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Pesquisa : D02.455.326.271.665.202.495.270 [Categoria DeCS]
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[PMID]:28988109
[Au] Autor:Wang C; Yang SNY; Smith K; Forwood JK; Jans DA
[Ad] Endereço:Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic. 3800, Australia.
[Ti] Título:Nuclear import inhibitor N-(4-hydroxyphenyl) retinamide targets Zika virus (ZIKV) nonstructural protein 5 to inhibit ZIKV infection.
[So] Source:Biochem Biophys Res Commun;493(4):1555-1559, 2017 Dec 02.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In the absence of approved therapeutics, Zika virus (ZIKV)'s recent prolific outbreaks in the Americas, together with impacts on unborn fetuses of infected mothers, make it a pressing human health concern worldwide. Although a key player in viral replication in the infected host cell cytoplasm, ZIKV non-structural protein 5 (NS5) appears to contribute integrally to pathogenesis by localising in the host cell nucleus, in similar fashion to NS5 from Dengue virus (DENV). We show here for the first time that ZIKV NS5 is recognized with high nanomolar affinity by the host cell importin α/ß1 heterodimer, and that this interaction can be blocked by the novel DENV NS5 targeting inhibitor N-(4-hydroxyphenyl) retinamide (4-HPR). Importantly, we show that 4-HPR has potent anti-ZIKV activity at low µM concentrations. With an established safety profile for human use, 4-HPR represents an exciting possibility as an anti-ZIKV agent.
[Mh] Termos MeSH primário: Antivirais/farmacologia
Fenretinida/farmacologia
Proteínas não Estruturais Virais/antagonistas & inibidores
Zika virus/efeitos dos fármacos
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular/efeitos dos fármacos
Transporte Ativo do Núcleo Celular/fisiologia
Sequência de Aminoácidos
Animais
Cercopithecus aethiops
Sequência Conservada
Seres Humanos
Células Vero
Proteínas não Estruturais Virais/genética
Proteínas não Estruturais Virais/fisiologia
Replicação Viral/efeitos dos fármacos
Zika virus/genética
Zika virus/fisiologia
Infecção pelo Zika virus/tratamento farmacológico
Infecção pelo Zika virus/prevenção & controle
Infecção pelo Zika virus/virologia
alfa Carioferinas/fisiologia
beta Carioferinas/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (NS5 protein, dengue virus); 0 (Viral Nonstructural Proteins); 0 (alpha Karyopherins); 0 (beta Karyopherins); 187EJ7QEXL (Fenretinide)
[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:171009
[St] Status:MEDLINE


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[PMID]:28429653
[Au] Autor:Cooper JP; Reynolds CP; Cho H; Kang MH
[Ad] Endereço:1 Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
[Ti] Título:Clinical development of fenretinide as an antineoplastic drug: Pharmacology perspectives.
[So] Source:Exp Biol Med (Maywood);242(11):1178-1184, 2017 Jun.
[Is] ISSN:1535-3699
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Fenretinide (4-HPR) is a synthetic retinoid that has cytotoxic activity against cancer cells. Despite substantial in vitro cytotoxicity, response rates in early clinical trials with 4-HPR have been less than anticipated, likely due to the low bioavailability of the initial oral capsule formulation. Several clinical studies have shown that the oral capsule formulation at maximum tolerated dose (MTD) achieved <10 µmol/L concentrations in patients. To improve bioavailability of 4-HPR, new oral powder (LYM-X-SORB®, LXS) and intravenous lipid emulsion (ILE) formulations are being tested in early-phase clinical trials. ILE 4-HPR administered as five-day continuous infusion achieved over 50 µmol/L at MTD with minimal systemic toxicities; multiple complete and partial responses were observed in peripheral T cell lymphomas. The LXS oral powder 4-HPR formulation increased plasma levels approximately two-fold at MTD in children without dose-limiting toxicities and demonstrated multiple complete responses in recurrent neuroblastoma. The clinical activity observed with new 4-HPR formulations is attributed to increased bioavailability. Phase I and II clinical trials of both LXS 4-HPR and ILE 4-HPR are in progress as a single agent or in combination with other drugs. Impact statement One of the critical components in drug development is understanding pharmacology (especially pharmacokinetics) of the drugs being developed. Often the pharmacokinetic properties, such as poor solubility leading to poor bioavailability, of the drug can limit further development of the drug. The development of numerous drugs has often halted at clinical testing stages, and several of them were due to the pharmacological properties of the agents, resulting in increased drug development cost. The current review provides an example of how improved clinical activity can be achieved by changing the formulations of a drug with poor bioavailability. Thus, it emphasizes the importance of understanding pharmacologic characteristics of the drug in drug development.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Antineoplásicos/farmacocinética
Fenretinida/farmacologia
Fenretinida/farmacocinética
Linfoma de Células T/tratamento farmacológico
Neuroblastoma/tratamento farmacológico
[Mh] Termos MeSH secundário: Administração Oral
Antineoplásicos/administração & dosagem
Antineoplásicos/efeitos adversos
Ensaios Clínicos Fase I como Assunto
Ensaios Clínicos Fase II como Assunto
Fenretinida/administração & dosagem
Fenretinida/efeitos adversos
Seres Humanos
Infusões Intravenosas
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 187EJ7QEXL (Fenretinide)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170422
[St] Status:MEDLINE
[do] DOI:10.1177/1535370217706952


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[PMID]:28340497
[Au] Autor:Lopez-Barcons L; Maurer BJ; Kang MH; Reynolds CP
[Ad] Endereço:Cancer Center and Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, 79430.
[Ti] Título:P450 inhibitor ketoconazole increased the intratumor drug levels and antitumor activity of fenretinide in human neuroblastoma xenograft models.
[So] Source:Int J Cancer;141(2):405-413, 2017 Jul 15.
[Is] ISSN:1097-0215
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We previously reported that concurrent ketoconazole, an oral anti-fungal agent and P450 enzyme inhibitor, increased plasma levels of the cytotoxic retinoid, fenretinide (4-HPR) in mice. We have now determined the effects of concurrent ketoconazole on 4-HPR cytotoxic dose-response in four neuroblastoma (NB) cell lines in vitro and on 4-HPR activity against two cell line-derived, subcutaneous NB xenografts (CDX) and three patient-derived NB xenografts (PDX). Cytotoxicity in vitro was assessed by DIMSCAN assay. Xenografted animals were treated with 4-HPR/LXS (240 mg/kg/day) + ketoconazole (38 mg/kg/day) in divided oral doses in cycles of five continuous days a week. In one model, intratumoral levels of 4-HPR and metabolites were assessed by HPLC assay, and in two models intratumoral apoptosis was assessed by TUNEL assay, on Day 5 of the first cycle. Antitumor activity was assessed by Kaplan-Meier event-free survival (EFS). The in vitro cytotoxicity of 4-HPR was not affected by ketoconazole (p ≥ 0.06). Ketoconazole increased intratumoral levels of 4-HPR (p = 0.02), of the active 4-oxo-4-HPR metabolite (p = 0.04), and intratumoral apoptosis (p ≤ 0.0006), compared to 4-HPR/LXS-alone. Concurrent ketoconazole increased EFS in both CDX models compared to 4-HPR/LXS-alone (p ≤ 0.008). 4-HPR + ketoconazole also increased EFS in PDX models compared to controls (p ≤ 0.03). Thus, concurrent ketoconazole decreased 4-HPR metabolism with resultant increases of plasma and intratumoral drug levels and antitumor effects in neuroblastoma murine xenografts. These results support the clinical testing of concurrent ketoconazole and oral fenretinide in neuroblastoma.
[Mh] Termos MeSH primário: Antineoplásicos/administração & dosagem
Inibidores do Citocromo P-450 CYP3A/administração & dosagem
Fenretinida/administração & dosagem
Cetoconazol/administração & dosagem
Neuroblastoma/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/uso terapêutico
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Linhagem Celular Tumoral
Inibidores do Citocromo P-450 CYP3A/uso terapêutico
Esquema de Medicação
Sinergismo Farmacológico
Fenretinida/uso terapêutico
Seres Humanos
Cetoconazol/uso terapêutico
Camundongos
Resultado do Tratamento
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Cytochrome P-450 CYP3A Inhibitors); 187EJ7QEXL (Fenretinide); R9400W927I (Ketoconazole)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170914
[Lr] Data última revisão:
170914
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170325
[St] Status:MEDLINE
[do] DOI:10.1002/ijc.30706


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[PMID]:28285324
[Au] Autor:Lu LJ; Liu J; Adelman RA
[Ad] Endereço:Department of Ophthalmology and Visual Science, Yale School of Medicine, 40 Temple St., New Haven, CT, 06510, USA.
[Ti] Título:Novel therapeutics for Stargardt disease.
[So] Source:Graefes Arch Clin Exp Ophthalmol;255(6):1057-1062, 2017 Jun.
[Is] ISSN:1435-702X
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:DESCRIPTION OF SITUATION: Stargardt disease, an inherited macular dystrophy caused by mutations in the ABCA4 gene encoding a retinal transporter protein, is the most prevalent form of macular degeneration in children. Patients with Stargardt disease develop severe vision loss within their first or second decades of life, which progresses to irreversible decreased visual acuity in almost all cases. Presently, there are no standard treatments for Stargardt disease. However, encouraging progress has been made in the development of innovative approaches to preventing vision loss in Stargardt patients. OBJECTIVE OF STUDY: Among the promising treatment candidates include ALK-001, fenretinide, and A1120 as pharmacological agents to modulate the visual cycle, StarGen as a vector for supplementation of a functional ABCA4 gene, and stem-cell transplantation of hESC-RPE cells for regeneration of the retinal pigment epithelium. This study aims to systematically review and summarize evidence concerning the most up-to-date developments in pharmacologic, gene, and stem-cell therapies as novel therapeutic strategies to improve vision for patients with Stargardt disease.
[Mh] Termos MeSH primário: Fenretinida/uso terapêutico
Terapia Genética/métodos
Degeneração Macular/congênito
Piperidinas/uso terapêutico
Transplante de Células-Tronco/métodos
[Mh] Termos MeSH secundário: Antineoplásicos/uso terapêutico
Seres Humanos
Ligantes
Degeneração Macular/diagnóstico
Degeneração Macular/terapia
Epitélio Pigmentado da Retina/efeitos dos fármacos
Epitélio Pigmentado da Retina/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (A1120 agent); 0 (Antineoplastic Agents); 0 (Ligands); 0 (Piperidines); 187EJ7QEXL (Fenretinide)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170313
[St] Status:MEDLINE
[do] DOI:10.1007/s00417-017-3619-8


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[PMID]:28275870
[Au] Autor:Anzaldi M; Viale M; Macciò C; Castagnola P; Oliveri V; Rosano C; Balbi A
[Ad] Endereço:Dipartimento di Farmacia, Università di Genova, Viale Benedetto XV, 3, 16132, Genoa, Italy.
[Ti] Título:Synthesis of short retinoidal amides related to fenretinide: antioxidant activities and differentiation-inducing ability.
[So] Source:Cancer Chemother Pharmacol;79(4):725-736, 2017 Apr.
[Is] ISSN:1432-0843
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:PURPOSE: By a scaffold shortening strategy, a small series of retinoidal amides fenretinide (4-HPR) analogs have been synthesized from α, ß-ionones and tested for their antiproliferative and differentiating activities, and antioxidant effect. METHODS: The antiproliferative activity and triggering of apoptosis of our short retinoids were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and 4'-6-diamidino-2-phenylindole staining and microscope evaluation after 3- or 6-day exposure, while their differentiating activity was established by the analysis of the expression of the CD11b marker of differentiation in treated HL60 target cells and by the superoxide production assayed colorimetrically by the nitro blue tetrazolium-reducing activity assay. Finally, the antioxidant activity was determined by the 2,2'-azino-bis-(3-ethylbenzthiazoline-6-sulphonic acid) diammonium salt radical cation decolourisation assay utilizing the antioxidant Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) as reference (Trolox equivalent antioxidant capacity, or TEAC). Docking analysis was performed to study the binding features to the Retinoic Acid Receptor alpha (RARα). RESULTS: While no pharmacologically relevant antiproliferative activity was evidenced, some of our short retinoids showed a differentiating and antioxidant activity similar to that of 4-HPR. In particular, compound 2b6 displayed a scavenging activity two times more efficient than 4-HPR itself. Finally, the docking analysis showed that these short retinoids, like 4-HPR, bind to the RARα protein with good fitness scores. CONCLUSION: Our data could pave the way for the design of new potent and less toxic antioxidant and differentiating compounds related to 4-HPR.
[Mh] Termos MeSH primário: Antineoplásicos/síntese química
Antineoplásicos/farmacologia
Antioxidantes/farmacologia
Diferenciação Celular/efeitos dos fármacos
Fenretinida/análogos & derivados
Fenretinida/farmacologia
[Mh] Termos MeSH secundário: Amidas/farmacologia
Apoptose/efeitos dos fármacos
Antígeno CD11b/metabolismo
Proliferação Celular/efeitos dos fármacos
Cromanos/química
Fenretinida/síntese química
Depuradores de Radicais Livres/síntese química
Depuradores de Radicais Livres/farmacologia
Células HL-60
Seres Humanos
Simulação de Acoplamento Molecular
Superóxidos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amides); 0 (Antineoplastic Agents); 0 (Antioxidants); 0 (CD11b Antigen); 0 (Chromans); 0 (Free Radical Scavengers); 0 (ITGAM protein, human); 11062-77-4 (Superoxides); 187EJ7QEXL (Fenretinide); S18UL9710X (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170310
[St] Status:MEDLINE
[do] DOI:10.1007/s00280-017-3265-1


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[PMID]:28179290
[Au] Autor:Boppana NB; Kraveka JM; Rahmaniyan M; Li LI; Bielawska A; Bielawski J; Pierce JS; Delor JS; Zhang K; Korbelik M; Separovic D
[Ad] Endereço:Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, U.S.A.
[Ti] Título:Fumonisin B1 Inhibits Endoplasmic Reticulum Stress Associated-apoptosis After FoscanPDT Combined with C6-Pyridinium Ceramide or Fenretinide.
[So] Source:Anticancer Res;37(2):455-463, 2017 02.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIM: Combining an anticancer agent fenretinide (HPR) or C6-pyridinium ceramide (LCL29) with Foscan-mediated photodynamic therapy (FoscanPDT) is expected to augment anticancer benefits of each substance. We showed that treatment with FoscanPDT+HPR enhanced accumulation of C16-dihydroceramide, and that fumonisin B1 (FB), an inhibitor of ceramide synthase, counteracted caspase-3 activation and colony-forming ability of head and neck squamous cell carcinoma (HNSCC) cells. Because cancer cells appear to be more susceptible to increased levels of the endoplasmic reticulum (ER) stress than normal cells, herein we tested the hypothesis that FoscanPDT combined with HPR or LCL29 induces FB-sensitive ER stress-associated apoptosis that affects cell survival. MATERIALS AND METHODS: Using an HNSCC cell line, we determined: cell survival by clonogenic assay, caspase-3 activity by spectrofluorometry, the expression of the ER markers BiP and CHOP by quantitative real-time polymerase chain reaction and western immunoblotting, and sphingolipid levels by mass spectrometry. RESULTS: Similar to HPR+FoscanPDT, LCL29+FoscanPDT induced enhanced loss of clonogenicity and caspase-3 activation, that were both inhibited by FB. Our additional pharmacological evidence showed that the enhanced loss of clonogenicity after the combined treatments was singlet oxygen-, ER stress- and apoptosis-dependent. The combined treatments induced enhanced, FB-sensitive, up-regulation of BiP and CHOP, as well as enhanced accumulation of sphingolipids. CONCLUSION: Our data suggest that enhanced clonogenic cell killing after the combined treatments is dependent on oxidative- and ER-stress, apoptosis, and FB-sensitive sphingolipid production, and should help develop more effective mechanism-based therapeutic strategies.
[Mh] Termos MeSH primário: Carcinoma de Células Escamosas/tratamento farmacológico
Ceramidas/farmacologia
Estresse do Retículo Endoplasmático/efeitos dos fármacos
Fenretinida/farmacologia
Fumonisinas/farmacologia
Neoplasias de Cabeça e Pescoço/tratamento farmacológico
Mesoporfirinas/farmacologia
Fotoquimioterapia/métodos
Compostos de Piridínio/farmacologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Carcinoma de Células Escamosas/metabolismo
Carcinoma de Células Escamosas/patologia
Caspase 3/metabolismo
Inibidores de Caspase/farmacologia
Linhagem Celular Tumoral
Terapia Combinada
Neoplasias de Cabeça e Pescoço/metabolismo
Neoplasias de Cabeça e Pescoço/patologia
Seres Humanos
Radiossensibilizantes/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-N-(6'-(1''-pyridinium)hexanoyl)sphingosine); 0 (Caspase Inhibitors); 0 (Ceramides); 0 (Fumonisins); 0 (Mesoporphyrins); 0 (Pyridinium Compounds); 0 (Radiation-Sensitizing Agents); 187EJ7QEXL (Fenretinide); 3ZZM97XZ32 (fumonisin B1); EC 3.4.22.- (Caspase 3); FU21S769PF (temoporfin)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170213
[Lr] Data última revisão:
170213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170210
[St] Status:MEDLINE


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[PMID]:28119491
[Au] Autor:Makena MR; Koneru B; Nguyen TH; Kang MH; Reynolds CP
[Ad] Endereço:Cancer Center, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.
[Ti] Título:Reactive Oxygen Species-Mediated Synergism of Fenretinide and Romidepsin in Preclinical Models of T-cell Lymphoid Malignancies.
[So] Source:Mol Cancer Ther;16(4):649-661, 2017 Apr.
[Is] ISSN:1538-8514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:T-cell lymphoid malignancies (TCLM) are in need of novel and more effective therapies. The histone deacetylase (HDAC) inhibitor romidepsin and the synthetic cytotoxic retinoid fenretinide both have achieved durable clinical responses in T-cell lymphomas as single agents. We investigated the potential for using these two agents in combination in TCLMs. We demonstrated cytotoxic synergy between romidepsin and fenretinide in 15 TCLM cell lines at clinically achievable concentrations that lacked cytotoxicity for nonmalignant cells (fibroblasts and blood mononuclear cells). , romidepsin + fenretinide + ketoconazole (enhances fenretinide exposures by inhibiting fenretinide metabolism) showed greater activity in subcutaneous and disseminated TCLM xenograft models than single-agent romidepsin or fenretinide + ketoconazole. Fenretinide + romidepsin caused a reactive oxygen species (ROS)-dependent increase in proapoptotic proteins (Bim, tBid, Bax, and Bak), apoptosis, and inhibition of HDAC enzymatic activity, which achieved a synergistic increase in histone acetylation. The synergistic cytotoxicity, apoptosis, and histone acetylation of fenretinide + romidepsin were abrogated by antioxidants (vitamins C or E). Romidepsin + fenretinide activated p38 and JNK via ROS, and knockdown of p38 and JNK1 significantly decreased the synergistic cytotoxicity. Romidepsin + fenretinide also showed synergistic cytotoxicity for B-lymphoid malignancy cell lines, but did not increase ROS, acetylation of histones, activation of p38 + JNK, or cytotoxicity in nonmalignant cells. Romidepsin + fenretinide achieved synergistic activity in preclinical models of TCLMs, but not in nonmalignant cells, via a novel molecular mechanism. These data support conducting clinical trials of romidepsin + fenretinide in relapsed and refractory TCLMs. .
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Depsipeptídeos/administração & dosagem
Fenretinida/administração & dosagem
Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico
Espécies Reativas de Oxigênio/metabolismo
[Mh] Termos MeSH secundário: Acetilação/efeitos dos fármacos
Animais
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Proteínas Reguladoras de Apoptose/genética
Linhagem Celular Tumoral
Depsipeptídeos/metabolismo
Sinergismo Farmacológico
Fenretinida/farmacologia
Regulação Neoplásica da Expressão Gênica
Histonas/metabolismo
Seres Humanos
Leucemia-Linfoma de Células T do Adulto/metabolismo
Camundongos
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apoptosis Regulatory Proteins); 0 (Depsipeptides); 0 (Histones); 0 (Reactive Oxygen Species); 187EJ7QEXL (Fenretinide); CX3T89XQBK (romidepsin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170801
[Lr] Data última revisão:
170801
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170126
[St] Status:MEDLINE
[do] DOI:10.1158/1535-7163.MCT-16-0749


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[PMID]:28055107
[Au] Autor:Cowan AJ; Stevenson PA; Gooley TA; Frayo SL; Oliveira GR; Smith SD; Green DJ; Roden JE; Pagel JM; Wood BL; Press OW; Gopal AK
[Ad] Endereço:Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
[Ti] Título:Results of a phase I-II study of fenretinide and rituximab for patients with indolent B-cell lymphoma and mantle cell lymphoma.
[So] Source:Br J Haematol;176(4):583-590, 2017 Feb.
[Is] ISSN:1365-2141
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Fenretinide, a synthetic retinoid, induces apoptotic cell death in B-cell non-Hodgkin lymphoma (B-NHL) and acts synergistically with rituximab in preclinical models. We report results from a phase I-II study of fenretinide with rituximab for B-NHLs. Eligible diagnoses included indolent B-NHL or mantle cell lymphoma. The phase I design de-escalated from fenretinide at 900 mg/m PO BID for days 1-5 of a 7-day cycle. The phase II portion added 375 mg/m IV rituximab weekly on weeks 5-9 then every 3 months. Fenretinide was continued until progression or intolerance. Thirty-two patients were treated: 7 in phase I, and 25 in phase II of the trial. No dose-limiting toxicities were observed. The phase II component utilized fenretinide 900 mg/m twice daily with rituximab. The most common treatment-related adverse events of grade 3 or higher were rash (n = 3) and neutropenia (n = 3). Responses were seen in 6 (24%) patients on the phase II study, with a median duration of response of 47 months (95% confidence interval, 2-56). The combination of fenretinide and rituximab was well tolerated, yielded a modest overall response rate, but with prolonged remission durations. Further study should focus on identifying the responsive subset of B-NHL.
[Mh] Termos MeSH primário: Fenretinida/administração & dosagem
Linfoma de Células B/tratamento farmacológico
Linfoma de Célula do Manto/tratamento farmacológico
Rituximab/administração & dosagem
[Mh] Termos MeSH secundário: Adulto
Idoso
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Sinergismo Farmacológico
Exantema/induzido quimicamente
Feminino
Seres Humanos
Linfoma de Células B/complicações
Linfoma de Célula do Manto/complicações
Masculino
Meia-Idade
Neutropenia/induzido quimicamente
Indução de Remissão
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE
[Nm] Nome de substância:
187EJ7QEXL (Fenretinide); 4F4X42SYQ6 (Rituximab)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170608
[Lr] Data última revisão:
170608
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170106
[St] Status:MEDLINE
[do] DOI:10.1111/bjh.14451


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[PMID]:27913199
[Au] Autor:Dong R; Gong Y; Meng W; Yuan M; Zhu H; Ying M; He Q; Cao J; Yang B
[Ad] Endereço:Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
[Ti] Título:The involvement of M2 macrophage polarization inhibition in fenretinide-mediated chemopreventive effects on colon cancer.
[So] Source:Cancer Lett;388:43-53, 2017 Mar 01.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Clinical studies have shown that fenretinide (4-HPR) is an attractive chemopreventive agent for cancer treatment. However, to date, few studies have demonstrated the mechanism of the preventive effect of 4-HPR. In our current study, we revealed that 4-HPR could significantly suppress IL-4/IL-13 induced M2-like polarization of macrophages, which was demonstrated by the reduced expression of M2 surface markers, the down-regulation of M2 marker genes, and the inhibition of M2-like macrophages promoted angiogenesis. Mechanistically, our study suggested that the inhibition of the phosphorylation of STAT6, rather than the generation of oxidative stress, is involved in the 4-HPR-driven inhibition of M2 polarization. More intriguingly, by utilizing adenomatous polyposis coli (APC ) transgenic mice, we demonstrated that the tumorigenesis was dramatically decreased by 4-HPR treatment accompanied with fewer M2-like macrophages in the tumor tissues, thereby profoundly blocking tumor angiogenesis. These findings, for the first time, reveal the involvement of M2 polarization inhibition in 4-HPR-mediated chemoprevention, which provides a new point of insight and indicates the potential mechanism underlying the chemopreventive effect of 4-HPR.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Quimioprevenção/métodos
Neoplasias do Colo/tratamento farmacológico
Fenretinida/uso terapêutico
Macrófagos/metabolismo
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/administração & dosagem
Neoplasias do Colo/prevenção & controle
Fenretinida/administração & dosagem
Seres Humanos
Camundongos
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 187EJ7QEXL (Fenretinide)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161204
[St] Status:MEDLINE


  10 / 772 MEDLINE  
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[PMID]:27756753
[Au] Autor:Mallery SR; Wang D; Santiago B; Pei P; Schwendeman SP; Nieto K; Spinney R; Tong M; Koutras G; Han B; Holpuch A; Lang J
[Ad] Endereço:Division of Oral Maxillofacial Pathology & Radiology, College of Dentistry, The Ohio State University, Columbus, Ohio. mallery.1@osu.edu.
[Ti] Título:Benefits of Multifaceted Chemopreventives in the Suppression of the Oral Squamous Cell Carcinoma (OSCC) Tumorigenic Phenotype.
[So] Source:Cancer Prev Res (Phila);10(1):76-88, 2017 Jan.
[Is] ISSN:1940-6215
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Over one third of patients who have undergone oral squamous cell carcinoma (OSCC) surgical resections develop life-threatening and often untreatable recurrences. A variety of drugs, intended for management of recurrent or disseminated cancers, were designed to exploit cancer cells' reliance upon overexpressed receptors and gratuitous signaling. Despite their conceptual promise, clinical trials showed these agents lacked efficacy and were often toxic. These findings are consistent with evasion of pathway-targeted treatments via extensive signaling redundancies and compensatory mechanisms common to cancers. Optimal secondary OSCC chemoprevention requires long-term efficacy with multifaceted, nontoxic agents. Accordingly, this study evaluated the abilities of three complementary chemopreventives, that is, the vitamin A derivative fenretinide (4-HPR, induces apoptosis and differentiation, inhibits signaling proteins, and invasion), the estrogen metabolite 2-methoxyestradiol (2-ME, apoptosis-inducing, antiangiogenic), and the humanized mAb to the IL6R receptor tocilizumab (TOC, reduces IL6 signaling) to suppress OSCC gratuitous signaling and tumorigenesis. Modeling studies demonstrated 4-HPR's high-affinity binding at STAT3's dimerization site and c-Abl and c-Src ATP-binding kinase sites. Although individual agents suppressed cancer-promoting pathways including STAT3 phosphorylation, STAT3-DNA binding, and production of the trans-signaling enabling sIL6R, maximal chemopreventive effects were observed with agent combinations. OSCC tumor xenograft studies showed that locally delivered TOC, TOC+4-HPR, and TOC+4-HPR+2-ME treatments all prevented significant tumor growth. Notably, the TOC+4-HPR+2-ME treatment resulted in the smallest overall increase in tumor volume. The selected agents use diverse mechanisms to disrupt tumorigenesis at multiple venues, that is, intracellular, tumor cell-ECM, and tumor microenvironment; beneficial qualities for secondary chemopreventives. Cancer Prev Res; 10(1); 76-88. ©2016 AACR.
[Mh] Termos MeSH primário: Anticarcinógenos/uso terapêutico
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Carcinogênese/efeitos dos fármacos
Carcinoma de Células Escamosas/prevenção & controle
Neoplasias Bucais/prevenção & controle
Recidiva Local de Neoplasia/prevenção & controle
[Mh] Termos MeSH secundário: Animais
Anticorpos Monoclonais Humanizados/administração & dosagem
Anticorpos Monoclonais Humanizados/efeitos adversos
Anticorpos Monoclonais Humanizados/uso terapêutico
Anticarcinógenos/administração & dosagem
Anticarcinógenos/efeitos adversos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
Apoptose/efeitos dos fármacos
Carcinoma de Células Escamosas/patologia
Carcinoma de Células Escamosas/cirurgia
Diferenciação Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Estradiol/administração & dosagem
Estradiol/efeitos adversos
Estradiol/análogos & derivados
Estradiol/uso terapêutico
Fenretinida/administração & dosagem
Fenretinida/efeitos adversos
Fenretinida/uso terapêutico
Regulação Neoplásica da Expressão Gênica
Seres Humanos
Masculino
Camundongos
Camundongos Nus
Neoplasias Bucais/patologia
Neoplasias Bucais/cirurgia
Invasividade Neoplásica
Fenótipo
Fosforilação
Receptores de Interleucina-6/antagonistas & inibidores
Fator de Transcrição STAT3/metabolismo
Transdução de Sinais/efeitos dos fármacos
Microambiente Tumoral/efeitos dos fármacos
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (Anticarcinogenic Agents); 0 (IL6R protein, human); 0 (Receptors, Interleukin-6); 0 (STAT3 Transcription Factor); 0 (STAT3 protein, human); 187EJ7QEXL (Fenretinide); 4TI98Z838E (Estradiol); 6I2QW73SR5 (2-methoxyestradiol); I031V2H011 (tocilizumab)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171102
[Lr] Data última revisão:
171102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161030
[St] Status:MEDLINE
[do] DOI:10.1158/1940-6207.CAPR-16-0180



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