wide range of bodily functions and to avoidance of disease conditions, such as cancer, that are mediated in part by aberrant level and regulation of cell cycle proliferation. Value of a gene in regulation depends on its ability to both receive input from multiple sources and transmit signals to multiple effectors. The expression of hTERT and the progression of the cell cycle have been shown to be regulated by an extensive network of gene products and signaling pathways, including the PI3K/Akt and TGF-ß pathways. The PI3K inhibitor PX-866 and the competitive estrogen receptor ligand raloxifene have been shown to modify progression of those pathways and, in combination, to decrease proliferation of estrogen receptor positive (ER+) MCF-7 breast cancer cells. We found that combinations of modulators of those pathways decreased not only hTERT transcription but also transcription of additional essential cell cycle regulators such as Cyclin D1. By evaluating known expression profile signatures for TGF-ß pathway diversions, we confirmed additional genes such as heparin-binding epidermal growth factor-like growth factor (HB EGF) by which those pathways and their perturbations may also modify cell cycle progression.
[Mh] Termos MeSH primário: Ciclina D1/genética
Regulação para Baixo/efeitos dos fármacos
Gonanos/farmacologia
Cloridrato de Raloxifeno/farmacologia
Transdução de Sinais/efeitos dos fármacos
Telomerase/genética
Transcrição Genética/efeitos dos fármacos
Fator de Crescimento Transformador beta/metabolismo
[Mh] Termos MeSH secundário: Proteína Axina/genética
Proteína Axina/metabolismo
Proliferação Celular/efeitos dos fármacos
Ciclina D1/metabolismo
Inibidor de Quinase Dependente de Ciclina p21/genética
Inibidor de Quinase Dependente de Ciclina p21/metabolismo
Perfilação da Expressão Gênica
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Immunoblotting
Células MCF-7
Fosfatidilinositol 3-Quinases/metabolismo
Fosforilação/efeitos dos fármacos
Proteínas Proto-Oncogênicas c-akt/metabolismo
Proteínas Proto-Oncogênicas c-mdm2/metabolismo
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Reação em Cadeia da Polimerase em Tempo Real
Proteínas Smad/metabolismo
Telomerase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AXIN2 protein, human); 0 (Axin Protein); 0 (CCND1 protein, human); 0 (CDKN1A protein, human); 0 (Cyclin-Dependent Kinase Inhibitor p21); 0 (Gonanes); 0 (PX-866); 0 (RNA, Messenger); 0 (Smad Proteins); 0 (Transforming Growth Factor beta); 136601-57-5 (Cyclin D1); 4F86W47BR6 (Raloxifene Hydrochloride); EC 2.3.2.27 (MDM2 protein, human); EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.7.49 (TERT protein, human); EC 2.7.7.49 (Telomerase)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170806
[Lr] Data última revisão:
170806
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160329
[St] Status:MEDLINE


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[PMID]:26850518
[Au] Autor:Shannan B; Chen Q; Watters A; Perego M; Krepler C; Thombre R; Li L; Rajan G; Peterson S; Gimotty PA; Wilson M; Nathanson KL; Gangadhar TC; Schuchter LM; Weeraratna AT; Herlyn M; Vultur A
[Ad] Endereço:Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
[Ti] Título:Enhancing the evaluation of PI3K inhibitors through 3D melanoma models.
[So] Source:Pigment Cell Melanoma Res;29(3):317-28, 2016 May.
[Is] ISSN:1755-148X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Targeted therapies for mutant BRAF metastatic melanoma are effective but not curative due to acquisition of resistance. PI3K signaling is a common mediator of therapy resistance in melanoma; thus, the need for effective PI3K inhibitors is critical. However, testing PI3K inhibitors in adherent cultures is not always reflective of their potential in vivo. To emphasize this, we compared PI3K inhibitors of different specificity in two- and three-dimensional (2D, 3D) melanoma models and show that drug response predictions gain from evaluation using 3D models. Our results in 3D demonstrate the anti-invasive potential of PI3K inhibitors and that drugs such as PX-866 have beneficial activity in physiological models alone and when combined with BRAF inhibition. These assays finally help highlight pathway effectors that could be involved in drug response in different environments (e.g. p4E-BP1). Our findings show the advantages of 3D melanoma models to enhance our understanding of PI3K inhibitors.
[Mh] Termos MeSH primário: Melanoma/patologia
Modelos Biológicos
Fosfatidilinositol 3-Quinases/antagonistas & inibidores
Inibidores de Proteínas Quinases/farmacologia
[Mh] Termos MeSH secundário: Animais
Adesão Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Colágeno/farmacologia
Gonanos/farmacologia
Indóis/farmacologia
Melanoma/enzimologia
Camundongos Endogâmicos NOD
Mutação/genética
Fosfatidilinositol 3-Quinases/metabolismo
Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores
Proteínas Proto-Oncogênicas B-raf/metabolismo
Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-akt/metabolismo
Transdução de Sinais/efeitos dos fármacos
Esferoides Celulares/efeitos dos fármacos
Esferoides Celulares/patologia
Sulfonamidas/farmacologia
Microambiente Tumoral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Gonanes); 0 (Indoles); 0 (PLX 4720); 0 (PX-866); 0 (Protein Kinase Inhibitors); 0 (Sulfonamides); 9007-34-5 (Collagen); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins B-raf); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170501
[Lr] Data última revisão:
170501
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160207
[St] Status:MEDLINE
[do] DOI:10.1111/pcmr.12465


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[PMID]:26660119
[Au] Autor:Peek GW; Tollefsbol TO
[Ad] Endereço:Department of Biology, University of Alabama, Birmingham, Alabama.
[Ti] Título:Combinatorial PX-866 and Raloxifene Decrease Rb Phosphorylation, Cyclin E2 Transcription, and Proliferation of MCF-7 Breast Cancer Cells.
[So] Source:J Cell Biochem;117(7):1688-96, 2016 07.
[Is] ISSN:1097-4644
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:As a potential means to reduce proliferation of breast cancer cells, a multiple-pathway approach with no effect on control cells was explored. The human interactome being constructed by the Center for Cancer Systems Biology will prove indispensable to understanding composite effects of multiple pathways, but its discovered protein-protein interactions require characterization. Accordingly, we explored the effects of regulators of one protein on downstream targets of the other protein. MCF-7 estrogen receptor-positive (ER+) breast cancer cells were treated with raloxifene to upregulate the TGF-ß pathway and PX-866 to down-regulate the PI3K/Akt pathway. This resulted in highly significant downstream reduction of cell cycle proliferation in breast cancer cells with no significant proliferation reduction following similar treatment of noncancerous MCF10A breast epithelial cells. Reduced phosphorylation of p107 and substantial reduction of Rb phosphorylation were observed in response. The effects of reduced Rb and p107 phosphorylation were reflected in significant decline in E2F-1 transcriptional activity, which is dependent on pocket protein phosphorylation status. The reduced proliferation was related to decreased expression of cyclins, including E2F-1-regulated Cyclin E2, which was also in response to raloxifene and PX-866. All combinations of raloxifene and PX-866 produced significant or highly significant results for reduced MCF-7 cell proliferation, reduced Cyclin E2 transcription, and reduced Rb phosphorylation. These studies demonstrated that uncontrolled proliferation of ER+ breast cancer cells can be significantly reduced by combinational targeting of two relevant pathways. J. Cell. Biochem. 117: 1688-1696, 2016. © 2015 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Neoplasias da Mama
Proliferação Celular/efeitos dos fármacos
Ciclinas/biossíntese
Gonanos/farmacologia
Cloridrato de Raloxifeno/farmacologia
Proteína do Retinoblastoma/metabolismo
Transcrição Genética/efeitos dos fármacos
[Mh] Termos MeSH secundário: Neoplasias da Mama/tratamento farmacológico
Neoplasias da Mama/metabolismo
Neoplasias da Mama/patologia
Fator de Transcrição E2F1/metabolismo
Feminino
Seres Humanos
Células MCF-7
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (CCNE2 protein, human); 0 (Cyclins); 0 (E2F1 Transcription Factor); 0 (E2F1 protein, human); 0 (Gonanes); 0 (PX-866); 0 (Retinoblastoma Protein); 4F86W47BR6 (Raloxifene Hydrochloride)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151215
[St] Status:MEDLINE
[do] DOI:10.1002/jcb.25462


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[PMID]:26652902
[Au] Autor:Treviño LS; Bolt MJ; Grimm SL; Edwards DP; Mancini MA; Weigel NL
[Ad] Endereço:Departments of Molecular and Cellular Biology (L.S.T., M.J.B., S.L.G., D.P.E., M.A.M., N.L.W.) and Pathology and Immunology (S.L.G., D.P.E.), Baylor College of Medicine, Houston, Texas 77030.
[Ti] Título:Differential Regulation of Progesterone Receptor-Mediated Transcription by CDK2 and DNA-PK.
[So] Source:Mol Endocrinol;30(2):158-72, 2016 Feb.
[Is] ISSN:1944-9917
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Progesterone receptor (PR) function is altered by cell signaling, but the mechanisms of kinase-specific regulation are not well defined. To examine the role of cell signaling in the regulation of PR transcriptional activity, we have utilized a previously developed mammalian-based estrogen-response element promoter array cell model and automated cell imaging and analysis platform to visualize and quantify effects of specific kinases on different mechanistic steps of PR-mediated target gene activation. For these studies, we generated stable estrogen-response element array cell lines expressing inducible chimeric PR that contains a swap of the estrogen receptor-α DNA-binding domain for the DNA-binding domain of PR. We have focused on 2 kinases important for steroid receptor activity: cyclin-dependent kinase 2 and DNA-dependent protein kinase. Treatment with either a Cdk1/2 inhibitor (NU6102) or a DNA-dependent protein kinase inhibitor (NU7441) decreased hormone-mediated chromatin decondensation and transcriptional activity. Further, we observed a quantitative reduction in the hormone-mediated recruitment of select coregulator proteins with NU6102 that is not observed with NU7441. In parallel, we determined the effect of kinase inhibition on hormone-mediated induction of primary and mature transcripts of endogenous genes in T47D breast cancer cells. Treatment with NU6102 was much more effective than NU7441, in inhibiting induction of PR target genes that exhibit a rapid increase in primary transcript expression in response to hormone. Taken together, these results indicate that the 2 kinases regulate PR transcriptional activity by distinct mechanisms.
[Mh] Termos MeSH primário: Quinase 2 Dependente de Ciclina/metabolismo
Proteína Quinase Ativada por DNA/metabolismo
Receptores de Progesterona/metabolismo
Transcrição Genética
[Mh] Termos MeSH secundário: Cromonas/farmacologia
Gonanos/farmacologia
Células HeLa
Seres Humanos
Complexo Mediador/metabolismo
Mifepristona/farmacologia
Modelos Biológicos
Morfolinas/farmacologia
Promegestona/farmacologia
Purinas/farmacologia
Proteínas Recombinantes/metabolismo
Transcrição Genética/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one); 0 (Chromones); 0 (Gonanes); 0 (Mediator Complex); 0 (Morpholines); 0 (NU6102); 0 (Purines); 0 (Receptors, Progesterone); 0 (Recombinant Proteins); 320T6RNW1F (Mifepristone); 9XE0V2SQYX (Promegestone); EC 2.7.11.1 (DNA-Activated Protein Kinase); EC 2.7.11.22 (CDK2 protein, human); EC 2.7.11.22 (Cyclin-Dependent Kinase 2); H6H7G23O3N (onapristone)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:170201
[Lr] Data última revisão:
170201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151215
[St] Status:MEDLINE
[do] DOI:10.1210/me.2015-1144


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[PMID]:26256696
[Au] Autor:Blanco B; Herrero-Sánchez C; Rodríguez-Serrano C; Sánchez-Barba M; Del Cañizo MC
[Ad] Endereço:Department of Hematology, Hospital Universitario de Salamanca/Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain. Electronic address: bblancod@saludcastillayleon.es.
[Ti] Título:Comparative effect of two pan-class I PI3K inhibitors used as anticancer drugs on human T cell function.
[So] Source:Int Immunopharmacol;28(1):675-85, 2015 Sep.
[Is] ISSN:1878-1705
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The phosphatidylinositol 3-kinase (PI3K) pathway is commonly deregulated in cancer and, thus, PI3K has been recognized as an attractive molecular target for novel anti-cancer therapies. However, the effect of PI3K inhibitors on T-cell function, a key component of antitumor immunity, has been scantly explored. The objective of this study was to investigate the effect on human T-cell activation of two PI3K inhibitors currently being tested in clinical trials: PX-866 and BKM120. Their activity against a leukemic T cell line was also assessed. For that purpose, Jurkat cells or anti-CD3/anti-CD28 stimulated human peripheral blood mononuclear cells were cultured in the presence of different concentrations of PX-866 or BKM120 and their effect on T-cell proliferation, apoptosis, expression of activation markers and cytokine secretion was analyzed by flow cytometry. In addition, Akt and Erk phosphorylation was analyzed by Western blotting. Both PX-866 and BKM120 decreased viability of Jurkat cells and blocked cell cycle progression. Regarding primary T cells, both compounds similarly inhibited expression of activation markers and cytokine secretion, although they did not induce apoptosis of stimulated T cells. Interestingly, we found differences in their ability to block T-cell proliferation and IL-2 secretion, exerting BKM120 a more potent inhibition. These disparate effects could be related to differences observed in PI3K/Akt and RAS/MEK/ERK signaling between PX-866 and BKM120 treated cells. Our results suggest that, when selecting a PI3K inhibitor for cancer therapy, immunosuppressive characteristics should be taken into account in order to minimize detrimental effects on immune function.
[Mh] Termos MeSH primário: Aminopiridinas/farmacologia
Antineoplásicos/farmacologia
Inibidores Enzimáticos/farmacologia
Gonanos/farmacologia
Morfolinas/farmacologia
Fosfatidilinositol 3-Quinases/antagonistas & inibidores
Linfócitos T/efeitos dos fármacos
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Técnicas de Cultura de Células
Ciclo Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Seres Humanos
Interleucina-2/secreção
Células Jurkat
Ativação Linfocitária/efeitos dos fármacos
Linfócitos T/imunologia
Células Th1/efeitos dos fármacos
Células Th1/imunologia
Células Th2/efeitos dos fármacos
Células Th2/imunologia
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Aminopyridines); 0 (Antineoplastic Agents); 0 (Enzyme Inhibitors); 0 (Gonanes); 0 (Interleukin-2); 0 (Morpholines); 0 (NVP-BKM120); 0 (PX-866); EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:150831
[Lr] Data última revisão:
150831
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150811
[St] Status:MEDLINE


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[PMID]:26245909
[Au] Autor:Zheng X; Li W; Lan Z; Yang X; Li L; Yuan Y; Xia Z; Chen X; Zhang X; Yu Y
[Ad] Endereço:Department of Pharmacy, Chongqing Medical and Pharmaceutical College, Chongqing, China.
[Ti] Título:Antitumour effects of tetrazanbigen against human hepatocellular carcinoma QGY-7701 through inducing lipid accumulation in vitro and in vivo.
[So] Source:J Pharm Pharmacol;67(11):1593-602, 2015 Nov.
[Is] ISSN:2042-7158
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: Tetrazanbigen (TNBG) is a newly synthesized compound with an isoquinoline moiety, and its antitumour effects were evaluated in in-vitro and in-vivo models. METHODS: 3-[4, 5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay was used to measure the antiproliferative activity of TNBG on cancer cell lines. Antitumour activity of TNGB in vivo was also assessed in a xenograft model of human hepatocellular carcinoma QGY-7701 cell line. Cell cycle and cell apoptosis analysis was performed. KEY FINDINGS: TNBG exhibited strong antitumour efficacy against six human cancer cell lines with IC50 range of 2.13-8.01 µg/ml. The IC50 of TNBG on normal hepatic cells was 11.25 µg/ml. Lots of lipid droplets were observed in cytoplasm of human hepatocellular carcinoma QGY-7701 cells after treatment of TNBG. S phase arrest and apoptosis induction by TNBG were also found on QGY-7701 cells. Intraperitoneal injection of TNBG (1.5 mg/kg/day) resulted in significant decreases in tumour volume and tumour weight on nude mice bearing QGY-7701 cells xenografts. Results from pathological analysis in nude mice demonstrated that TNBG could induce lipid accumulation specifically in cancer tissue rather than in other normal organs, tissues and blood. CONCLUSIONS: These results suggested that TNBG might exert potent antitumour activity through inducing lipid accumulation in cancer cell.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Compostos Azo/farmacologia
Carcinoma Hepatocelular/tratamento farmacológico
Gonanos/farmacologia
Neoplasias Hepáticas/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/administração & dosagem
Apoptose/efeitos dos fármacos
Compostos Azo/administração & dosagem
Carcinoma Hepatocelular/patologia
Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Feminino
Gonanos/administração & dosagem
Seres Humanos
Concentração Inibidora 50
Lipídeos/química
Neoplasias Hepáticas/patologia
Camundongos
Camundongos Nus
Neoplasias/tratamento farmacológico
Neoplasias/patologia
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Azo Compounds); 0 (Gonanes); 0 (Lipids); 0 (tetrazanbigen)
[Em] Mês de entrada:1607
[Cu] Atualização por classe:151016
[Lr] Data última revisão:
151016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150807
[St] Status:MEDLINE
[do] DOI:10.1111/jphp.12467


  9 / 359 MEDLINE  
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[PMID]:26170259
[Au] Autor:Nichol D; Mellinghoff IK
[Ad] Endereço:Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (D.N., I.K.M.); Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York (I.K.M.); Department of Pharmacology, Weill-Cornell Graduate School of Biomedical Sciences, New York, New York (I.K.M.).
[Ti] Título:PI3K pathway inhibition in GBM­is there a signal?
[So] Source:Neuro Oncol;17(9):1183-4, 2015 Sep.
[Is] ISSN:1523-5866
[Cp] País de publicação:England
[La] Idioma:eng
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Neoplasias Encefálicas/tratamento farmacológico
Neoplasias Encefálicas/radioterapia
Dacarbazina/análogos & derivados
Everolimo/uso terapêutico
Glioblastoma/tratamento farmacológico
Glioblastoma/radioterapia
Gonanos/uso terapêutico
[Mh] Termos MeSH secundário: Feminino
Seres Humanos
Masculino
[Pt] Tipo de publicação:COMMENT; EDITORIAL; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Gonanes); 7GR28W0FJI (Dacarbazine); 9HW64Q8G6G (Everolimus)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150715
[St] Status:MEDLINE
[do] DOI:10.1093/neuonc/nov124


  10 / 359 MEDLINE  
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[PMID]:26006702
[Au] Autor:Rezai K; Chassard D; Denot C; Proniuk S; Zukiwski A; Gilles E; Ramos HL; Patat A; Bexon A; Lokiec F
[Ad] Endereço:Radiopharmacology Department, Institut Curie, Saint Cloud, France, keyvan.rezai@curie.fr.
[Ti] Título:A single-dose PK study of onapristone including the effect of food on absorption.
[So] Source:Cancer Chemother Pharmacol;76(1):171-7, 2015 Jul.
[Is] ISSN:1432-0843
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Onapristone is an antiprogestin with activity in breast cancer and is under investigation for use in endometrial, ovarian and prostate cancers. Megestrol acetate and abiraterone generally show variability in absorption and, depending on the formulation, food effect. This study was conducted to determine the effect of food on 10 mg oral immediate-release (IR) onapristone and to help identify a formulation to minimize variability. METHODS: This is an open-label, randomized, crossover study to determine the pharmacokinetic profile of onapristone and its main metabolite, N-mono-desmethyl onapristone. Twelve healthy female subjects received 10 mg of oral IR onapristone after an overnight fast, or within 30 min of a high-fat, high-calorie meal with a 2-week washout between dosing periods. RESULTS: Onapristone plasma t1/2 (mean ± SD) was 4.36 ± 0.81 h for the fasted state and 3.76 ± 0.36 h for the fed state. Following food, onapristone tmax was delayed from 1 to 4 h. Food intake was also associated with a small increase in AUC0-∞ of approximately 13 % and a statistically significant decrease in Cmax of approximately 18 %. One subject experienced a 23-day delay in menses after one 10 mg onapristone dose, while another subject experienced transient grade 2 NCI-CTCAE liver enzyme elevation 3 weeks post dose. CONCLUSION: The results are consistent with previous observations, indicating that there is a small increase in onapristone exposure and a significant decrease in Cmax when taken with food. These changes are within acceptable limits set out by the FDA. Thus, our findings indicate that onapristone could be administered without regard to food.
[Mh] Termos MeSH primário: Antineoplásicos/farmacocinética
Interações Alimento-Droga
Gonanos/farmacocinética
[Mh] Termos MeSH secundário: Adulto
Antineoplásicos/sangue
Estudos Cross-Over
Jejum/sangue
Jejum/metabolismo
Feminino
Gonanos/sangue
Seres Humanos
Absorção Intestinal
Estrutura Molecular
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Gonanes); H6H7G23O3N (onapristone)
[Em] Mês de entrada:1510
[Cu] Atualização por classe:150630
[Lr] Data última revisão:
150630
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150527
[St] Status:MEDLINE
[do] DOI:10.1007/s00280-015-2754-3



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