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[PMID]:26918678
[Au] Autor:Lv D; Li L; Lu Q; Li Y; Xie F; Li H; Cao J; Liu M; Wu D; He L; Chen L
[Ad] Endereço:Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, University of South China, Hengyang, China.
[Ti] Título:PAK1-cofilin phosphorylation mediates human lung adenocarcinoma cells migration induced by apelin-13.
[So] Source:Clin Exp Pharmacol Physiol;43(5):569-79, 2016 May.
[Is] ISSN:1440-1681
[Cp] País de publicação:Australia
[La] Idioma:eng
[Ab] Resumo:Adipocytokines apelin peptide, the ligand of APJ (putative receptor related to the angiotensin receptor AT1), plays key roles in the pathogenesis and deterioration of cancer. In lung cancer, apelin elevating microvessel densities has been reported. Our previous research has characterized that apelin-13 promoted lung adenocarcinoma cell proliferation. However, the effect of apelin on metastasis in lung adenocarcinoma and the underlying mechanisms remain unclear. This study shows that apelin-13 induced human adenocarcinoma cell migration via the APJ receptor. Apelin-13 phosphorylated PAK1 and cofilin increase the migration of lung adenocarcinoma cells. Moreover, the results verify that over-expression of apelin and APJ contributed to reducing the effect of doxorubicin and razoxane on inhibiting lung adenocarcinoma cells metastasis. Hypoxia activated APJ expression and apelin release in lung adenocarcinoma cells. The results demonstrate a PAK1-cofilin phosphorylation mechanism to mediate lung adenocarcinoma cells migration promoted by apelin-13. This discovery further suggests that APJ and its downstream signalling is a potential target for anti-metastatic therapies in lung adenocarcinoma patients.
[Mh] Termos MeSH primário: Fatores de Despolimerização de Actina/metabolismo
Adenocarcinoma/patologia
Movimento Celular/efeitos dos fármacos
Peptídeos e Proteínas de Sinalização Intercelular/farmacologia
Neoplasias Pulmonares/patologia
Quinases Ativadas por p21/metabolismo
[Mh] Termos MeSH secundário: Receptores de Apelina
Hipóxia Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Relação Dose-Resposta a Droga
Doxorrubicina/farmacologia
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Fosforilação/efeitos dos fármacos
Razoxano/farmacologia
Receptores Acoplados a Proteínas-G/metabolismo
Transdução de Sinais/efeitos dos fármacos
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (APLNR protein, human); 0 (Actin Depolymerizing Factors); 0 (Apelin Receptors); 0 (Intercellular Signaling Peptides and Proteins); 0 (Receptors, G-Protein-Coupled); 0 (apelin-13 peptide); 5AR83PR647 (Razoxane); 80168379AG (Doxorubicin); EC 2.7.11.1 (PAK1 protein, human); EC 2.7.11.1 (p21-Activated Kinases)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160227
[St] Status:MEDLINE
[do] DOI:10.1111/1440-1681.12563


  2 / 808 MEDLINE  
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[PMID]:23831762
[Au] Autor:Jirkovský E; Lencová-Popelová O; Hroch M; Adamcová M; Mazurová Y; Vávrová J; Micuda S; Simunek T; Gersl V; Sterba M
[Ad] Endereço:Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Simkova 870, Hradec Králové 500 38, Czech Republic.
[Ti] Título:Early and delayed cardioprotective intervention with dexrazoxane each show different potential for prevention of chronic anthracycline cardiotoxicity in rabbits.
[So] Source:Toxicology;311(3):191-204, 2013 Sep 15.
[Is] ISSN:1879-3185
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Despite incomplete understanding to its mechanism of action, dexrazoxane (DEX) is still the only clearly effective cardioprotectant against chronic anthracycline (ANT) cardiotoxicity. However, its clinical use is currently restricted to patients exceeding significant ANT cumulative dose (300mg/m(2)), although each ANT cycle may induce certain potentially irreversible myocardial damage. Therefore, the aim of this study was to compare early and delayed DEX intervention against chronic ANT cardiotoxicity and study the molecular events involved. The cardiotoxicity was induced in rabbits with daunorubicin (DAU; 3mg/kg/week for 10 weeks); DEX (60mg/kg) was administered either before the 1st or 7th DAU dose (i.e. after ≈300mg/m(2) cumulative dose). While both DEX administration schedules prevented DAU-induced premature deaths and severe congestive heart failure, only the early intervention completely prevented the left ventricular dysfunction, myocardial morphological changes and mitochondrial damage. Further molecular analyses did not support the assumption that DEX cardioprotection is based and directly proportional to protection from DAU-induced oxidative damage and/or deletions in mtDNA. Nevertheless, DAU induced significant up-regulation of heme oxygenase 1 pathway while heme synthesis was inversely regulated and both changes were schedule-of-administration preventable by DEX. Early and delayed DEX interventions also differed in ability to prevent DAU-induced down-regulation of expression of mitochondrial proteins encoded by both nuclear and mitochondrial genome. Hence, the present functional, morphological as well as the molecular data highlights the enormous cardioprotective effects of DEX and provides novel insights into the molecular events involved. Furthermore, the data suggests that currently recommended delayed intervention may not be able to take advantage of the full cardioprotective potential of the drug.
[Mh] Termos MeSH primário: Antibióticos Antineoplásicos/toxicidade
Cardiotônicos/administração & dosagem
Daunorrubicina/toxicidade
Cardiopatias/prevenção & controle
Razoxano/administração & dosagem
[Mh] Termos MeSH secundário: Animais
Citrato (si)-Sintase/metabolismo
Cardiopatias/induzido quimicamente
Cardiopatias/metabolismo
Cardiopatias/patologia
Masculino
Fator 2 Relacionado a NF-E2/metabolismo
Estresse Oxidativo
Coelhos
Troponina T/sangue
Função Ventricular Esquerda/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antibiotics, Antineoplastic); 0 (Cardiotonic Agents); 0 (NF-E2-Related Factor 2); 0 (Troponin T); 5AR83PR647 (Razoxane); EC 2.3.3.1 (Citrate (si)-Synthase); ZS7284E0ZP (Daunorubicin)
[Em] Mês de entrada:1311
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130709
[St] Status:MEDLINE


  3 / 808 MEDLINE  
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[PMID]:23733910
[Au] Autor:Brower V
[Ti] Título:Cardiotoxicity debated for anthracyclines and trastuzumab in breast cancer.
[So] Source:J Natl Cancer Inst;105(12):835-6, 2013 Jun 19.
[Is] ISSN:1460-2105
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Antraciclinas/efeitos adversos
Anticorpos Monoclonais Humanizados/efeitos adversos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
Neoplasias da Mama/tratamento farmacológico
Insuficiência Cardíaca/induzido quimicamente
Coração/efeitos dos fármacos
Receptor ErbB-2/análise
[Mh] Termos MeSH secundário: Antraciclinas/administração & dosagem
Anticorpos Monoclonais Humanizados/administração & dosagem
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Biomarcadores Tumorais/análise
Neoplasias da Mama/química
Cardiotônicos/uso terapêutico
Quelantes/uso terapêutico
Feminino
Insuficiência Cardíaca/epidemiologia
Insuficiência Cardíaca/prevenção & controle
Seres Humanos
Terapia de Alvo Molecular
Razoxano/uso terapêutico
Volume Sistólico/efeitos dos fármacos
Trastuzumab
[Pt] Tipo de publicação:NEWS
[Nm] Nome de substância:
0 (Anthracyclines); 0 (Antibodies, Monoclonal, Humanized); 0 (Biomarkers, Tumor); 0 (Cardiotonic Agents); 0 (Chelating Agents); 5AR83PR647 (Razoxane); EC 2.7.10.1 (ERBB2 protein, human); EC 2.7.10.1 (Receptor, ErbB-2); P188ANX8CK (Trastuzumab)
[Em] Mês de entrada:1308
[Cu] Atualização por classe:151119
[Lr] Data última revisão:
151119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130605
[St] Status:MEDLINE
[do] DOI:10.1093/jnci/djt161


  4 / 808 MEDLINE  
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[PMID]:23714670
[Au] Autor:Wang P; Zhang S; Zhang XB; Li WJ; Hao XM; Zhang J
[Ad] Endereço:3rd Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
[Ti] Título:[Protective effect of dexrazoxane on cardiotoxicity in breast cancer patients who received anthracycline-containing chemotherapy].
[So] Source:Zhonghua Zhong Liu Za Zhi;35(2):135-9, 2013 Feb.
[Is] ISSN:0253-3766
[Cp] País de publicação:China
[La] Idioma:chi
[Ab] Resumo:OBJECTIVE: To evaluate the cardioprotective effects of dexrazoxane (DEX) on breast cancer patients who received anthracycline-containing chemotherapy. METHODS: A total of 122 breast cancer patients after operation were randomly divided into two groups: The experimental group of 61 cases treated with EPI plus DEX (DEX:EPI = 10:1) as adjuvant chemotherapy regimen, and the control group of 61 cases treated with EPI but without DEX. All patients received four cycles of adjuvant chemotherapy and their changes of specific cardiac functional status and hematology status before and after chemotherapy, as well as non-cardiac toxicity were observed and analyzed. RESULTS: Brain natriuretic peptide (BNP) before chemotherapy and after four cycles of chemotherapy in the control group was (106.78 ± 4.52)×10(-6) µg/ml and (187.19 ± 8.71)×10(-6) µg/ml, respectively, with a significant difference between them (P < 0.05). It in the experimental group was (102.34 ± 8.76)×10(-6) µg/ml and (105.29 ± 7.21)×10(-6) µg/ml, respectively, without a significant difference (P > 0.05). Cardiac troponin T (cTnT) before chemotherapy and after four cycles of chemotherapy in the control group was (12.55 ± 2.73)×10(-3) µg/ml and ( 31.05 ± 7.10 )×10(-3) µg/ml, respectively, with a significant difference between them (P < 0.05). It in the experimental group was (12.70 ± 2.15)×10(-3) µg/ml and (13.65 ± 7.82)×10(-3) µg/ml, respectively, without a significant difference (P > 0.05). The hart rate (HR) before chemotherapy and after four cycles of chemotherapy in the control group, was 75.32 ± 7.14 bpm and 89.60 ± 9.21 bpm, respectively, with a significant difference (P < 0.05). It in the experimental group was 78.60 ± 6.29 bpm and 83.10 ± 7.56 bpm, respectively, without a significant difference (P > 0.05). The left ventricular ejection fraction (LVEF) before chemotherapy and after four cycles of chemotherapy in the control group was (65.23 ± 7.82)% and (55.21 ± 7.23)%, respectively, with a significant difference between them (P < 0.05). It in the experimental group was (64.12 ± 6.25)% and (59.6 ± 4.72)%, respectively, without a significant difference (P > 0.05). The absolute neutrophil count before chemotherapy and after four cycles of chemotherapy in the control group was (3.95 ± 1.36)×10(9)/L and (3.50 ± 1.52)×10(9)/L, respectively, without a significant difference (P > 0.05). It in the experimental group, was (4.96 ± 1.41)×10(9)/L and (3.10 ± 1.26)×10(9)/L, respectively, with a significant difference (P < 0.05). The incidence of grade I-IV bone marrow suppression in the experimental group was 21.3%, 16.4%, 24.6%, and 4.9%, respectively. It in the control group was 16.4%, 11.5%, 9.8%, and 5.5%, respectively, with a significant difference (P < 0.05). CONCLUSIONS: Cardiac toxicity after anthracycline treatment in breast cancer patients may be significantly reduced by DEX, without increase of non-cardiac and and non-hematologic toxicity. DEX combined with anthracycline increases the risk of bone marrow suppression, therefore, peripheral blood picture should be monitored or routine bone marrow support may be needed.
[Mh] Termos MeSH primário: Antibióticos Antineoplásicos/uso terapêutico
Neoplasias da Mama/tratamento farmacológico
Fármacos Cardiovasculares/uso terapêutico
Epirubicina/uso terapêutico
Razoxano/uso terapêutico
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Antibióticos Antineoplásicos/efeitos adversos
Medula Óssea/efeitos dos fármacos
Neoplasias da Mama/metabolismo
Neoplasias da Mama/patologia
Neoplasias da Mama/fisiopatologia
Neoplasias da Mama/cirurgia
Fármacos Cardiovasculares/efeitos adversos
Quimioterapia Adjuvante
Epirubicina/efeitos adversos
Feminino
Seguimentos
Frequência Cardíaca/efeitos dos fármacos
Seres Humanos
Contagem de Leucócitos
Meia-Idade
Peptídeo Natriurético Encefálico/metabolismo
Neutrófilos/citologia
Razoxano/efeitos adversos
Volume Sistólico/efeitos dos fármacos
Adulto Jovem
[Pt] Tipo de publicação:ENGLISH ABSTRACT; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Antibiotics, Antineoplastic); 0 (Cardiovascular Agents); 114471-18-0 (Natriuretic Peptide, Brain); 3Z8479ZZ5X (Epirubicin); 5AR83PR647 (Razoxane)
[Em] Mês de entrada:1310
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130530
[St] Status:MEDLINE
[do] DOI:10.3760/cma.j.issn.0253-3766.2013.02.013


  5 / 808 MEDLINE  
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[PMID]:23550461
[Au] Autor:Doornaert M; Monstrey S; Roche N
[Ad] Endereço:Plastic and Reconstructive Surgery, University Hospital Ghent, Belgium. Maarten.Doornaert@Ugent.be
[Ti] Título:Extravasation injuries: current medical and surgical treatment.
[So] Source:Acta Chir Belg;113(1):1-7, 2013 Jan-Feb.
[Is] ISSN:0001-5458
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Extravasation is a devastating complication of intravenous therapy that develops when a drug infiltrates the interstitial tissue surrounding the vein. Due to the uncertain and possibly dramatic outcome, early recognition and adequate treatment with the aid of a standardized protocol are needed. METHODS: A pubmed literature search was conducted and all relevant articles were reviewed for the development of an extravasation treatment protocol. RESULTS: An overview of current treatment guidelines and clinical experience is provided. The extravasation treatment protocol was implied during 1 year in this university hospital with satisfactory outcome. CONCLUSION: Treatment starts with prevention. In case of an established extravasation injury, early recognition, assessment of severity, and treatment with medical and/or surgical therapies are recommended.
[Mh] Termos MeSH primário: Extravasamento de Materiais Terapêuticos e Diagnósticos/terapia
[Mh] Termos MeSH secundário: Animais
Fármacos Cardiovasculares/uso terapêutico
Protocolos Clínicos
Citostáticos/efeitos adversos
Citostáticos/uso terapêutico
Extravasamento de Materiais Terapêuticos e Diagnósticos/cirurgia
Seres Humanos
Necrose
Razoxano/uso terapêutico
Pele/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Cardiovascular Agents); 0 (Cytostatic Agents); 5AR83PR647 (Razoxane)
[Em] Mês de entrada:1306
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130405
[St] Status:MEDLINE


  6 / 808 MEDLINE  
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[PMID]:23474841
[Au] Autor:Polanski AK; Ebner A; Ebner B; Hofmann A; Steinbronn N; Brandt A; Forkmann M; Tausche AK; Morawietz H; Strasser RH; Wunderlich C
[Ad] Endereço:Department of Medicine and Cardiology; University of Technology-Dresden, Germany.
[Ti] Título:Dexrazoxane prevents the development of the impaired cardiac phenotype in caveolin-1-disrupted mice.
[So] Source:J Cardiovasc Pharmacol;61(6):545-52, 2013 Jun.
[Is] ISSN:1533-4023
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:: Caveolin-1-deficient (cav1) mice display a severely diseased cardiac phenotype with systolic and diastolic heart failure. Accumulating evidence supports a causative role of uncoupled endothelial nitric oxide synthase in the development of these abnormalities. Interestingly, a similar molecular mechanism was proposed for anthracycline-induced cardiomyopathy. Currently, dexrazoxane is approved for the prevention of anthracycline-induced cardiomyopathy. Given the molecular similarities between the anthracycline-induced cardiomyopathy and the cardiomyopathy in cav1 mice, we questioned whether dexrazoxane may also prevent the evolution of the cardiac pathologies in cav1 mice. We evaluated dexrazoxane treatment for 6 weeks in cav1 mice and wild-type controls. This study provides the first evidence for a reduced reactive oxygen species formation in the vessels of dexrazoxane-treated cav1 mice. This reduced oxidative stress resulted in a markedly reduced rate of apoptosis, which finally was translated into a significantly improved heart function in dexrazoxane-treated cav1 mice. These hemodynamic improvements were accompanied by significantly lowered proatrial natriuretic peptide levels. Notably, these protective properties of dexrazoxane were not evident in wild-type animals. Taken together, these novel findings indicate that dexrazoxane significantly reduces vascular reactive oxygen species formation cav1. Because this is paralleled by an improved cardiac performance in cav1 mice, our data suggest dexrazoxane as a novel therapeutic strategy in this specific cardiomyopathy.
[Mh] Termos MeSH primário: Cardiomiopatias/prevenção & controle
Fármacos Cardiovasculares/uso terapêutico
Caveolina 1/deficiência
Razoxano/uso terapêutico
Espécies Reativas de Oxigênio/metabolismo
Função Ventricular Esquerda/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Fator Natriurético Atrial/sangue
Fator Natriurético Atrial/efeitos dos fármacos
Cardiomiopatias/genética
Cardiomiopatias/metabolismo
Cardiomiopatias/fisiopatologia
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Óxido Nítrico Sintase/efeitos dos fármacos
Óxido Nítrico Sintase/metabolismo
Fenótipo
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cardiovascular Agents); 0 (Caveolin 1); 0 (Reactive Oxygen Species); 5AR83PR647 (Razoxane); 85637-73-6 (Atrial Natriuretic Factor); EC 1.14.13.39 (Nitric Oxide Synthase)
[Em] Mês de entrada:1310
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130312
[St] Status:MEDLINE
[do] DOI:10.1097/FJC.0b013e31828de47c


  7 / 808 MEDLINE  
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[PMID]:23409691
[Au] Autor:Muthuramalingam S; Gale J; Bradbury J
[Ad] Endereço:Queen Alexandra Hospital, Portsmouth, UK. muthuramalingam@porthosp.nhs.uk
[Ti] Título:Dexrazoxane efficacy for anthracycline extravasation: use in UK clinical practice.
[So] Source:Int J Clin Pract;67(3):244-9, 2013 Mar.
[Is] ISSN:1742-1241
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Extravasation is recognised as a major complication of administering intravenous chemotherapy treatment. Of the agents involved in extravasation, anthracyclines are associated with the greatest risk to patients because they are vesicant agents, having the potential to cause blistering and ulceration. If not identified and left untreated, anthracycline extravasation can lead to more serious complications such as tissue necrosis and functional impairment. Dexrazoxane (Savene(®) ) is the only licensed antidote for the treatment of anthracycline extravasation and clinical evidence has shown Savene(®) to be highly effective for preventing the need for surgery following anthracycline extravasation, allowing full recovery in the majority of patients. To date, there have been eight published studies reporting a total of 102 cases of Savene(®) use. Here, we review the published data on the efficacy of Savene(®) and present an analysis of 12 UK case studies. All UK oncology centres where Savene(®) has been used to manage anthracycline extravasation were contacted by SpePharm UK, who requested case studies for this publication. All of the cases received, including two from our own experience of using Savene(®) have been included in the analysis.
[Mh] Termos MeSH primário: Antraciclinas/efeitos adversos
Antídotos/uso terapêutico
Antineoplásicos/efeitos adversos
Quelantes/uso terapêutico
Extravasamento de Materiais Terapêuticos e Diagnósticos/tratamento farmacológico
Razoxano/uso terapêutico
[Mh] Termos MeSH secundário: Adulto
Idoso
Neoplasias da Mama/tratamento farmacológico
Neoplasias Esofágicas/tratamento farmacológico
Feminino
Seres Humanos
Masculino
Meia-Idade
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Anthracyclines); 0 (Antidotes); 0 (Antineoplastic Agents); 0 (Chelating Agents); 5AR83PR647 (Razoxane)
[Em] Mês de entrada:1311
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130216
[St] Status:MEDLINE
[do] DOI:10.1111/ijcp.12103


  8 / 808 MEDLINE  
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[PMID]:23344961
[Au] Autor:Lin RK; Ho CW; Liu LF; Lyu YL
[Ad] Endereço:Department of Pharmacology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
[Ti] Título:Topoisomerase IIß deficiency enhances camptothecin-induced apoptosis.
[So] Source:J Biol Chem;288(10):7182-92, 2013 Mar 08.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Camptothecin (CPT), a topoisomerase (Top) I-targeting drug that stabilizes Top1-DNA covalent adducts, can induce S-phase-specific cytotoxicity due to the arrest of progressing replication forks. However, CPT-induced non-S-phase cytotoxicity is less well characterized. In this study, we have identified topoisomerase IIß (Top2ß) as a specific determinant for CPT sensitivity, but not for many other cytotoxic agents, in non-S-phase cells. First, quiescent mouse embryonic fibroblasts (MEFs) lacking Top2ß were shown to be hypersensitive to CPT with prominent induction of apoptosis. Second, ICRF-187, a Top2 catalytic inhibitor known to deplete Top2ß, specifically sensitized MEFs to CPT. To explore the molecular basis for CPT hypersensitivity in Top2ß-deficient cells, we found that upon CPT exposure, the RNA polymerase II large subunit (RNAP LS) became progressively depleted, followed by recovery to nearly the original level in wild-type MEFs, whereas RNAP LS remained depleted without recovery in Top2ß-deficient cells. Concomitant with the reduction of the RNAP LS level, the p53 protein level was greatly induced. Interestingly, RNAP LS depletion has been well documented to lead to p53-dependent apoptosis. Altogether, our findings support a model in which Top2ß deficiency promotes CPT-induced apoptosis in quiescent non-S-phase cells, possibly due to RNAP LS depletion and p53 accumulation.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Camptotecina/farmacologia
DNA Topoisomerases Tipo II/deficiência
Proteínas de Ligação a DNA/deficiência
Fibroblastos/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/farmacologia
Western Blotting
Sobrevivência Celular/efeitos dos fármacos
Células Cultivadas
DNA Topoisomerases Tipo II/genética
Proteínas de Ligação a DNA/genética
RNA Polimerases Dirigidas por DNA/metabolismo
Relação Dose-Resposta a Droga
Embrião de Mamíferos/citologia
Embrião de Mamíferos/metabolismo
Fibroblastos/metabolismo
Camundongos
Camundongos Knockout
Subunidades Proteicas/metabolismo
Razoxano/farmacologia
Inibidores da Topoisomerase I/farmacologia
Transcrição Genética/efeitos dos fármacos
Proteína Supressora de Tumor p53/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (DNA-Binding Proteins); 0 (Protein Subunits); 0 (Topoisomerase I Inhibitors); 0 (Tumor Suppressor Protein p53); 5AR83PR647 (Razoxane); EC 2.7.7.6 (DNA-Directed RNA Polymerases); EC 5.99.1.3 (DNA Topoisomerases, Type II); XT3Z54Z28A (Camptothecin)
[Em] Mês de entrada:1304
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130125
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M112.415471


  9 / 808 MEDLINE  
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[PMID]:23339990
[Au] Autor:Kovarikova P; Pasakova-Vrbatova I; Vavrova A; Stariat J; Klimes J; Simunek T
[Ad] Endereço:Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic. petra.kovarikova@faf.cuni.cz
[Ti] Título:Development of LC-MS/MS method for the simultaneous analysis of the cardioprotective drug dexrazoxane and its metabolite ADR-925 in isolated cardiomyocytes and cell culture medium.
[So] Source:J Pharm Biomed Anal;76:243-51, 2013 Mar 25.
[Is] ISSN:1873-264X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Dexrazoxane (DEX) is the only clinically used drug effective against anthracycline-induced cardiotoxicity and extravasation injury. However, the mechanism of its cardioprotective action still remains elusive. This paucity of comprehensive data is at least partially caused by the analytical difficulties associated with selective and sensitive simultaneous determination of the parent drug and its putative active metabolite ADR-925 in the relevant biological material. The aim of this study was to develop and validate the first LC-MS/MS method for simultaneous determination of DEX and ADR-925 in the isolated rat neonatal ventricular cardiomyocytes (NVCMs) and the cell culture medium. The analysis was performed on a Synergi Polar-RP column using the gradient profile of the mobile phase composed of 2mM ammonium formate and methanol. Electrospray ionization and ion trap mass analyzer were used as ionization and detection techniques, respectively. NVCMs were precipitated with methanol and the cell culture medium samples were diluted with the same solvent prior the LC-MS/MS analysis. The method was validated within the range of 4-80pmol/10(6) NVCMs and 7-70pmol/10(6) NVCMs for DEX and ADR-925, respectively, and at the concentrations of 8-100µM for both compounds in the culture cell medium. The practical applicability of this method was confirmed by the pilot analysis of NVCMs and the corresponding cell medium samples from relevant in vitro experiment. Hence, the LC-MS/MS method developed in this study represents a modern analytical tool suitable for investigation of DEX bioactivation inside the cardiomyocytes. In addition, the basic utility of the method for the analysis of DEX and ADR-925 in plasma samples was proved in a pilot experiment.
[Mh] Termos MeSH primário: Cromatografia Líquida/métodos
Etilenodiaminas/farmacocinética
Glicina/análogos & derivados
Razoxano/farmacocinética
Espectrometria de Massas em Tandem/métodos
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Fármacos Cardiovasculares/farmacocinética
Células Cultivadas
Glicina/farmacocinética
Miócitos Cardíacos/metabolismo
Projetos Piloto
Coelhos
Ratos
Ratos Wistar
Sensibilidade e Especificidade
Espectrometria de Massas por Ionização por Electrospray/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; VALIDATION STUDIES
[Nm] Nome de substância:
0 (Cardiovascular Agents); 0 (Ethylenediamines); 5AR83PR647 (Razoxane); 75459-34-6 (ICRF 198); TE7660XO1C (Glycine)
[Em] Mês de entrada:1307
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130124
[St] Status:MEDLINE


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[PMID]:23000430
[Au] Autor:Vuong MC; Hasegawa LS; Eastmond DA
[Ad] Endereço:Environmental Toxicology Graduate Program and Department of Cell Biology & Neuroscience, University of California, Riverside, CA 92521, USA.
[Ti] Título:A comparative study of the cytotoxic and genotoxic effects of ICRF-154 and bimolane, two catalytic inhibitors of topoisomerase II.
[So] Source:Mutat Res;750(1-2):63-71, 2013 Jan 20.
[Is] ISSN:0027-5107
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:ICRF-154 and bimolane have been used for the treatment of cancer, psoriasis, and uveitis in humans. Previous reports have revealed that the two drugs are topoisomerase II catalytic inhibitors, and patients treated with these agents have developed unique types of secondary leukemia. A study published in 1984 by Camerman and colleagues proposed that the therapeutic effects of bimolane could be due to ICRF-154, an impurity present within the bimolane samples that may also be responsible for the toxic effects attributed to bimolane. To date, this hypothesis has not been evaluated. In addition, little is known about the potential cytotoxic and genotoxic effects of ICRF-154. In this study, a combination of in vitro tests in human TK6 lymphoblastoid cells has been used to characterize the cytotoxic and genotoxic effects of ICRF-154 and bimolane as well as to compare the results for the two chemicals. ICRF-154 and bimolane were both cytotoxic, exhibiting very similar effects in three measures of cytotoxicity and cell proliferation. In the cytokinesis-block micronucleus assay with CREST-antibody staining, the two agents similarly induced chromosome breakage and, to a lesser extent, chromosome loss. Intriguingly, both drugs resulted in the formation of binucleated cells, perhaps as a consequence of an interference with cytokinesis. To further investigate their aneugenic effects, flow cytometry and fluorescence in situ hybridization analyses revealed that both compounds also produced similar levels of non-disjunction and polyploidy. In each of the cellular and cytogenetic assays employed, the responses of the ICRF-154-treated cells were very similar to those observed with the bimolane, and generally occurred at equimolar test concentrations. Our results, combined with those from previous studies, strongly suggest that bimolane degrades to ICRF-154, and that ICRF-154 is most likely the chemical species responsible for the cytotoxic, genotoxic, and leukemogenic effects exerted by bimolane.
[Mh] Termos MeSH primário: Antineoplásicos/toxicidade
Sobrevivência Celular/efeitos dos fármacos
Aberrações Cromossômicas/induzido quimicamente
Linfócitos/ultraestrutura
Mutagênicos/toxicidade
Razoxano/análogos & derivados
Inibidores da Topoisomerase II/toxicidade
[Mh] Termos MeSH secundário: Linhagem Celular
Citocinese
Seres Humanos
Testes para Micronúcleos
Testes de Mutagenicidade
Razoxano/toxicidade
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Mutagens); 0 (Topoisomerase II Inhibitors); 25O7OKR315 (bimolane); 5AR83PR647 (Razoxane); QML51S42CD (1,2-bis(3,5-dioxopiperazin-1-yl)ethane)
[Em] Mês de entrada:1304
[Cu] Atualização por classe:151119
[Lr] Data última revisão:
151119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120925
[St] Status:MEDLINE



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