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[PMID]: 28220519 [Au] Autor: Cancelas JA; Gottschall JL; Rugg N; Graminske S; Schott MA; North A; Huang N; Mufti N; Erickson A; Rico S; Corash L [Ad] Endereço: Hoxworth Blood Center, Cincinnati, OH, USA. [Ti] Título: Red blood cell concentrates treated with the amustaline (S-303) pathogen reduction system and stored for 35 days retain post-transfusion viability: results of a two-centre study. [So] Source: Vox Sang;112(3):210-218, 2017 Apr. [Is] ISSN: 1423-0410 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND AND OBJECTIVES: Pathogen reduction technology using amustaline (S-303) was developed to reduce the risk of transfusion-transmitted infection and adverse effects of residual leucocytes. In this study, the viability of red blood cells (RBCs) prepared with a second-generation process and stored for 35 days was evaluated in two different blood centres. MATERIALS AND METHODS: In a single-blind, randomized, controlled, two-period crossover study (n = 42 healthy subjects), amustaline-treated (Test) or Control RBCs were prepared in random sequence and stored for 35 days. On day 35, an aliquot of Cr/ Tc radiolabeled RBCs was transfused. In a subgroup of 26 evaluable subjects, 24-h RBC post-transfusion recovery, mean life span, median life span (T ) and life span area under the curve (AUC) were analysed. RESULTS: The mean 24-h post-transfusion recovery of Test and Control RBCs was comparable (83·2 ± 5·2 and 84·9 ± 5·9%, respectively; P = 0·06) and consistent with the US Food and Drug Administration (FDA) criteria for acceptable RBC viability. There were differences in the T between Test and Control RBCs (33·5 and 39·7 days, respectively; P < 0·001), however, these were within published reference ranges of 28-35 days. The AUC (per cent surviving × days) for Test and Control RBCs was similar (22·6 and 23·1 per cent surviving cells × days, respectively; P > 0·05). Following infusion of Test RBCs, there were no clinically relevant abnormal laboratory values or adverse events. CONCLUSION: RBCs prepared using amustaline pathogen reduction meet the FDA criteria for post-transfusion recovery and are metabolically and physiologically appropriate for transfusion following 35 days of storage. [Mh] Termos MeSH primário: Acridinas/farmacologia Preservação de Sangue Eritrócitos/efeitos dos fármacos Compostos de Mostarda Nitrogenada/farmacologia [Mh] Termos MeSH secundário: Acridinas/química Adulto Idoso Área Sob a Curva Sobrevivência Celular/efeitos dos fármacos Isótopos do Cromo/química Estudos Cross-Over Contagem de Eritrócitos Transfusão de Eritrócitos/efeitos adversos Eritrócitos/química Eritrócitos/citologia Eritrócitos/metabolismo Feminino Meia-Vida Hematoma/etiologia Seres Humanos Marcação por Isótopo Masculino Viabilidade Microbiana/efeitos dos fármacos Meia-Idade Compostos de Mostarda Nitrogenada/química Curva ROC Método Simples-Cego Tecnécio/química Fatores de Tempo Inativação de Vírus/efeitos dos fármacos Adulto Jovem [Pt] Tipo de publicação: CLINICAL TRIAL; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL [Nm] Nome de substância: 0 ((N,N-bis(2-chloroethyl))-2-aminoethyl-3-((acridin-9-yl)amino)propionate); 0 (Acridines); 0 (Chromium Isotopes); 0 (Nitrogen Mustard Compounds); 7440-26-8 (Technetium) [Em] Mês de entrada: 1705 [Cu] Atualização por classe: 171114 [Lr] Data última revisão: 171114 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170222 [St] Status: MEDLINE [do] DOI: 10.1111/vox.12500

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[PMID]: 28164306 [Au] Autor: Laughhunn A; Santa Maria F; Broult J; Lanteri MC; Stassinopoulos A; Musso D; Aubry M [Ad] Endereço: Cerus Corporation, Concord, California. [Ti] Título: Amustaline (S-303) treatment inactivates high levels of Zika virus in red blood cell components. [So] Source: Transfusion;57(3pt2):779-789, 2017 Mar. [Is] ISSN: 1537-2995 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: The potential for Zika virus (ZIKV) transfusion-transmission (TT) has been demonstrated in French Polynesia and Brazil. Pathogen inactivation (PI) of blood products is a proactive strategy to inactivate TT pathogens including arboviruses. Inactivation of West Nile, dengue, Zika, and chikungunya viruses was previously demonstrated by photochemical treatment with amotosalen and ultraviolet A (UVA) illumination. In this study, we evaluated ZIKV inactivation in red blood cell (RBC) components by a chemical approach that uses amustaline (S-303) and glutathione (GSH). STUDY DESIGN AND METHODS: RBC components were spiked with a high titer of ZIKV. Viral titers (infectivity) and ZIKV RNA loads (reverse transcription-polymerase chain reaction) were measured in spiked RBCs before and after S-303 and GSH treatment and confirmed using repetitive passages in cell culture. A mock-treated arm validated the approach by demonstrating stability of the virus (infectivity and RNA load) during the process. RESULTS: The mean ZIKV infectivity titer and RNA load in RBCs were 5.99 ± 0.2 log 50% tissue culture infectious dose (TCID )/mL and 7.75 ± 0.16 log genomic equivalents/mL before inactivation. No infectivity was detected immediately after S-303 and GSH treatment and after five serial passages in cell culture. CONCLUSION: Complete ZIKV inactivation of more than 5.99 log TCID /mL in RBCs was achieved using S-303 and GSH at levels higher than those found in asymptomatic ZIKV-infected blood donors. Therefore, the S-303 and GSH PI system is promising for mitigating the risk of ZIKV TT. [Mh] Termos MeSH primário: Acridinas/farmacologia Desinfecção/métodos Eritrócitos/virologia Compostos de Mostarda Nitrogenada/farmacologia RNA Viral/sangue Inativação de Vírus Zika virus [Mh] Termos MeSH secundário: Acridinas/química Feminino Seres Humanos Masculino Compostos de Mostarda Nitrogenada/química [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 ((N,N-bis(2-chloroethyl))-2-aminoethyl-3-((acridin-9-yl)amino)propionate); 0 (Acridines); 0 (Nitrogen Mustard Compounds); 0 (RNA, Viral) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 170621 [Lr] Data última revisão: 170621 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170207 [St] Status: MEDLINE [do] DOI: 10.1111/trf.13993

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[PMID]: 28140568 [Au] Autor: Stornetta A; Villalta PW; Gossner F; Wilson WR; Balbo S; Sturla SJ [Ad] Endereço: Department of Health Sciences and Technology, ETH Zurich , Schmelzbergstrasse 9, 8092 Zurich, Switzerland. [Ti] Título: DNA Adduct Profiles Predict in Vitro Cell Viability after Treatment with the Experimental Anticancer Prodrug PR104A. [So] Source: Chem Res Toxicol;30(3):830-839, 2017 Mar 20. [Is] ISSN: 1520-5010 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: PR104A is an experimental DNA-alkylating hypoxia-activated prodrug that can also be activated in an oxygen-independent manner by the two-electron aldo-keto reductase 1C3. Nitroreduction leads to the formation of cytotoxic hydroxylamine (PR104H) and amine (PR104M) metabolites, which induce DNA mono and cross-linked adducts in cells. PR104A-derived DNA adducts can be utilized as drug-specific biomarkers of efficacy and as a mechanistic tool to elucidate the cellular and molecular effects of PR104A. Toward this goal, a mass spectrometric bioanalysis approach based on a stable isotope-labeled adduct mixture (SILAM) and selected reaction monitoring (SRM) data acquisition for relative quantitation of PR104A-derived DNA adducts in cells was developed. Use of this SILAM-based approach supported simultaneous relative quantitation of 33 PR104A-derived DNA adducts in the same sample, which allowed testing of the hypothesis that the enhanced cytotoxicity, observed by preconditioning cells with the transcription-activating isothiocyanate sulforaphane, is induced by an increased level of DNA adducts induced by PR104H and PR104M, but not PR104A. By applying the new SILAM-SRM approach, we found a 2.4-fold increase in the level of DNA adducts induced by PR104H and PR104M in HT-29 cells preconditioned with sulforaphane and a corresponding 2.6-fold increase in cytotoxicity. These results suggest that DNA adduct levels correlate with drug potency and underly the possibility of monitoring PR104A-derived DNA adducts as biomarkers of efficacy. [Mh] Termos MeSH primário: Antineoplásicos/farmacologia Adutos de DNA Compostos de Mostarda Nitrogenada/farmacologia Pró-Fármacos/farmacologia [Mh] Termos MeSH secundário: Células HT29 Seres Humanos Técnicas In Vitro [Pt] Tipo de publicação: JOURNAL ARTICLE; VALIDATION STUDIES [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (DNA Adducts); 0 (Nitrogen Mustard Compounds); 0 (PR-104A); 0 (Prodrugs) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 170714 [Lr] Data última revisão: 170714 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170201 [St] Status: MEDLINE [do] DOI: 10.1021/acs.chemrestox.6b00412

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[PMID]: 27936622 [Au] Autor: Stornetta A; Zimmermann M; Cimino GD; Henderson PT; Sturla SJ [Ad] Endereço: Department of Health Sciences and Technology, ETH Zurich , Schmelzbergstrasse 9, 8092 Zurich, Switzerland. [Ti] Título: DNA Adducts from Anticancer Drugs as Candidate Predictive Markers for Precision Medicine. [So] Source: Chem Res Toxicol;30(1):388-409, 2017 01 17. [Is] ISSN: 1520-5010 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Biomarker-driven drug selection plays a central role in cancer drug discovery and development, and in diagnostic strategies to improve the use of traditional chemotherapeutic drugs. DNA-modifying anticancer drugs are still used as first line medication, but drawbacks such as resistance and side effects remain an issue. Monitoring the formation and level of DNA modifications induced by anticancer drugs is a potential strategy for stratifying patients and predicting drug efficacy. In this perspective, preclinical and clinical data concerning the relationship between drug-induced DNA adducts and biological response for platinum drugs and combination therapies, nitrogen mustards and half-mustards, hypoxia-activated drugs, reductase-activated drugs, and minor groove binding agents are presented and discussed. Aspects including measurement strategies, identification of adducts, and biological factors that influence the predictive relationship between DNA modification and biological response are addressed. A positive correlation between DNA adduct levels and response was observed for the majority of the studies, demonstrating the high potential of using DNA adducts from anticancer drugs as mechanism-based biomarkers of susceptibility, especially as bioanalysis approaches with higher sensitivity and throughput emerge. [Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico Adutos de DNA/metabolismo [Mh] Termos MeSH secundário: Animais Biomarcadores/metabolismo Seres Humanos Hipóxia/metabolismo Compostos de Mostarda Nitrogenada/uso terapêutico Oxirredutases/metabolismo Compostos de Platina/uso terapêutico Medicina de Precisão Pró-Fármacos/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Biomarkers); 0 (DNA Adducts); 0 (Nitrogen Mustard Compounds); 0 (Platinum Compounds); 0 (Prodrugs); EC 1.- (Oxidoreductases) [Em] Mês de entrada: 1703 [Cu] Atualização por classe: 170426 [Lr] Data última revisão: 170426 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161213 [St] Status: MEDLINE [do] DOI: 10.1021/acs.chemrestox.6b00380

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[PMID]: 27871834 [Au] Autor: Yang MM; Wilson WR; Wu Z [Ad] Endereço: School of Pharmacy, The University of Auckland, Auckland 1142, New Zealand. [Ti] Título: pH-Sensitive PEGylated liposomes for delivery of an acidic dinitrobenzamide mustard prodrug: Pathways of internalization, cellular trafficking and cytotoxicity to cancer cells. [So] Source: Int J Pharm;516(1-2):323-333, 2017 Jan 10. [Is] ISSN: 1873-3476 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: This paper aims to develop and evaluate a pH-sensitive PEGylated liposomal (pPSL) system for tumor-targeted intracellular delivery of SN25860, a weakly acidic, poorly water-soluble dinitrobenzamide mustard prodrug which is activated by the E. coli nitroreductase nfB. pPSL and non pH-sensitive liposomes (nPSL), as reference, were formulated by thin-film hydration; an active drug loading method was developed with the aid of solubilizers. Cytotoxicity was evaluated in an nfsB-transfected EMT6 mouse mammary carcinoma cell line. Cellular uptake of liposomes was evaluated by both high performance liquid chromatography and flow cytometry. Intracellular trafficking was visualised by confocal microscopy. High drug loading (7.0±0.2% w/w) was achieved after systematic optimization of drug loading conditions. pPSL-SN25860 demonstrated a 21 and 24- fold increase in antiproliferative potency compared to nPSL-SN25860 and free drug, respectively. Cells treated with pPSL had a 1.6-2.5- fold increase in intracellular drug concentration compared to nPSL. This trend was consistent with flow cytometry results. Cells treated with chlorpromazine demonstrated reduced uptake of both nPSL (40%) and pPSL (46%), indicating clathrin-mediated endocytosis was the major pathway. Confocal microscopy showed that pPSL had not only undergone faster and greater endocytosis than nPSL but was also homogeneously distributed in the cytosol and nuclei suggesting endosome escape, in contrast to nPSL. [Mh] Termos MeSH primário: Antineoplásicos/administração & dosagem Benzamidas/administração & dosagem Sistemas de Liberação de Medicamentos Neoplasias Mamárias Animais/tratamento farmacológico Compostos de Mostarda Nitrogenada/administração & dosagem [Mh] Termos MeSH secundário: Animais Antineoplásicos/farmacocinética Antineoplásicos/farmacologia Benzamidas/farmacocinética Benzamidas/farmacologia Linhagem Celular Tumoral Proliferação Celular/efeitos dos fármacos Cromatografia Líquida de Alta Pressão/métodos Endossomos/metabolismo Feminino Citometria de Fluxo Concentração de Íons de Hidrogênio Lipossomos Neoplasias Mamárias Animais/patologia Camundongos Microscopia Confocal Compostos de Mostarda Nitrogenada/farmacocinética Compostos de Mostarda Nitrogenada/farmacologia Polietilenoglicóis/química Pró-Fármacos Solubilidade Transfecção [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Benzamides); 0 (Liposomes); 0 (Nitrogen Mustard Compounds); 0 (Prodrugs); 30IQX730WE (Polyethylene Glycols) [Em] Mês de entrada: 1705 [Cu] Atualização por classe: 170509 [Lr] Data última revisão: 170509 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161123 [St] Status: MEDLINE

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[PMID]: 27783294 [Au] Autor: Popova NA; Kaledin VI; Nikolin VP; Bogdanova LA; Morozkova TS; Tornuev YV [Ad] Endereço: Institute of Cytology and Genetics, Siberian Division of the Russian Academy of Sciences, Novosibirsk, Russia. pathol@inbox.ru. [Ti] Título: Different Efficiency of Liposomal Forms with Hydrophilic and Hydrophobic Antitumor Agents in Relation to Solid Transplants of Mouse Tumor and Its Metastases in the Liver. [So] Source: Bull Exp Biol Med;161(6):811-815, 2016 Oct. [Is] ISSN: 1573-8221 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Experiments were performed on the model of transplanted mouse tumor with high incidence of liver metastases. Hydrophilic drug cycloplatam (injected intravenously in liposomes) was more potent than "free cycloplatam" (injected intravenously or intraperitoneally in physiological saline) in inhibiting the growth of natural and experimental metastases in the liver. By contrast, liposomal cycloplatam had lower efficiency than free cycloplatam in suppressing the growth of solid tumor. Liposomal and free cortifen (hydrophobic hormonal cytostatic) produced nearly the same effects on solid tumor growth. Our results suggest that liposomal forms of hydrophobic compounds producing nonselective effect on tumor cells (e.g., actinomycin D or Cosmegen), should not have advantages over free forms. [Mh] Termos MeSH primário: Antineoplásicos/farmacologia Corticosterona/análogos & derivados Neoplasias Hepáticas/tratamento farmacológico Neoplasias Musculares/tratamento farmacológico Compostos de Mostarda Nitrogenada/farmacologia Compostos Organoplatínicos/farmacologia [Mh] Termos MeSH secundário: Animais Antineoplásicos/farmacocinética Linhagem Celular Tumoral Corticosterona/farmacocinética Corticosterona/farmacologia Sistemas de Liberação de Medicamentos Injeções Intraperitoneais Injeções Intravenosas Lipossomos/química Lipossomos/farmacocinética Neoplasias Hepáticas/mortalidade Neoplasias Hepáticas/secundário Camundongos Neoplasias Musculares/mortalidade Neoplasias Musculares/patologia Transplante de Neoplasias Compostos de Mostarda Nitrogenada/farmacocinética Compostos Organoplatínicos/farmacocinética Análise de Sobrevida Resultado do Tratamento [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Liposomes); 0 (Nitrogen Mustard Compounds); 0 (Organoplatinum Compounds); 0 (cortifen); 109837-67-4 (cycloplatam); W980KJ009P (Corticosterone) [Em] Mês de entrada: 1702 [Cu] Atualização por classe: 170209 [Lr] Data última revisão: 170209 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161027 [St] Status: MEDLINE

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[PMID]: 26950072 [Au] Autor: Erzinger MM; Bovet C; Hecht KM; Senger S; Winiker P; Sobotzki N; Cristea S; Beerenwinkel N; Shay JW; Marra G; Wollscheid B; Sturla SJ [Ad] Endereço: Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland. [Ti] Título: Sulforaphane Preconditioning Sensitizes Human Colon Cancer Cells towards the Bioreductive Anticancer Prodrug PR-104A. [So] Source: PLoS One;11(3):e0150219, 2016. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The chemoprotective properties of sulforaphane (SF), derived from cruciferous vegetables, are widely acknowledged to arise from its potent induction of xenobiotic-metabolizing and antioxidant enzymes. However, much less is known about the impact of SF on the efficacy of cancer therapy through the modulation of drug-metabolizing enzymes. To identify proteins modulated by a low concentration of SF, we treated HT29 colon cancer cells with 2.5 µM SF. Protein abundance changes were detected by stable isotope labeling of amino acids in cell culture. Among 18 proteins found to be significantly up-regulated, aldo-keto reductase 1C3 (AKR1C3), bioactivating the DNA cross-linking prodrug PR-104A, was further characterized. Preconditioning HT29 cells with SF reduced the EC50 of PR-104A 3.6-fold. The increase in PR-104A cytotoxicity was linked to AKR1C3 abundance and activity, both induced by SF in a dose-dependent manner. This effect was reproducible in a second colon cancer cell line, SW620, but not in other colon cancer cell lines where AKR1C3 abundance and activity were absent or barely detectable and could not be induced by SF. Interestingly, SF had no significant influence on PR-104A cytotoxicity in non-cancerous, immortalized human colonic epithelial cell lines expressing either low or high levels of AKR1C3. In conclusion, the enhanced response of PR-104A after preconditioning with SF was apparent only in cancer cells provided that AKR1C3 is expressed, while its expression in non-cancerous cells did not elicit such a response. Therefore, a subset of cancers may be susceptible to combined food-derived component and prodrug treatments with no harm to normal tissues. [Mh] Termos MeSH primário: Antineoplásicos/farmacologia Neoplasias do Colo/patologia Isotiocianatos/farmacologia Compostos de Mostarda Nitrogenada/farmacologia [Mh] Termos MeSH secundário: 3-Hidroxiesteroide Desidrogenases/metabolismo Membro C3 da Família 1 de alfa-Ceto Redutase Antineoplásicos/efeitos adversos Transporte Biológico Linhagem Celular Tumoral Diploide Sinergismo Farmacológico Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos Seres Humanos Hidroxiprostaglandina Desidrogenases/metabolismo Mucosa Intestinal/citologia Mucosa Intestinal/efeitos dos fármacos Isotiocianatos/metabolismo Compostos de Mostarda Nitrogenada/efeitos adversos Pró-Fármacos/efeitos adversos Pró-Fármacos/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Isothiocyanates); 0 (Nitrogen Mustard Compounds); 0 (PR-104A); 0 (Prodrugs); EC 1.1.- (3-Hydroxysteroid Dehydrogenases); EC 1.1.1.- (Hydroxyprostaglandin Dehydrogenases); EC 1.1.1.357 (AKR1C3 protein, human); EC 1.1.1.357 (Aldo-Keto Reductase Family 1 Member C3); GA49J4310U (sulforafan) [Em] Mês de entrada: 1608 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160308 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0150219

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[PMID]: 26936530 [Au] Autor: Lopez JP; Shore TB [Ad] Endereço: a Division of Hematology and Oncology , NewYork-Presbyterian/Weill Cornell Medical College , NY , USA. [Ti] Título: Bendamustine and stem-cell mobilization: not so bad! [So] Source: Leuk Lymphoma;57(5):993-4, 2016 May. [Is] ISSN: 1029-2403 [Cp] País de publicação: England [La] Idioma: eng [Mh] Termos MeSH primário: Cloridrato de Bendamustina Mobilização de Células-Tronco Hematopoéticas [Mh] Termos MeSH secundário: Antineoplásicos Alquilantes/uso terapêutico Seres Humanos Compostos de Mostarda Nitrogenada/uso terapêutico [Pt] Tipo de publicação: COMMENT; JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents, Alkylating); 0 (Nitrogen Mustard Compounds); 981Y8SX18M (Bendamustine Hydrochloride) [Em] Mês de entrada: 1608 [Cu] Atualização por classe: 160421 [Lr] Data última revisão: 160421 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160304 [St] Status: MEDLINE [do] DOI: 10.3109/10428194.2016.1153091

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[PMID]: 26718494 [Au] Autor: Yang Y; Li C; Fu Y; Liu Y; Zhang Y; Zhang Y; Zhou P; Yuan Y; Zhou S; Li S; Li C [Ad] Endereço: Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China. [Ti] Título: Redox cycling of a copper complex with benzaldehyde nitrogen mustard-2-pyridine carboxylic acid hydrazone contributes to its enhanced antitumor activity, but no change in the mechanism of action occurs after chelation. [So] Source: Oncol Rep;35(3):1636-44, 2016 Mar. [Is] ISSN: 1791-2431 [Cp] País de publicação: Greece [La] Idioma: eng [Ab] Resumo: Many anticancer drugs used in the clinical have potent metal chelating ability. The formed metal complex(es) may exhibit improved (or antagonistic) antitumor activity. However, the underlying mechanism has received limited attention. Therefore, investigation of the mechanism involved in the change upon chelation is required to extend our understanding of the effects of various drugs. In the present study, the proliferation inhibition effect of benzaldehyde nitrogen mustard-2-pyridine carboxylic acid hydrazone (BNMPH) and its copper complex on tumor cell lines was investigated. The copper chelate exhibited almost a 10-fold increase in antitumor activity (with IC50 <5 µM). The results showed that both BNMPH and its copper complex induced reactive oxygen species (ROS) generation, and caused upregulation of caspase 8 and Bax as well as the downregulation of Bcl-2, indicating that apoptosis was involved in the cytotoxic effects. DNA fragmentation noted in the comet assay further supported ROS involvement. The present study indicated that BNMPH and its copper complex effectively induced S phase arrest and the cell cycle arrest was associated with the downregulation of cyclin D1. The formation of acidic vesicular organelles (AVOs) and an increase in cleaved LC3-II demonstrated that autophagy occurred in the HepG2 cells treated with the agents. Taken together, BNMPH and its copper complex exhibited proliferation inhibition via apoptosis, cell cycle arrest and autophagy, which was dependent on ROS. The enhanced antitumor activity of the copper complex was due to its redox-cycling ability, but the mechanism was not altered compared to BNMPH. Our findings may significantly contribute to the understanding of the anti-proliferative effect of BNMPH and its copper complex. [Mh] Termos MeSH primário: Antineoplásicos/administração & dosagem Autofagia/efeitos dos fármacos Hidrazonas/administração & dosagem Neoplasias Hepáticas/tratamento farmacológico Compostos de Mostarda Nitrogenada/administração & dosagem [Mh] Termos MeSH secundário: Caspase 8/biossíntese Pontos de Checagem do Ciclo Celular/efeitos dos fármacos Complexos de Coordenação/administração & dosagem Cobre/administração & dosagem Fragmentação do DNA/efeitos dos fármacos Regulação Neoplásica da Expressão Gênica Células Hep G2 Seres Humanos Neoplasias Hepáticas/genética Neoplasias Hepáticas/patologia Espécies Reativas de Oxigênio/metabolismo Proteína X Associada a bcl-2/biossíntese [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Coordination Complexes); 0 (Hydrazones); 0 (Nitrogen Mustard Compounds); 0 (Reactive Oxygen Species); 0 (bcl-2-Associated X Protein); 0 (benzaldehyde nitrogen mustard-2-pyridine carboxyl acid hydrazone); 789U1901C5 (Copper); EC 3.4.22.- (CASP8 protein, human); EC 3.4.22.- (Caspase 8) [Em] Mês de entrada: 1610 [Cu] Atualização por classe: 161230 [Lr] Data última revisão: 161230 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160101 [St] Status: MEDLINE [do] DOI: 10.3892/or.2015.4530

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[PMID]: 26692166 [Au] Autor: Groehler A; Villalta PW; Campbell C; Tretyakova N [Ad] Endereço: Department of Medicinal Chemistry, ‡Department of Pharmacology, and §Masonic Cancer Center, University of Minnesota , Minneapolis, Minnesota 55455, United States. [Ti] Título: Covalent DNA-Protein Cross-Linking by Phosphoramide Mustard and Nornitrogen Mustard in Human Cells. [So] Source: Chem Res Toxicol;29(2):190-202, 2016 Feb 15. [Is] ISSN: 1520-5010 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: N,N-Bis-(2-chloroethyl)-phosphorodiamidic acid (phosphoramide mustard, PM) and N,N-bis-(2-chloroethyl)-amine (nornitrogen mustard, NOR) are the two biologically active metabolites of cyclophosphamide, a DNA alkylating drug commonly used to treat lymphomas, breast cancer, certain brain cancers, and autoimmune diseases. PM and NOR are reactive bis-electrophiles capable of cross-linking cellular biomolecules to form covalent DNA-DNA and DNA-protein cross-links (DPCs). In the present work, a mass spectrometry-based proteomics approach was employed to characterize PM- and NOR-mediated DNA-protein cross-linking in human cells. Following treatment of human fibrosarcoma cells (HT1080) with cytotoxic concentrations of PM, over 130 proteins were found to be covalently trapped to DNA, including those involved in transcriptional regulation, RNA splicing/processing, chromatin organization, and protein transport. HPLC-ESI(+)-MS/MS analysis of proteolytic digests of DPC-containing DNA from NOR-treated cells revealed a concentration-dependent formation of N-[2-[cysteinyl]ethyl]-N-[2-(guan-7-yl)ethyl]amine (Cys-NOR-N7G) conjugates, confirming that it cross-links cysteine thiols of proteins to the N7 position of guanines in DNA. Cys-NOR-N7G adduct numbers were higher in NER-deficient xeroderma pigmentosum cells (XPA) as compared with repair proficient cells. Furthermore, both XPA and FANCD2 deficient cells were sensitized to PM treatment as compared to that of wild type cells, suggesting that Fanconi anemia and nucleotide excision repair pathways are involved in the removal of cyclophosphamide-induced DNA damage. [Mh] Termos MeSH primário: Alquilantes/química DNA/química Compostos de Mostarda Nitrogenada/química Mostardas de Fosforamida/química Proteínas/química [Mh] Termos MeSH secundário: Linhagem Celular Tumoral Cromatografia Líquida de Alta Pressão DNA/metabolismo Adutos de DNA/análise Seres Humanos Peptídeos/análise Proteínas/metabolismo Proteômica Espectrometria de Massas por Ionização por Electrospray [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL [Nm] Nome de substância: 0 (Alkylating Agents); 0 (DNA Adducts); 0 (Nitrogen Mustard Compounds); 0 (Peptides); 0 (Phosphoramide Mustards); 0 (Proteins); 10159-53-2 (phosphoramide mustard); 9007-49-2 (DNA); IHV3I38UXH (nornitrogen mustard) [Em] Mês de entrada: 1610 [Cu] Atualização por classe: 170220 [Lr] Data última revisão: 170220 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 151223 [St] Status: MEDLINE [do] DOI: 10.1021/acs.chemrestox.5b00430

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