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Pesquisa : A11.251.210.190.400.500 [Categoria DeCS]
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  1 / 2051 MEDLINE  
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[PMID]:29211454
[Au] Autor:Vlahov IR; Qi L; Kleindl PJ; Santhapuram HK; Felten A; Parham GL; Wang K; You F; Vaughn JF; Hahn SJ; Klein HF; Vetzel M; Reddy JA; Nelson M; Nicoson J; Leamon CP
[Ad] Endereço:Endocyte Inc. , 3000 Kent Avenue, West Lafayette, Indiana 47906, United States.
[Ti] Título:Latent Warheads for Targeted Cancer Therapy: Design and Synthesis of pro-Pyrrolobenzodiazepines and Conjugates.
[So] Source:Bioconjug Chem;28(12):2921-2931, 2017 Dec 20.
[Is] ISSN:1520-4812
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pyrrolobenzodiazepines (PBDs) and their dimers (bis-PBDs) have emerged as some of the most potent chemotherapeutic compounds, and are currently under development as novel payloads in antibody-drug conjugates (ADCs). However, when used as stand-alone therapeutics or as warheads for small molecule drug conjugates (SMDCs), dose-limiting toxicities are often observed. As an elegant solution to this inherent problem, we designed diazepine-ring-opened conjugated prodrugs lacking the imine moiety. Once the prodrug (pro-PBD) conjugate enters a targeted cell, cleavage of the linker system triggers the generation of a reactive intermediate possessing an aldehyde and aromatic amine. An intramolecular ring-closing reaction subsequently takes place as the aromatic amine adds to the aldehyde with the loss of water to give the imine and, as a result, the diazepine ring. In our pro-PBDs, we mask the aldehyde as a hydrolytically sensitive oxazolidine moiety which in turn is a part of a reductively labile self-immolative linker system. To prove the range of applications for this new class of latent DNA-alkylators, we designed and synthesized several novel latent warheads: pro-PBD dimers and hybrids of pro-PBD with other sequence-selective DNA minor groove binders. Preliminary preclinical pharmacology studies showed excellent biological activity and specificity.
[Mh] Termos MeSH primário: Benzodiazepinas/química
Benzodiazepinas/metabolismo
Desenho de Drogas
Terapia de Alvo Molecular
Neoplasias/tratamento farmacológico
Pró-Fármacos/síntese química
Pró-Fármacos/metabolismo
Pirróis/química
Pirróis/metabolismo
[Mh] Termos MeSH secundário: Antineoplásicos/química
Antineoplásicos/metabolismo
Antineoplásicos/farmacologia
Antineoplásicos/uso terapêutico
Benzodiazepinas/farmacologia
Benzodiazepinas/uso terapêutico
Técnicas de Química Sintética
Seres Humanos
Células KB
Neoplasias/patologia
Pró-Fármacos/química
Pirróis/farmacologia
Pirróis/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Prodrugs); 0 (Pyrroles); 0 (pyrrolo(2,1-c)(1,4)benzodiazepine); 12794-10-4 (Benzodiazepines)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180105
[Lr] Data última revisão:
180105
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171207
[St] Status:MEDLINE
[do] DOI:10.1021/acs.bioconjchem.7b00476


  2 / 2051 MEDLINE  
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[PMID]:28705434
[Au] Autor:Rattan R; Bhattacharjee S; Zong H; Swain C; Siddiqui MA; Visovatti SH; Kanthi Y; Desai S; Pinsky DJ; Goonewardena SN
[Ad] Endereço:Division of Cardiovascular Medicine, Internal Medicine, University of Michigan, Ann Arbor, MI, United States; Michigan Nanotechnology Institute for Medicine and Biological Sciences, and Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, United States.
[Ti] Título:Nanoparticle-macrophage interactions: A balance between clearance and cell-specific targeting.
[So] Source:Bioorg Med Chem;25(16):4487-4496, 2017 Aug 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The surface properties of nanoparticles (NPs) are a major factor that influences how these nanomaterials interact with biological systems. Interactions between NPs and macrophages of the reticuloendothelial system (RES) can reduce the efficacy of NP diagnostics and therapeutics. Traditionally, to limit NP clearance by the RES system, the NP surface is neutralized with molecules like poly(ethylene glycol) (PEG) which are known to resist protein adsorption and RES clearance. Unfortunately, PEG modification is not without drawbacks including difficulties with the synthesis and associations with immune reactions. To overcome some of these obstacles, we neutralized the NP surface by acetylation and compared this modification to PEGylation for RES clearance and tumor-specific targeting. We found that acetylation was comparable to PEGylation in reducing RES clearance. Additionally, we found that dendrimer acetylation did not impact folic acid (FA)-mediated targeting of tumor cells whereas PEG surface modification reduced the targeting ability of the NP. These results clarify the impact of different NP surface modifications on RES clearance and cell-specific targeting and provide insights into the design of more effective NPs.
[Mh] Termos MeSH primário: Ácido Fólico/farmacologia
Macrófagos/química
Nanopartículas/química
[Mh] Termos MeSH secundário: Animais
Sobrevivência Celular/efeitos dos fármacos
Células Cultivadas
Relação Dose-Resposta a Droga
Ácido Fólico/química
Seres Humanos
Células KB
Camundongos
Estrutura Molecular
Polietilenoglicóis/síntese química
Polietilenoglicóis/química
Células RAW 264.7
Relação Estrutura-Atividade
Propriedades de Superfície
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
30IQX730WE (Polyethylene Glycols); 935E97BOY8 (Folic Acid)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170715
[St] Status:MEDLINE


  3 / 2051 MEDLINE  
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[PMID]:28614728
[Au] Autor:Muhammad D; Lalun N; Bobichon H; Le Magrex Debar E; Gangloff SC; Nour M; Voutquenne-Nazabadioko L
[Ad] Endereço:UMR CNRS 7312, Université de Reims Champagne-Ardenne, Bât. 18, Moulin de la Housse, BP 1039, 51687 Reims, Cedex 2, France.
[Ti] Título:Triterpenoid saponins and other glycosides from the stems and bark of Jaffrea xerocarpa and their biological activity.
[So] Source:Phytochemistry;141:121-130, 2017 Sep.
[Is] ISSN:1873-3700
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Six previously undescribed triterpenoid saponins and two previously undescribed norlupane triterpenes were isolated with five known saponins, three known lupane derivatives, 17,20-didehydro-20-deoxyjujubogenin, rutin, (±) 3α-O-ß-d-glucopyranosyl-lyoniresinol, (±) 4-O-ß-d-glucopyranosyl-maesopsin, three phenol glycosides, and uridine from the stems and bark of Jaffrea xerocarpa (Baill.) H. C. Hopkins & Pillon (= Basionym Alphitonia xerocarpus Baill.) (Rhamnaceae), an endemic tree of New Caledonia. The chemical structures of the purified compounds were identified by nuclear magnetic resonance and mass spectrometry. The isolated compounds were tested for their antioxidant, antityrosinase, antibacterial and cytotoxic activities. The aqueous methanol extract showed antioxidant activity (DPPH assay) due to the presence of rutin and other phenolic compounds. Three lupane triterpenes showed good cytotoxic activities against KB cells line (IC from 7.7 to 8.5 µM). The previously undescribed 2α-formyl-A(1)norlup-20(29)-en-28-oic acid showed antibacterial activity against Staphylococcus aureus and Enterococcus faecalis with both MIC values of 4 µg/mL.
[Mh] Termos MeSH primário: Rhamnaceae/química
Saponinas/química
Triterpenos/química
[Mh] Termos MeSH secundário: Antibacterianos/química
Antibacterianos/isolamento & purificação
Antioxidantes/química
Antioxidantes/isolamento & purificação
Enterococcus faecalis/efeitos dos fármacos
Seres Humanos
Células KB
Testes de Sensibilidade Microbiana
Estrutura Molecular
Casca de Planta/química
Caules de Planta/química
Saponinas/isolamento & purificação
Staphylococcus aureus/efeitos dos fármacos
Triterpenos/isolamento & purificação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Antioxidants); 0 (Saponins); 0 (Triterpenes); 464-99-3 (lupane)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170721
[Lr] Data última revisão:
170721
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170615
[St] Status:MEDLINE


  4 / 2051 MEDLINE  
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[PMID]:28590124
[Au] Autor:Gao J; Aisa HA
[Ad] Endereço:Key Laboratory of Chemistry of Plant Resources in Arid Regions and ‡State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences , Urumqi 830011, People's Republic of China.
[Ti] Título:Terpenoids from Euphorbia soongarica and Their Multidrug Resistance Reversal Activity.
[So] Source:J Nat Prod;80(6):1767-1775, 2017 Jun 23.
[Is] ISSN:1520-6025
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ten new terpenoids, including five diterpenoids (1-5), three nortriterpenoids (6-8), and two triterpenoids (9, 10), and 15 known terpenoids (11-25) were isolated from an acetone extract of Euphorbia soongarica. Sooneuphoramine (1) is the first example of a euphoractine B-type diterpenoid alkaloid, while sooneuphanones A-C (6-8) are rare nortriterpenoids from the Euphorbia genus. The isolated terpenoids were tested for their cytotoxicity and multidrug resistance (MDR) reversal activity, 10 of which showed moderate cytotoxicity against the KB and KBv200 cell lines, while 11 compounds exhibited P-gp modulating potential. The triterpenoid sooneuphanone D (9) possessed a remarkable MDR reversal activity much higher than the positive control, verapamil.
[Mh] Termos MeSH primário: Resistência a Múltiplos Medicamentos/efeitos dos fármacos
Medicamentos de Ervas Chinesas/isolamento & purificação
Medicamentos de Ervas Chinesas/farmacologia
Euphorbia/química
Terpenos/isolamento & purificação
Terpenos/farmacologia
[Mh] Termos MeSH secundário: Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/farmacologia
Algoritmos
Diterpenos
Doxorrubicina
Resistência a Medicamentos Antineoplásicos
Ensaios de Seleção de Medicamentos Antitumorais
Medicamentos de Ervas Chinesas/química
Seres Humanos
Células KB
Estrutura Molecular
Ressonância Magnética Nuclear Biomolecular
Terpenos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ATP-Binding Cassette, Sub-Family B, Member 1); 0 (Diterpenes); 0 (Drugs, Chinese Herbal); 0 (Terpenes); 0 (ent-7beta,14-dihydroxy-11alpha-methoxy-18-aldehyde-11beta-20-epoxy-kaur-16-en-15-one); 80168379AG (Doxorubicin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170608
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jnatprod.6b01099


  5 / 2051 MEDLINE  
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[PMID]:28499169
[Au] Autor:Gao E; Qi Z; Qu Y; Ding Y; Zhan Y; Sun N; Zhang S; Qiu X; Zhu M
[Ad] Endereço:International Key Laboratory of Liaoning Inorganic Molecule-Based Chemical, Department of Coordination Chemistry, Shenyang University of Chemical Technology, Shenyang 110142, China. Electronic address: enjungao@163.com.
[Ti] Título:Two novel dinuclear ellipsoid Ni(II) and Co(II) complexes bridged by 4,5-bis(pyrazol-1-yl)phthalic acid: Synthesis, structural characterization and biological evaluation.
[So] Source:Eur J Med Chem;136:235-245, 2017 Aug 18.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Two novel complexes, [Ni (L) (H O) ]·4(H O) (1) and [Co (L) (H O) ]·5(H O) (2) [H L = 4,5-bis(pyrazol-1-yl) phthalic acid] were synthesized and characterized by spectroscopy (IR, H NMR), and elemental analysis. The structures for the complexes were determined by X-ray crystallography providing the dinuclear ellipsoid Ni(II) and Co(II) complexes bridged by 4,5-bis(pyrazol-1-yl)phthalic acid ligands with same coordination modes. The interaction capacity of the complexes with FS-DNA (fish sperm DNA) has been investigated by UV and fluorescence spectroscopy. Gel electrophoresis assay demonstrated the ability of the complexes to cleave the pBR322 plasmid DNA. The cytotoxic activity of the complexes was tested against two different cancer cell lines, HeLa (human cervix epithelia carcinoma cells) and KB (human oral epithelial carcinoma cells), exhibiting significant cancer cell inhibitory rate. Furthermore, flow cytometry experiments and morphological apoptosis studies showed that the complexes induced apoptosis of KB tumor cell lines. The good visualization images supported with the experimental results of structure-activity relationship.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Cobalto/farmacologia
Níquel/farmacologia
Compostos Organometálicos/farmacologia
Ácidos Ftálicos/farmacologia
Pirazóis/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Apoptose/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Cobalto/química
Cristalografia por Raios X
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Células HeLa
Seres Humanos
Células KB
Modelos Moleculares
Estrutura Molecular
Níquel/química
Compostos Organometálicos/síntese química
Compostos Organometálicos/química
Ácidos Ftálicos/química
Pirazóis/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (4,5-bis(pyrazol-1-yl)phthalic acid); 0 (Antineoplastic Agents); 0 (Organometallic Compounds); 0 (Phthalic Acids); 0 (Pyrazoles); 3G0H8C9362 (Cobalt); 7OV03QG267 (Nickel)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170928
[Lr] Data última revisão:
170928
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170513
[St] Status:MEDLINE


  6 / 2051 MEDLINE  
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[PMID]:28496320
[Au] Autor:Kameyama K; Motoyama K; Tanaka N; Yamashita Y; Higashi T; Arima H
[Ad] Endereço:Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences.
[Ti] Título:Induction of mitophagy-mediated antitumor activity with folate-appended methyl-ß-cyclodextrin.
[So] Source:Int J Nanomedicine;12:3433-3446, 2017.
[Is] ISSN:1178-2013
[Cp] País de publicação:New Zealand
[La] Idioma:eng
[Ab] Resumo:Mitophagy is the specific autophagic elimination system of mitochondria, which regulates cellular survival via the removal of damaged mitochondria. Recently, we revealed that folate-appended methyl-ß-cyclodextrin (FA-M-ß-CyD) provides selective antitumor activity in folate receptor-α (FR-α)-expressing cells by the induction of autophagy. In this study, to gain insight into the detailed mechanism of this antitumor activity, we focused on the induction of mitophagy by the treatment of FR-α-expressing tumor cells with FA-M-ß-CyD. In contrast to methyl-ß-cyclodextrin, FA-M-ß-CyD entered KB cells, human epithelial cells from a fatal cervical carcinoma (FR-α (+)) through FR-α-mediated endocytosis. The transmembrane potential of isolated mitochondria after treatment with FA-M-ß-CyD was significantly elevated. In addition, FA-M-ß-CyD lowered adenosine triphosphate (ATP) production and promoted reactive oxygen species production in KB cells (FR-α (+)). Importantly, FA-M-ß-CyD enhanced light chain 3 (LC3) conversion (LC3-I to LC3-II) in KB cells (FR-α (+)) and induced PTEN-induced putative kinase 1 (PINK1) protein expression, which is involved in the induction of mitophagy. Furthermore, FA-M-ß-CyD had potent antitumor activity in BALB/c mice xenografted with KB cells (FR-α (+)) without any significant side effects. Taken together, these findings demonstrate that the autophagic cell death elicited by FA-M-ß-CyD could be associated with mitophagy induced by an impaired mitochondrial function.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Ácido Fólico/farmacologia
beta-Ciclodextrinas/farmacologia
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/química
Autofagia/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Receptor 1 de Folato/metabolismo
Ácido Fólico/química
Seres Humanos
Células KB/efeitos dos fármacos
Masculino
Camundongos
Camundongos Endogâmicos BALB C
Degradação Mitocondrial/efeitos dos fármacos
Terapia de Alvo Molecular/métodos
Proteínas Quinases/metabolismo
Ensaios Antitumorais Modelo de Xenoenxerto
beta-Ciclodextrinas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Folate Receptor 1); 0 (beta-Cyclodextrins); 0 (methyl-beta-cyclodextrin); 935E97BOY8 (Folic Acid); EC 2.7.- (Protein Kinases); EC 2.7.11.1 (PTEN-induced putative kinase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170513
[St] Status:MEDLINE
[do] DOI:10.2147/IJN.S133482


  7 / 2051 MEDLINE  
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[PMID]:28440085
[Au] Autor:Wang L; Pang XC; Yu ZR; Yang SQ; Liu AL; Wang JH; Du GH
[Ad] Endereço:a Beijing Key Laboratory of Drug Targets Research and New Drug Screening , Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100050 , China.
[Ti] Título:Actinomycin D synergistically enhances the cytotoxicity of CDDP on KB cells by activating P53 via decreasing P53-MDM2 complex.
[So] Source:J Asian Nat Prod Res;19(6):630-643, 2017 Jun.
[Is] ISSN:1477-2213
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The aim of this study is to investigate the synergism of low dose of actinomycin D (LDActD) to the cytotoxicity of cisplatin (CDDP) on KB cells. The role of P53 reactivation by LDActD in the synergism and its mechanism were further studied. Cell viability was determined by MTT assay. Apoptosis was determined by AnnexinV-FITC/PI staining. Mitochondrial membrane potential (MMP) was detected by JC-1 staining. Expression of proteins was detected by Western blotting (WB) and/or immunofluorescence (IF). Molecular docking of actinomycin D (ACTD) to Mouse double minute 2 homolog (MDM2) and Mouse double minute 2 homolog X (MDMX). MDMX was analyzed by Discovery Studio. The content of P53-MDM2 complex was detected by ELISA assay. The cytotoxicity of CDDP was increased by the combination of LDActD in kinds of cancer cells. Molecular docking showed strong interaction between ACTD and MDM2/MDMX. Meanwhile, LDActD significantly decreased P53-MDM2 complex. Significant increase of the apoptotic activity by the combination therapy in KB cells is P53 upregulated modulator of apoptosis (PUMA) dependent. In addition to the decrease in MMP, LDActD increased P53 regulated protein and decreased BCL-XL in KB cells. LDActD efficiently enhanced the cytotoxicity of CDDP in cancer cells and induced P53-PUMA-dependent and mitochondria-mediated apoptosis in KB cells. The reactivation of P53 was probably achieved by disturbing the interaction of P53 and MDM2/MDMX.
[Mh] Termos MeSH primário: Cisplatino/farmacologia
Dactinomicina/farmacologia
Proteína Supressora de Tumor p53/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Benzimidazóis/química
Carbocianinas/química
Sobrevivência Celular/efeitos dos fármacos
Dactinomicina/química
Seres Humanos
Imidazóis/farmacologia
Células KB
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Camundongos
Simulação de Acoplamento Molecular
Estrutura Molecular
Transdução de Sinais/efeitos dos fármacos
Proteína Supressora de Tumor p53/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzimidazoles); 0 (Carbocyanines); 0 (Imidazoles); 0 (Tumor Suppressor Protein p53); 1CC1JFE158 (Dactinomycin); 21527-78-6 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine); Q20Q21Q62J (Cisplatin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170809
[Lr] Data última revisão:
170809
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170426
[St] Status:MEDLINE
[do] DOI:10.1080/10286020.2017.1318853


  8 / 2051 MEDLINE  
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[PMID]:28408821
[Au] Autor:Yang T; Xu L; Li B; Li W; Ma X; Fan L; Lee RJ; Xu C; Xiang G
[Ad] Endereço:Department of Biopharmaceuticals, School of Pharmacy.
[Ti] Título:Antitumor activity of a folate receptor-targeted immunoglobulin G-doxorubicin conjugate.
[So] Source:Int J Nanomedicine;12:2505-2515, 2017.
[Is] ISSN:1178-2013
[Cp] País de publicação:New Zealand
[La] Idioma:eng
[Ab] Resumo:Development of antibody-drug conjugates (ADCs) is a promising therapeutic strategy for cancer therapy. In this study, folate was conjugated via a polyethyleneglycol (PEG) linker to immunoglobulin G (IgG), which was linked to doxorubicin (DOX), to form a novel ADC folate-PEG-IgG-DOX (FA-PEG-IgG-DOX). The FA-PEG-IgG-DOX showed high targeting efficiency in HeLa and KB cells and significantly improved the uptake and retention of DOX compared with IgG-DOX about 10-fold. Subsequently, FA-PEG-IgG-DOX was shown to have at least 8 times higher antitumor activity than IgG-DOX both in HeLa and KB cells and also induced more apoptosis in those cells than IgG-DOX. Moreover, FA-PEG-IgG-DOX had a 2 times longer circulating time than FA-IgG-DOX, but did not increase the DOX distribution in mouse hearts. Importantly, FA-PEG-IgG-DOX treatment significantly inhibited tumor growth in xenograft mice. Together, our results indicate that FA-PEG-IgG is an effective ADC carrier for delivery of chemotherapeutic agents and that conjugating tumor targeting ligands to antibodies is a promising strategy for producing ADC drugs.
[Mh] Termos MeSH primário: Doxorrubicina/farmacologia
Sistemas de Liberação de Medicamentos/métodos
Receptores de Folato com Âncoras de GPI/metabolismo
Imunoglobulina G/química
[Mh] Termos MeSH secundário: Animais
Antibióticos Antineoplásicos/administração & dosagem
Antibióticos Antineoplásicos/farmacologia
Doxorrubicina/administração & dosagem
Doxorrubicina/farmacocinética
Portadores de Fármacos/farmacocinética
Feminino
Ácido Fólico/análogos & derivados
Ácido Fólico/química
Células HeLa/efeitos dos fármacos
Seres Humanos
Células KB/efeitos dos fármacos
Masculino
Camundongos Endogâmicos BALB C
Terapia de Alvo Molecular/métodos
Polietilenoglicóis/química
Distribuição Tecidual
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibiotics, Antineoplastic); 0 (Drug Carriers); 0 (Folate Receptors, GPI-Anchored); 0 (Immunoglobulin G); 0 (poly(ethylene glycol)-folate); 30IQX730WE (Polyethylene Glycols); 80168379AG (Doxorubicin); 935E97BOY8 (Folic Acid)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170522
[Lr] Data última revisão:
170522
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170415
[St] Status:MEDLINE
[do] DOI:10.2147/IJN.S125591


  9 / 2051 MEDLINE  
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[PMID]:28388844
[Au] Autor:Sun X; Ponte JF; Yoder NC; Laleau R; Coccia J; Lanieri L; Qiu Q; Wu R; Hong E; Bogalhas M; Wang L; Dong L; Setiady Y; Maloney EK; Ab O; Zhang X; Pinkas J; Keating TA; Chari R; Erickson HK; Lambert JM
[Ad] Endereço:ImmunoGen, Inc. , 830 Winter Street, Waltham, Massachusetts 02451, United States.
[Ti] Título:Effects of Drug-Antibody Ratio on Pharmacokinetics, Biodistribution, Efficacy, and Tolerability of Antibody-Maytansinoid Conjugates.
[So] Source:Bioconjug Chem;28(5):1371-1381, 2017 May 17.
[Is] ISSN:1520-4812
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Antibody-drug conjugates (ADCs) are being actively pursued as a treatment option for cancer following the regulatory approval of brentuximab vedotin (Adcetris) and ado-trastuzumab emtansine (Kadcyla). ADCs consist of a cytotoxic agent conjugated to a targeting antibody through a linker. The two approved ADCs (and most ADCs now in the clinic that use a microtubule disrupting agent as the payload) are heterogeneous conjugates with an average drug-to-antibody ratio (DAR) of 3-4 (potentially ranging from 0 to 8 for individual species). Ado-trastuzumab emtansine employs DM1, a semisynthetic cytotoxic payload of the maytansinoid class, which is conjugated via lysine residues of the antibody to an average DAR of 3.5. To understand the effect of DAR on the preclinical properties of ADCs using maytansinoid cytotoxic agents, we prepared a series of conjugates with a cleavable linker (M9346A-sulfo-SPDB-DM4 targeting folate receptor α (FRα)) or an uncleavable linker (J2898A-SMCC-DM1 targeting the epidermal growth factor receptor (EGFR)) with varying DAR and evaluated their biochemical characteristics, in vivo stability, efficacy, and tolerability. For both formats, a series of ADCs with DARs ranging from low (average of ∼2 and range of 0-4) to very high (average of 10 and range of 7-14) were prepared in good yield with high monomer content and low levels of free cytotoxic agent. The in vitro potency consistently increased with increasing DAR at a constant antibody concentration. We then characterized the in vivo disposition of these ADCs. Pharmacokinetic analysis showed that conjugates with an average DAR below ∼6 had comparable clearance rates, but for those with an average DAR of ∼9-10, rapid clearance was observed. Biodistribution studies in mice showed that these 9-10 DAR ADCs rapidly accumulate in the liver, with maximum localization for this organ at 24-28% percentage injected dose per gram (%ID/g) compared with 7-10% for lower-DAR conjugates (all at 2-6 h post-injection). Our preclinical findings on tolerability and efficacy suggest that maytansinoid conjugates with DAR ranging from 2 to 6 have a better therapeutic index than conjugates with very high DAR (∼9-10). These very high DAR ADCs suffer from decreased efficacy, likely due to faster clearance. These results support the use of DAR 3-4 for maytansinoid ADCs but suggest that the exploration of lower or higher DAR may be warranted depending on the biology of the target antigen.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/imunologia
Antineoplásicos Fitogênicos/farmacocinética
Imunoconjugados/farmacocinética
Maitansina/farmacocinética
[Mh] Termos MeSH secundário: Animais
Antineoplásicos Fitogênicos/farmacologia
Feminino
Seres Humanos
Imunoconjugados/farmacologia
Células KB
Maitansina/farmacologia
Camundongos
Distribuição Tecidual
Células Tumorais Cultivadas
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Antineoplastic Agents, Phytogenic); 0 (Immunoconjugates); 14083FR882 (Maytansine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170409
[St] Status:MEDLINE
[do] DOI:10.1021/acs.bioconjchem.7b00062


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[PMID]:28384525
[Au] Autor:Intaraudom C; Bunbamrung N; Dramae A; Boonyuen N; Kongsaeree P; Srichomthong K; Supothina S; Pittayakhajonwut P
[Ad] Endereço:National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Thailand Science Park, Paholyothin Road, Klong Luang, Pathumthani, 12120, Thailand.
[Ti] Título:Terphenyl derivatives and drimane - Phathalide/isoindolinones from Hypoxylon fendleri BCC32408.
[So] Source:Phytochemistry;139:8-17, 2017 Jul.
[Is] ISSN:1873-3700
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The genus Hypoxylon, a member of the family Xylariaceae, has been known to produce significant secondary metabolites in terms of chemical diversity. Moreover, the compounds isolated can also be used as chemotaxonomic characters for differentiation among the two sections, which are sect. Annulata and sect. Hypoxylon. In our continuing chemical screening programme for novel compounds, the crude extracts of H. fendleri BCC32408 gave significant chemical profiles in HPLC analyses. Thus, the chemical investigation of these crude extracts was then carried out. The investigation led to the isolation of ten previously undescribed compounds including three terphenylquinones (fendleryls A - C), one terphenyl (fendleryl D), and six novel drimane - phthalide-type lactone/isoindolinones derivatives (fendlerinines A - F) along with seven known compounds (2-O-methylatromentin, rickenyl E, atromentin, rickenyls C - D, (+)-ramulosin, and O-hydroxyphenyl acetic acid). The chemical structures were determined on the basis of spectroscopic analyses, including 1D, 2D NMR and high-resolution mass spectrometry, as well as chemical transformations. In addition, these isolated compounds were assessed for antimicrobial activity including antimalarial (against Plasmodium falciparum, K-1 strain), antifungal (against Candida albicans), antibacterial (against Bacillus cereus) activities. Cytotoxicity against both cancerous (KB, MCF-7, NCI-H187) and non-cancerous (Vero) cells of these compounds were also evaluated.
[Mh] Termos MeSH primário: Antifúngicos/isolamento & purificação
Antifúngicos/farmacologia
Antimaláricos/isolamento & purificação
Antimaláricos/farmacologia
Sesquiterpenos/isolamento & purificação
Compostos de Terfenil/isolamento & purificação
Compostos de Terfenil/farmacologia
Xylariales/química
[Mh] Termos MeSH secundário: Animais
Antibacterianos/química
Antifúngicos/química
Antimaláricos/química
Bacillus cereus/efeitos dos fármacos
Candida albicans/efeitos dos fármacos
Cromatografia Líquida de Alta Pressão
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Células KB
Lactonas/química
Testes de Sensibilidade Microbiana
Estrutura Molecular
Ressonância Magnética Nuclear Biomolecular
Fenilacetatos/química
Plasmodium falciparum/efeitos dos fármacos
Sesquiterpenos/química
Sesquiterpenos/farmacologia
Compostos de Terfenil/química
Células Vero
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Antifungal Agents); 0 (Antimalarials); 0 (Lactones); 0 (Phenylacetates); 0 (Sesquiterpenes); 0 (Terphenyl Compounds); 0 (drimane); UK3R9Q59AV (2-hydroxyphenylacetic acid)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170804
[Lr] Data última revisão:
170804
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170407
[St] Status:MEDLINE



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