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  1 / 130 MEDLINE  
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[PMID]:28645477
[Au] Autor:Borowa-Mazgaj B; Mróz A; Augustin E; Paluszkiewicz E; Mazerska Z
[Ad] Endereço:Department of Pharmaceutical Technology and Biochemistry, Gdansk University of Technology, Gdansk, Poland. Electronic address: barborow@pg.gda.pl.
[Ti] Título:The overexpression of CPR and P450 3A4 in pancreatic cancer cells changes the metabolic profile and increases the cytotoxicity and pro-apoptotic activity of acridine antitumor agent, C-1748.
[So] Source:Biochem Pharmacol;142:21-38, 2017 Oct 15.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Drug resistance is one of the major causes of pancreatic cancer treatment failure. Thus, it is still imperative to develop new active compounds and novel approach to improve drug efficacy. Here we present 9-amino-1-nitroacridine antitumor agent, C-1748, developed in our laboratory, as a candidate for pancreatic cancer treatment. We examined (i) the cellular response of pancreatic cancer cell lines: Panc-1, MiaPaCa-2, BxPC-3 and AsPC-1, differing in expression levels of commonly mutated genes for this cancer type, to C-1748 treatment and (ii) the role of P450 3A4 isoenzyme and cytochrome P450 reductase (CPR) in the modulation of this response. C-1748 exhibited the highest cytotoxic activity against MiaPaCa-2, while AsPC-1 cells were the most resistant (IC : 0.015, 0.075µM, respectively). A considerable amount of apoptosis was detected in Panc-1 and MiaPaCa-2 cells but only limited apoptosis was observed in AsPC-1 and BxPC-3 cells as indicated by morphological changes and biochemical markers. Furthermore, only AsPC-1 cells underwent senescence. Since AsPC-1 cells were the most resistant to C-1748 as evidenced by the lowest P450 3A4 and CPR protein levels, this cell line was subjected to transient transfection either with P450 3A4 or CPR gene. The overexpression of P450 3A4 or CPR changed the pro-apoptotic activity of C-1748 and sensitized AsPC-1 cells to this drug compared to wild-type cells. However, metabolism was changed significantly only for CPR overexpressing cells. In conclusion, the antitumor effectiveness of C-1748 would be improved by multi-drug therapy with chemotherapeutics, that are able to induce P450 3A4 and/or CPR gene expression.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Apoptose/efeitos dos fármacos
Citocromo P-450 CYP3A/metabolismo
NADPH-Ferri-Hemoproteína Redutase/metabolismo
Nitracrina/análogos & derivados
Neoplasias Pancreáticas
[Mh] Termos MeSH secundário: Técnicas de Cultura de Células
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Citocromo P-450 CYP3A/genética
Resistência a Medicamentos Antineoplásicos/genética
Citometria de Fluxo
Expressão Gênica
Seres Humanos
Potencial da Membrana Mitocondrial/efeitos dos fármacos
NADPH-Ferri-Hemoproteína Redutase/genética
Nitracrina/farmacologia
Neoplasias Pancreáticas/enzimologia
Neoplasias Pancreáticas/genética
Neoplasias Pancreáticas/patologia
Transfecção
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine); 0 (Antineoplastic Agents); 712MLZ30SB (Nitracrine); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP3A); EC 1.6.2.4 (NADPH-Ferrihemoprotein Reductase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170625
[St] Status:MEDLINE


  2 / 130 MEDLINE  
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[PMID]:26046973
[Au] Autor:Hoffmann GR; Gray CL; Lange PB; Marando CI
[Ad] Endereço:Department of Biology, College of the Holy Cross, Worcester, MA 01610-2395, USA. Electronic address: ghoffmann@holycross.edu.
[Ti] Título:A source of artifact in the lacZ reversion assay in Escherichia coli.
[So] Source:Mutat Res Genet Toxicol Environ Mutagen;784-785:23-30, 2015 Jun.
[Is] ISSN:1879-3592
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The lacZ reversion assay in Escherichia coli measures point mutations that occur by specific base substitutions and frameshift mutations. The tester strains cannot use lactose as a carbon source (Lac(-)), and revertants are easily detected by growth on lactose medium (Lac(+)). Six strains identify the six possible base substitutions, and five strains measure +G, -G, -CG, +A and -A frameshifts. Strong mutagens give dose-dependent increases in numbers of revertants per plate and revertant frequencies. Testing compounds that are arguably nonmutagens or weakly mutagenic, we often noted statistically significant dose-dependent increases in revertant frequency that were not accompanied by an absolute increase in numbers of revertants. The increase in frequency was wholly ascribable to a declining number of viable cells owing to toxicity. Analysis of the conditions revealed that the frequency of spontaneous revertants is higher when there are fewer viable cells per plate. The phenomenon resembles "adaptive" or "stress" mutagenesis, whereby lactose revertants accumulate in Lac(-) bacteria under starvation conditions in the absence of catabolite repression. Adaptive mutation is observed after long incubation and might be expected to be irrelevant in a standard assay using 48-h incubation. However, we found that elevated revertant frequencies occur under typical assay conditions when the bacterial lawn is thin, and this can cause increases in revertant frequency that mimic chemical mutagenesis when treatments are toxic but not mutagenic. Responses that resemble chemical mutagenesis were observed in the absence of mutagenic treatment in strains that revert by different frameshift mutations. The magnitude of the artifact is affected by cell density, dilution, culture age, incubation time, catabolite repression and the age and composition of media. Although the specific reversion assay is effective for quickly distinguishing classes of mutations induced by potent mutagens, its utility for discerning effects of weak mutagens may be compromised by the artifact.
[Mh] Termos MeSH primário: Escherichia coli/genética
Óperon Lac/efeitos dos fármacos
Nitracrina/efeitos adversos
[Mh] Termos MeSH secundário: Adaptação Biológica/efeitos dos fármacos
Substituição de Aminoácidos
Escherichia coli/efeitos dos fármacos
Mutação da Fase de Leitura
Mutagênese
Taxa de Mutação
Mutação Puntual
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
712MLZ30SB (Nitracrine)
[Em] Mês de entrada:1508
[Cu] Atualização por classe:150606
[Lr] Data última revisão:
150606
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150606
[St] Status:MEDLINE


  3 / 130 MEDLINE  
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[PMID]:24890801
[Au] Autor:Augustin E; Niemira M; Holownia A; Mazerska Z
[Ad] Endereço:Department of Pharmaceutical Technology and Biochemistry, Chemical Faculty, Gdansk University of Technology, Narutowicza Str. 11/12, 80-233, Gdansk, Poland.
[Ti] Título:CYP3A4-dependent cellular response does not relate to CYP3A4-catalysed metabolites of C-1748 and C-1305 acridine antitumor agents in HepG2 cells.
[So] Source:Cell Biol Int;38(11):1291-303, 2014 Nov.
[Is] ISSN:1095-8355
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:High CYP3A4 expression sensitizes tumor cells to certain antitumor agents while for others it can lower their therapeutic efficacy. We have elucidated the influence of CYP3A4 overexpression on the cellular response induced by antitumor acridine derivatives, C-1305 and C-1748, in two hepatocellular carcinoma (HepG2) cell lines, Hep3A4 stably transfected with CYP3A4 isoenzyme, and HepC34 expressing empty vector. The compounds were selected considering their different chemical structures and different metabolic pathways seen earlier in human and rat liver microsomes C-1748 was transformed to several metabolites at a higher rate in Hep3A4 than in HepC34 cells. In contrast, C-1305 metabolism in Hep3A4 cells was unchanged compared to HepC34 cells, with each cell line producing a single metabolite of comparable concentration. C-1748 resulted in a progressive appearance of sub-G1 population to its high level in both cell lines. In turn, the sub-G1 fraction was dominated in CYP3A4-overexpressing cells following C-1305 exposure. Both compounds induced necrosis and to a lesser extent apoptosis, which were more pronounced in Hep3A4 than in wild-type cells. In conclusion, CYP3A4-overexpressing cells produce higher levels of C-1748 metabolites, but they do not affect the cellular responses to the drug. Conversely, cellular response was modulated following C-1305 treatment in CYP3A4-overexpressing cells, although metabolism of this drug was unaltered.
[Mh] Termos MeSH primário: Acridinas/toxicidade
Antineoplásicos/toxicidade
Citocromo P-450 CYP3A/metabolismo
Nitracrina/análogos & derivados
Triazóis/toxicidade
[Mh] Termos MeSH secundário: Acridinas/química
Acridinas/metabolismo
Antineoplásicos/análise
Antineoplásicos/metabolismo
Biocatálise
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Cromatografia Líquida de Alta Pressão
Células Hep G2
Seres Humanos
Espectrometria de Massas
Nitracrina/química
Nitracrina/metabolismo
Nitracrina/toxicidade
Triazóis/química
Triazóis/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine); 0 (Acridines); 0 (Antineoplastic Agents); 0 (C 1305); 0 (Triazoles); 712MLZ30SB (Nitracrine); EC 1.14.14.1 (Cytochrome P-450 CYP3A)
[Em] Mês de entrada:1506
[Cu] Atualização por classe:141007
[Lr] Data última revisão:
141007
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140604
[St] Status:MEDLINE
[do] DOI:10.1002/cbin.10322


  4 / 130 MEDLINE  
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[PMID]:23688499
[Au] Autor:Niemira M; Dastych J; Mazerska Z
[Ad] Endereço:Department of Pharmaceutical Technology and Biochemistry, Chemical Faculty, Gdansk University of Technology, Narutowicza 11/12, 80-233, Gdansk, Poland. m.niemira@gmail.com
[Ti] Título:Pregnane X receptor dependent up-regulation of CYP2C9 and CYP3A4 in tumor cells by antitumor acridine agents, C-1748 and C-1305, selectively diminished under hypoxia.
[So] Source:Biochem Pharmacol;86(2):231-41, 2013 Jul 15.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Induction of proteins involved in drug metabolism and in drug delivery has a significant impact on drug-drug interactions and on the final therapeutic effects. Two antitumor acridine derivatives selected for present studies, C-1748 (9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine) and C-1305 (5-dimethylaminopropylamino-8-hydroxy-triazoloacridinone), expressed high and low susceptibility to metabolic transformations with liver microsomes, respectively. In the current study, we examined the influence of these compounds on cytochrome P450 3A4 (CYP3A4) and 2C9 (CYP2C9) enzymatic activity and gene expression in HepG2 tumor cells. Luminescence and HPLC examination, real-time RT-PCR and western blot analyses along with transfection of pregnane X receptor (PXR) siRNA and CYP3A4 reporter gene assays were applied. We found that both compounds strongly induced CYP3A4 and CYP2C9 activity and expression as well as expression of UGT1A1 and MDR1 in a concentration- and time-dependent manner. C-1748-mediated CYP3A4 and CYP2C9 mRNA induction equal to rifampicin occurred at extremely low concentrations (0.001 and 0.01µM), whereas 10µM C-1305 induced three-times higher CYP3A4 and CYP2C9 mRNA levels than rifampicin did. CYP3A4 and CYP2C9 expressions were shown to be PXR-dependent; however, neither compound influenced PXR expression. Thus, the observed drug-mediated induction of isoenzymes occurs on a PXR-mediated regulatory level. Furthermore, C-1748 and C-1305 were demonstrated to be selective PXR agonists. These effects are hypoxia-inhibited only in the case of C-1748, which is sensitive to P450 metabolism. In summary, PXR was found to be a new target of the studied compounds. Thus, possible combinations of these compounds with other therapeutics might lead to the PXR-dependent enzyme-mediated drug-drug interactions.
[Mh] Termos MeSH primário: Acridinas/farmacologia
Antineoplásicos/farmacologia
Hidrocarboneto de Aril Hidroxilases/metabolismo
Citocromo P-450 CYP3A/metabolismo
Hipóxia/metabolismo
Nitracrina/análogos & derivados
Receptores de Esteroides/fisiologia
Triazóis/farmacologia
Regulação para Cima
[Mh] Termos MeSH secundário: Sequência de Bases
Western Blotting
Citocromo P-450 CYP2C9
Primers do DNA
Células Hep G2
Seres Humanos
Hipóxia/enzimologia
Nitracrina/farmacologia
Reação em Cadeia da Polimerase em Tempo Real
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine); 0 (Acridines); 0 (Antineoplastic Agents); 0 (C 1305); 0 (DNA Primers); 0 (Receptors, Steroid); 0 (Triazoles); 0 (pregnane X receptor); 712MLZ30SB (Nitracrine); EC 1.14.13.- (CYP2C9 protein, human); EC 1.14.13.- (Cytochrome P-450 CYP2C9); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases); EC 1.14.14.1 (Cytochrome P-450 CYP3A)
[Em] Mês de entrada:1309
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130522
[St] Status:MEDLINE


  5 / 130 MEDLINE  
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[PMID]:22484277
[Au] Autor:Wisniewska A; Niemira M; Jagiello K; Potega A; Swist M; Henderson C; Skwarska A; Augustin E; Konopa J; Mazerska Z
[Ad] Endereço:Department of Pharmaceutical Technology and Biochemistry, Chemical Faculty, Gdansk University of Technology, Narutowicza Street 11/12, 80-233 Gdansk, Poland. awisniewska2@gmail.com.pl
[Ti] Título:Diminished toxicity of C-1748, 4-methyl-9-hydroxyethylamino-1-nitroacridine, compared with its demethyl analog, C-857, corresponds to its resistance to metabolism in HepG2 cells.
[So] Source:Biochem Pharmacol;84(1):30-42, 2012 Jul 01.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The narrow "therapeutic window" of anti-tumour therapy may be the result of drug metabolism leading to the activation or detoxification of antitumour agents. The aim of this work is to examine (i) whether the diminished toxicity of a potent antitumour drug, C-1748, 9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine, compared with its 4-demethyl analogue, C-857, results from the differences between the metabolic pathways for the two compounds and (ii) the impact of reducing and/or hypoxic conditions on studied metabolism. We investigated the metabolites of C-1748 and C-857 formed in rat and human liver microsomes, with human P450 reductase (POR) and in HepG2 cells under normoxia and hypoxia. The elimination rate of C-1748 from POR knockout mice (HRN) was also evaluated. Three products, 1-amino-9-hydroxyethylaminoacridine, 1-aminoacridinone and a compound with an additional 6-membered ring, were identified for C-1748 and C-857 in all studied metabolic systems. The new metabolite was found in HepG2 cells. We showed that metabolic rate and the reactivity of metabolites of C-1748 were considerably lower than those of C-857, in all investigated metabolic models. Compared with metabolism under normoxia, cellular metabolism under hypoxia led to higher levels of 1-aminoacridine and aza-acridine derivatives of both compounds and of the 6-membered ring metabolite of C-1748. In conclusion, the crucial role of hypoxic conditions and the direct involvement of POR in the metabolism of both compounds were demonstrated. Compared with C-857, the low reactivity of C-1748 and the stability of its metabolites are postulated to contribute significantly to the diminished toxicity of this compound observed in animals.
[Mh] Termos MeSH primário: Aminoacridinas/metabolismo
Aminoacridinas/farmacologia
Antineoplásicos/metabolismo
Antineoplásicos/farmacologia
Nitracrina/análogos & derivados
[Mh] Termos MeSH secundário: Aminoacridinas/química
Animais
Antineoplásicos/química
Biotransformação
Técnicas de Cultura de Células
Hipóxia Celular/fisiologia
Cromatografia Líquida de Alta Pressão
Células Hep G2
Seres Humanos
Masculino
Camundongos
Camundongos Knockout
Microssomos Hepáticos/enzimologia
Microssomos Hepáticos/metabolismo
Estrutura Molecular
NADPH-Ferri-Hemoproteína Redutase/genética
NADPH-Ferri-Hemoproteína Redutase/fisiologia
Nitracrina/química
Nitracrina/metabolismo
Nitracrina/farmacologia
Ratos
Espectrometria de Massas por Ionização por Electrospray
Relação Estrutura-Atividade
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (1-nitro-9-(2'-hydroxyethylamino)acridine hydrochloride); 0 (9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine); 0 (Aminoacridines); 0 (Antineoplastic Agents); 712MLZ30SB (Nitracrine); EC 1.6.2.4 (NADPH-Ferrihemoprotein Reductase)
[Em] Mês de entrada:1207
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120410
[St] Status:MEDLINE
[do] DOI:10.1016/j.bcp.2012.03.013


  6 / 130 MEDLINE  
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[PMID]:21444205
[Au] Autor:Christodoulou A; Kostakis IK; Kourafalos V; Pouli N; Marakos P; Trougakos IP; Tsitsilonis OE
[Ad] Endereço:Division of Pharmaceutical Chemistry, Department of Pharmacy, University of Athens, Panepistimiopolis-Zografou, Athens 15771, Greece.
[Ti] Título:Design, synthesis and antiproliferative activity of novel aminosubstituted benzothiopyranoisoindoles.
[So] Source:Bioorg Med Chem Lett;21(10):3110-2, 2011 May 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The synthesis of a number of new benzothiopyrano[4,3,2-cd]isoindole aminoderivatives designed as structural analogues of the key metabolite of the anticancer agent Ledacrine (nitracrine) and their in vitro cytotoxic activity evaluation against HCT-116, MES-SA, and MES-SA/Dx cancer cell lines is reported. The majority of the derivatives possessed noticeable cytotoxicity in a low µM range indicating an interesting structure-activity relationship.
[Mh] Termos MeSH primário: Aminas/química
Antineoplásicos/síntese química
Antineoplásicos/farmacologia
Desenho de Drogas
Indóis/síntese química
[Mh] Termos MeSH secundário: Aminas/síntese química
Aminas/farmacologia
Antineoplásicos/química
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Seres Humanos
Indóis/química
Indóis/farmacologia
Concentração Inibidora 50
Estrutura Molecular
Nitracrina/química
Piranos/síntese química
Piranos/química
Piranos/farmacologia
Relação Estrutura-Atividade
Compostos de Sulfidrila/síntese química
Compostos de Sulfidrila/química
Compostos de Sulfidrila/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amines); 0 (Antineoplastic Agents); 0 (Indoles); 0 (Pyrans); 0 (Sulfhydryl Compounds); 712MLZ30SB (Nitracrine)
[Em] Mês de entrada:1108
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:110330
[St] Status:MEDLINE
[do] DOI:10.1016/j.bmcl.2011.03.021


  7 / 130 MEDLINE  
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[PMID]:20026080
[Au] Autor:Augustin E; Mos-Rompa A; Nowak-Ziatyk D; Konopa J
[Ad] Endereço:Department of Pharmaceutical Technology and Biochemistry, Gdansk University of Technology, Chemical Faculty, Narutowicza Str. 11/12, 80-233 Gdansk, Poland. augustin@chem.pg.gda.pl
[Ti] Título:Antitumor 1-nitroacridine derivative C-1748, induces apoptosis, necrosis or senescence in human colon carcinoma HCT8 and HT29 cells.
[So] Source:Biochem Pharmacol;79(9):1231-41, 2010 May 01.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:C-1748 is a DNA-binding agent with potent antitumor activity, especially towards prostate and colon carcinoma xenografts in mice. Here, we elucidated the nature of cellular response of human colon carcinoma HCT8 and HT29 cells to C-1748 treatment, at biologically relevant concentrations (EC(90) and their multiplicity). Cell cycle analysis showed gradual increase in HCT8 cells with sub-G1 DNA content (25% after 72h) considered as apoptotic. Hypodiploid cell population increased up to 60% upon treatment with 4x EC(90) concentration of the drug. Compared with HCT8 cells, the fraction of sub-G1 HT29 cells did not exceed 14%, even following 4-fold dose escalation. Morphological changes and biochemical markers such as: phosphatydylserine externalization, apoptotic DNA breaks, mitochondrial dysfunction and caspase activation confirmed the presence of considerable amount of apoptotic HCT8 cells but only a low amount of apoptotic HT29 cells. Next, we demonstrated that HCT8 cells surviving after exposure to C-1748 were in the state of senescence, based on altered cell morphology and expression of a pH 6-dependent beta-galactosidase. On the contrary, no beta-galactosidase staining was observed in HT29 cells after C-1748 treatment. Moreover, prolonged drug incubation (up to 168h) resulted in massive detachment of cells from culture plates, which together with Annexin V/PI results, indicated that necrosis was the main response of HT29 cells to C-1748 treatment. We also determined the ability of C-1748 to induce reactive oxygen species (ROS) in colon cancer cells and demonstrated, that generation of ROS was not essential for C-1748-induced apoptosis and cytotoxic activity of this drug.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Apoptose/efeitos dos fármacos
Neoplasias do Colo/tratamento farmacológico
Necrose/induzido quimicamente
Nitracrina/análogos & derivados
[Mh] Termos MeSH secundário: Antineoplásicos/química
Linhagem Celular Tumoral
Relação Dose-Resposta a Droga
Seres Humanos
Estrutura Molecular
Nitracrina/química
Nitracrina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine); 0 (Antineoplastic Agents); 712MLZ30SB (Nitracrine)
[Em] Mês de entrada:1004
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:091223
[St] Status:MEDLINE
[do] DOI:10.1016/j.bcp.2009.12.012


  8 / 130 MEDLINE  
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[PMID]:17921700
[Au] Autor:Tadi K; Ashok BT; Chen Y; Banerjee D; Wysocka-Skrzela B; Konopa J; Darzynkiewicz Z; Tiwari RK
[Ad] Endereço:Department of Microbiology and Immunology, New York Medical College, Valhalla, New York 10595, USA.
[Ti] Título:Pre-clinical evaluation of 1-nitroacridine derived chemotherapeutic agent that has preferential cytotoxic activity towards prostate cancer.
[So] Source:Cancer Biol Ther;6(10):1632-7, 2007 Oct.
[Is] ISSN:1555-8576
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chemotherapy in prostate cancer (CaP) even as an adjunct has not been a success. In this communication, we report the pre-clinical efficacy of a nitroacridine derivative, C-1748 (9[2'-hydroxyethylamino]-4-methyl-1-nitroacridine) in CaP cell culture and human xenograft animal models. C-1748, a DNA intercalating agent has been derived from its precursor C-857 that was a potent anti-cancer drug, but failed clinical development due to "high" systemic toxicities. Chemical modifications such as the introduction of a "methyl" group imparted novel properties, the most interesting of which is the difference in the IC(50) values between LnCaP (22.5 nM), a CaP cell line and HL-60, a leukemia cell line (>100 nM). Using gammaH2AX as an intervention marker of DNA double strand breaks, we concluded that C-1748 is more efficacious in CaP cells than in HL-60 cells. In hormone dependent cells, the androgen receptor (AR) was identified as an additional target of C-1748. In xenograft studies, administration of C-1748 intra-peritoneally inhibited tumor growth by 80-90% with minimal toxicity. These studies identify C-1748 as a novel acridine drug that has a high therapeutic index and low cytotoxicity on myelocytic cells with potential for clinical development.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Substâncias Intercalantes/uso terapêutico
Nitracrina/análogos & derivados
Neoplasias da Próstata/tratamento farmacológico
[Mh] Termos MeSH secundário: Antagonistas de Receptores de Andrógenos
Animais
Antineoplásicos/farmacologia
Linhagem Celular Tumoral
Regulação para Baixo
Avaliação Pré-Clínica de Medicamentos
Histonas/metabolismo
Seres Humanos
Substâncias Intercalantes/farmacologia
Masculino
Camundongos
Camundongos Endogâmicos BALB C
Nitracrina/farmacologia
Nitracrina/uso terapêutico
Neoplasias da Próstata/metabolismo
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine); 0 (Androgen Receptor Antagonists); 0 (Antineoplastic Agents); 0 (H2AFX protein, human); 0 (Histones); 0 (Intercalating Agents); 712MLZ30SB (Nitracrine)
[Em] Mês de entrada:0804
[Cu] Atualização por classe:161025
[Lr] Data última revisão:
161025
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:071009
[St] Status:MEDLINE


  9 / 130 MEDLINE  
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Fotocópia
[PMID]:17159506
[Au] Autor:Ashok BT; Tadi K; Garikapaty VP; Chen Y; Huang Q; Banerjee D; Konopa J; Tiwari RK
[Ad] Endereço:Department of Microbiology & Immunology, New York Medical College, Valhalla, New York 10595, USA.
[Ti] Título:Preclinical toxicological examination of a putative prostate cancer-specific 4-methyl-1-nitroacridine derivative in rodents.
[So] Source:Anticancer Drugs;18(1):87-94, 2007 Jan.
[Is] ISSN:0959-4973
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Nitroacridines are potent DNA-binding and cytotoxic agents in cancer cells, but could not be developed clinically due to high systemic toxicities. We are developing a 1-nitroacridine derivative, 9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine (C-1748), as an effective chemotherapeutic agent for prostate cancer. C-1748 demonstrates high antitumor efficacy against human prostate cancer xenografts with markedly low mutagenicity and toxicity in dogs compared with its parent 9-(2'-hydroxyethylamino)-1-nitroacridine (C-857). A surprising feature of C-1748 is the 40-fold difference in 50% inhibitory concentration between DU145 prostate cancer and HL-60 leukemia cells. In this study, we report the preclinical toxicity study of a single acute dose of C-1748 in Copenhagen rats and BALB/c mice, intraperitoneally and intravenously for 24 h and 7 days. The effect of C-1748 on hematology, cardiac and liver enzymes, and renal electrolytes was assessed by blood and serum analysis. The LD50 (lethal dose, 50%) for C-1748 was 9 and 13.42 mg/kg compared with 2.2 and 3 mg/kg for C-857 intraperitoneally and intravenously, respectively, in mice. In Copenhagen rats, LD50 was 15 and 14.4 mg/kg intraperitoneally and intravenously, respectively, compared to 4 and 1.3 mg/kg for C-857. No changes in blood cell counts were observed, which were in the normal range for rodents. No changes were observed in clinical chemistries of enzymes such as aspartate aminotransferase, alkaline phosphatase and creatine phosphokinase, which were within the normal range of values. No genome alterations were seen in prostate cancer cell lines by comparative genomic hybridization together with a lack of systemic toxicity, making it a unique cancer cell-type-specific drug that needs further clinical evaluation for toxicity and synergy in combination chemotherapy regimens.
[Mh] Termos MeSH primário: Sangue/efeitos dos fármacos
Rim/efeitos dos fármacos
Fígado/efeitos dos fármacos
Nitracrina/análogos & derivados
[Mh] Termos MeSH secundário: Animais
DNA de Neoplasias/efeitos dos fármacos
Injeções Intraperitoneais
Injeções Intravenosas
Dose Letal Mediana
Fígado/enzimologia
Masculino
Camundongos
Camundongos Endogâmicos BALB C
Nitracrina/administração & dosagem
Nitracrina/uso terapêutico
Nitracrina/toxicidade
Hibridização de Ácido Nucleico
Neoplasias da Próstata/tratamento farmacológico
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine); 0 (DNA, Neoplasm); 712MLZ30SB (Nitracrine)
[Em] Mês de entrada:0701
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:061213
[St] Status:MEDLINE


  10 / 130 MEDLINE  
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Fotocópia
[PMID]:16824751
[Au] Autor:Hadjipavlou C; Kostakis IK; Pouli N; Marakos P; Pratsinis H; Kletsas D
[Ad] Endereço:Division of Pharmaceutical Chemistry, Department of Pharmacy, University of Athens, Panepistimiopolis-Zografou, Athens 15771, Greece.
[Ti] Título:Synthesis and antiproliferative activity of substituted benzopyranoisoindoles: a new class of cytotoxic compounds.
[So] Source:Bioorg Med Chem Lett;16(18):4822-5, 2006 Sep 15.
[Is] ISSN:0960-894X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A series of novel aminosubstituted benzopyranoisoindoles possessing structural analogy to an active nitracrine metabolite are reported. The compounds exhibited interesting cytotoxic activity against a panel of cell lines, which was maximized by the presence of both 1-dialkylaminoethyl and 3-nitro substituents.
[Mh] Termos MeSH primário: Indóis/química
Indóis/toxicidade
[Mh] Termos MeSH secundário: Linhagem Celular
Proliferação Celular/efeitos dos fármacos
DNA/genética
Seres Humanos
Indóis/síntese química
Indóis/classificação
Estrutura Molecular
Nitracrina/química
Nitracrina/metabolismo
Relação Estrutura-Atividade
Xantenos/química
Xantenos/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Indoles); 0 (Xanthenes); 712MLZ30SB (Nitracrine); 9007-49-2 (DNA)
[Em] Mês de entrada:0610
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:060711
[St] Status:MEDLINE



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