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[PMID]:27758143
[Au] Autor:Hattinger CM; Tavanti E; Fanelli M; Vella S; Picci P; Serra M
[Ad] Endereço:a Pharmacogenomics and Pharmacogenetics Research Unit, Laboratory of Experimental Oncology , Orthopaedic Rizzoli Institute , Bologna , Italy.
[Ti] Título:Pharmacogenomics of genes involved in antifolate drug response and toxicity in osteosarcoma.
[So] Source:Expert Opin Drug Metab Toxicol;13(3):245-257, 2017 Mar.
[Is] ISSN:1744-7607
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Antifolates are structural analogs of folates, which have been used as antitumor drugs for more than 60 years. The antifolate drug most commonly used for treating human tumors is methotrexate (MTX), which is utilized widely in first-line treatment protocols of high-grade osteosarcoma (HGOS). In addition to MTX, two other antifolates, trimetrexate and pemetrexed, have been tested in clinical settings for second-line treatment of recurrent HGOS with patients unfortunately showing modest activity. Areas covered: There is clinical evidence which suggsest that, like other chemotherapeutic agents, not all HGOS patients are equally responsive to antifolates and do not have the same susceptibility to experience adverse drug-related toxicities. Here, we summarize the pharmacogenomic information reported so far for genes involved in antifolate metabolism and transport and in MTX-related toxicity in HGOS patients. Expert opinion: Identification and validation of genetic biomarkers that significantly impact clinical antifolate treatment response and related toxicity may provide the basis for a future treatment modulation based on the pharmacogenetic and pharmacogenomic features of HGOS patients.
[Mh] Termos MeSH primário: Neoplasias Ósseas/tratamento farmacológico
Osteossarcoma/tratamento farmacológico
Farmacogenética
[Mh] Termos MeSH secundário: Antimetabólitos Antineoplásicos/efeitos adversos
Antimetabólitos Antineoplásicos/uso terapêutico
Neoplasias Ósseas/genética
Neoplasias Ósseas/patologia
Antagonistas do Ácido Fólico/efeitos adversos
Antagonistas do Ácido Fólico/uso terapêutico
Seres Humanos
Metotrexato/efeitos adversos
Metotrexato/uso terapêutico
Gradação de Tumores
Osteossarcoma/genética
Osteossarcoma/patologia
Pemetrexede/efeitos adversos
Pemetrexede/uso terapêutico
Trimetrexato/efeitos adversos
Trimetrexato/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antimetabolites, Antineoplastic); 0 (Folic Acid Antagonists); 04Q9AIZ7NO (Pemetrexed); UPN4ITI8T4 (Trimetrexate); YL5FZ2Y5U1 (Methotrexate)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170227
[Lr] Data última revisão:
170227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161021
[St] Status:MEDLINE
[do] DOI:10.1080/17425255.2017.1246532


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[PMID]:26848874
[Au] Autor:Cheng YS; Sacchettini JC
[Ad] Endereço:Department of Chemistry, Texas A&M University , College Station, Texas 77842, United States.
[Ti] Título:Structural Insights into Mycobacterium tuberculosis Rv2671 Protein as a Dihydrofolate Reductase Functional Analogue Contributing to para-Aminosalicylic Acid Resistance.
[So] Source:Biochemistry;55(7):1107-19, 2016 Feb 23.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mycobacterium tuberculosis (Mtb) Rv2671 is annotated as a 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione 5'-phosphate (AROPP) reductase (RibD) in the riboflavin biosynthetic pathway. Recently, a strain of Mtb with a mutation in the 5' untranslated region of Rv2671, which resulted in its overexpression, was found to be resistant to dihydrofolate reductase (DHFR) inhibitors including the anti-Mtb drug para-aminosalicylic acid (PAS). In this study, a biochemical analysis of Rv2671 showed that it was able to catalyze the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF), which explained why the overexpression of Rv2671 was sufficient to confer PAS resistance. We solved the structure of Rv2671 in complex with the NADP(+) and tetrahydrofolate (THF), which revealed the structural basis for the DHFR activity. The structures of Rv2671 complexed with two DHFR inhibitors, trimethoprim and trimetrexate, provided additional details of the substrate binding pocket and elucidated the differences between their inhibitory activities. Finally, Rv2671 was unable to catalyze the reduction of AROPP, which indicated that Rv2671 and its closely related orthologues are not involved in riboflavin biosynthesis.
[Mh] Termos MeSH primário: Proteínas de Bactérias/química
Modelos Moleculares
Mycobacterium tuberculosis/enzimologia
NADP/química
Nucleotídeo Desaminases/química
Tetra-Hidrofolato Desidrogenase/química
Tetra-Hidrofolatos/química
[Mh] Termos MeSH secundário: Ácido Aminossalicílico/farmacologia
Antituberculosos/química
Antituberculosos/metabolismo
Antituberculosos/farmacologia
Proteínas de Bactérias/antagonistas & inibidores
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Domínio Catalítico
Farmacorresistência Bacteriana
Inibidores Enzimáticos/química
Inibidores Enzimáticos/metabolismo
Inibidores Enzimáticos/farmacologia
Antagonistas do Ácido Fólico/química
Antagonistas do Ácido Fólico/metabolismo
Antagonistas do Ácido Fólico/farmacologia
Cinética
Ligantes
Conformação Molecular
Mycobacterium tuberculosis/efeitos dos fármacos
Mycobacterium tuberculosis/crescimento & desenvolvimento
NADP/metabolismo
Nucleotídeo Desaminases/antagonistas & inibidores
Nucleotídeo Desaminases/genética
Nucleotídeo Desaminases/metabolismo
Filogenia
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Tetra-Hidrofolato Desidrogenase/genética
Tetra-Hidrofolato Desidrogenase/metabolismo
Tetra-Hidrofolatos/metabolismo
Trimetoprima/química
Trimetoprima/metabolismo
Trimetoprima/farmacologia
Trimetrexato/química
Trimetrexato/metabolismo
Trimetrexato/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 (Antitubercular Agents); 0 (Bacterial Proteins); 0 (Enzyme Inhibitors); 0 (Folic Acid Antagonists); 0 (Ligands); 0 (Recombinant Proteins); 0 (Tetrahydrofolates); 43ZWB253H4 (5,6,7,8-tetrahydrofolic acid); 53-59-8 (NADP); 5B2658E0N2 (Aminosalicylic Acid); AN164J8Y0X (Trimethoprim); EC 1.5.1.3 (Tetrahydrofolate Dehydrogenase); EC 3.5.4.- (Nucleotide Deaminases); UPN4ITI8T4 (Trimetrexate)
[Em] Mês de entrada:1607
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160206
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.5b00993


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[PMID]:26022931
[Au] Autor:Zhang Q; Nguyen T; McMichael M; Velu SE; Zou J; Zhou X; Wu H
[Ad] Endereço:State Key Laboratory of Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, PR China; Department of Pediatric Dentistry, University of Alabama at Birmingham School of Dentistry, Birmingham, AL 35294, USA.
[Ti] Título:New small-molecule inhibitors of dihydrofolate reductase inhibit Streptococcus mutans.
[So] Source:Int J Antimicrob Agents;46(2):174-82, 2015 Aug.
[Is] ISSN:1872-7913
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Streptococcus mutans is a major aetiological agent of dental caries. Formation of biofilms is a key virulence factor of S. mutans. Drugs that inhibit S. mutans biofilms may have therapeutic potential. Dihydrofolate reductase (DHFR) plays a critical role in regulating the metabolism of folate. DHFR inhibitors are thus potent drugs and have been explored as anticancer and antimicrobial agents. In this study, a library of analogues based on a DHFR inhibitor, trimetrexate (TMQ), an FDA-approved drug, was screened and three new analogues that selectively inhibited S. mutans were identified. The most potent inhibitor had a 50% inhibitory concentration (IC50) of 454.0±10.2nM for the biofilm and 8.7±1.9nM for DHFR of S. mutans. In contrast, the IC50 of this compound for human DHFR was ca. 1000nM, a >100-fold decrease in its potency, demonstrating the high selectivity of the analogue. An analogue that exhibited the least potency for the S. mutans biofilm also had the lowest activity towards inhibiting S. mutans DHFR, further indicating that inhibition of biofilms is related to reduced DHFR activity. These data, along with docking of the most potent analogue to the modelled DHFR structure, suggested that the TMQ analogues indeed selectively inhibited S. mutans through targeting DHFR. These potent and selective small molecules are thus promising lead compounds to develop new effective therapeutics to prevent and treat dental caries.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Antagonistas do Ácido Fólico/farmacologia
Streptococcus mutans/efeitos dos fármacos
Trimetrexato/farmacologia
[Mh] Termos MeSH secundário: Biofilmes/efeitos dos fármacos
Avaliação Pré-Clínica de Medicamentos/métodos
Antagonistas do Ácido Fólico/química
Concentração Inibidora 50
Testes de Sensibilidade Microbiana
Modelos Moleculares
Simulação de Dinâmica Molecular
Streptococcus mutans/fisiologia
Tetra-Hidrofolato Desidrogenase/química
Trimetrexato/análogos & derivados
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Folic Acid Antagonists); EC 1.5.1.3 (Tetrahydrofolate Dehydrogenase); UPN4ITI8T4 (Trimetrexate)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:161025
[Lr] Data última revisão:
161025
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150530
[St] Status:MEDLINE


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[PMID]:23987246
[Au] Autor:van der Heijden JW; Assaraf YG; Gerards AH; Oerlemans R; Lems WF; Scheper RJ; Dijkmans BA; Jansen G
[Ad] Endereço:Department of Rheumatology, VU University Medical Center , Amsterdam , The Netherlands.
[Ti] Título:Methotrexate analogues display enhanced inhibition of TNF-α production in whole blood from RA patients.
[So] Source:Scand J Rheumatol;43(1):9-16, 2014.
[Is] ISSN:1502-7732
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: Although methotrexate (MTX) is the anchor drug in the treatment of rheumatoid arthritis (RA), patients experience clinical resistance to MTX upon prolonged treatment. We explored whether new-generation antifolates elicit superior anti-inflammatory properties when compared to MTX, based on their capacity to inhibit tumour necrosis factor (TNF)-α production. METHOD: T cells in whole blood from 18 RA patients (including MTX-naïve, MTX- responsive, and MTX non-responsive patients) and seven healthy volunteers were stimulated with αCD3/αCD28 antibodies and incubated ex vivo for 72 h with MTX and eight novel antifolate drugs with potentially favourable biochemical and pharmacological properties. Drug concentrations exerting 50% inhibition (IC-50) of TNF-α production (by enzyme-linked immunosorbent assay, ELISA) were determined as an estimate for their anti-inflammatory capacity. In addition, induction of T-cell apoptosis was evaluated by flow cytometry. RESULTS: The new-generation antifolates PT523, PT644, raltitrexed, and GW1843 proved to be potent inhibitors of TNF-α production in activated T cells from all three groups of RA patients and from healthy volunteers. Based on IC-50 values, these antifolates were up to 10.3 times more potent than MTX. The anti-inflammatory effects were observed at drug concentrations that provoked suppression of T-cell activation and induction of apoptosis in 20-40% of activated T cells. CONCLUSION: In an ex-vivo setting, novel antifolates elicited marked inhibition of TNF-α production in activated T cells from RA patients. Further clinical evaluation is warranted to investigate whether a low dosage of these antifolates can elicit immunosuppressive effects equivalent to MTX, and whether they are superior to MTX in patients who fail to respond to MTX.
[Mh] Termos MeSH primário: Antirreumáticos/farmacologia
Artrite Reumatoide/tratamento farmacológico
Metotrexato/análogos & derivados
Linfócitos T/efeitos dos fármacos
Fator de Necrose Tumoral alfa/biossíntese
[Mh] Termos MeSH secundário: Antirreumáticos/uso terapêutico
Artrite Reumatoide/imunologia
Artrite Reumatoide/metabolismo
Feminino
Antagonistas do Ácido Fólico/farmacologia
Seres Humanos
Masculino
Metotrexato/farmacologia
Metotrexato/uso terapêutico
Meia-Idade
Ornitina/análogos & derivados
Ornitina/farmacologia
Pterinas/farmacologia
Quinazolinas/farmacologia
Linfócitos T/metabolismo
Tiofenos/farmacologia
Trimetrexato/farmacologia
Fator de Necrose Tumoral alfa/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antirheumatic Agents); 0 (Folic Acid Antagonists); 0 (Pterins); 0 (Quinazolines); 0 (Thiophenes); 0 (Tumor Necrosis Factor-alpha); 113857-87-7 (N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine); E524N2IXA3 (Ornithine); FCB9EGG971 (raltitrexed); UPN4ITI8T4 (Trimetrexate); YL5FZ2Y5U1 (Methotrexate)
[Em] Mês de entrada:1403
[Cu] Atualização por classe:141120
[Lr] Data última revisão:
141120
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130831
[St] Status:MEDLINE
[do] DOI:10.3109/03009742.2013.797490


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[PMID]:22397715
[Au] Autor:Dasgupta A; Shields JE; Spencer HT
[Ad] Endereço:Aflac Cancer Center and Blood Disorders Service, Division of Hematology/Oncology and Bone Marrow Transplantation, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
[Ti] Título:Treatment of a solid tumor using engineered drug-resistant immunocompetent cells and cytotoxic chemotherapy.
[So] Source:Hum Gene Ther;23(7):711-21, 2012 Jul.
[Is] ISSN:1557-7422
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Multimodal therapy approaches, such as combining chemotherapy agents with cellular immunotherapy, suffers from potential drug-mediated toxicity to immune effector cells. Overcoming such toxic effects of anticancer cellular products is a potential critical barrier to the development of combined therapeutic approaches. We are evaluating an anticancer strategy that focuses on overcoming such a barrier by genetically engineering drug-resistant variants of immunocompetent cells, thereby allowing for the coadministration of cellular therapy with cytotoxic chemotherapy, a method we refer to as drug-resistant immunotherapy (DRI). The strategy relies on the use of cDNA sequences that confer drug resistance and recombinant lentiviral vectors to transfer nucleic acid sequences into immunocompetent cells. In the present study, we evaluated a DRI-based strategy that incorporates the immunocompetent cell line NK-92, which has intrinsic antitumor properties, genetically engineered to be resistant to both temozolomide and trimetrexate. These immune effector cells efficiently lysed neuroblastoma cell lines, which we show are also sensitive to both chemotherapy agents. The antitumor efficacy of the DRI strategy was demonstrated in vivo, whereby neuroblastoma-bearing NOD/SCID/γ-chain knockout (NSG) mice treated with dual drug-resistant NK-92 cell therapy followed by dual cytotoxic chemotherapy showed tumor regression and significantly enhanced survival compared with animals receiving either nonengineered cell-based therapy and chemotherapy, immunotherapy alone, or chemotherapy alone. These data show there is a benefit to using drug-resistant cellular therapy when combined with cytotoxic chemotherapy approaches.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Imunoterapia Adotiva
Células Matadoras Naturais/transplante
Neuroblastoma/terapia
[Mh] Termos MeSH secundário: Animais
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Linhagem Celular
Sobrevivência Celular
Técnicas de Cocultura
Terapia Combinada
Citotoxicidade Imunológica
Metilases de Modificação do DNA/biossíntese
Metilases de Modificação do DNA/genética
Enzimas Reparadoras do DNA/biossíntese
Enzimas Reparadoras do DNA/genética
Dacarbazina/administração & dosagem
Dacarbazina/análogos & derivados
Resistência a Medicamentos Antineoplásicos/genética
Engenharia Genética
Seres Humanos
Células Matadoras Naturais/efeitos dos fármacos
Células Matadoras Naturais/metabolismo
Camundongos
Camundongos Endogâmicos NOD
Camundongos SCID
Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo
Neuroblastoma/imunologia
Neuroblastoma/patologia
Proteínas Recombinantes/biossíntese
Proteínas Recombinantes/genética
Tetra-Hidrofolato Desidrogenase/biossíntese
Tetra-Hidrofolato Desidrogenase/genética
Trimetrexato/administração & dosagem
Carga Tumoral
Proteínas Supressoras de Tumor/biossíntese
Proteínas Supressoras de Tumor/genética
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (NK Cell Lectin-Like Receptor Subfamily K); 0 (Recombinant Proteins); 0 (Tumor Suppressor Proteins); 7GR28W0FJI (Dacarbazine); EC 1.5.1.3 (Tetrahydrofolate Dehydrogenase); EC 2.1.1.- (DNA Modification Methylases); EC 2.1.1.63 (MGMT protein, human); EC 6.5.1.- (DNA Repair Enzymes); UPN4ITI8T4 (Trimetrexate); YF1K15M17Y (temozolomide)
[Em] Mês de entrada:1211
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120309
[St] Status:MEDLINE
[do] DOI:10.1089/hum.2011.172


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[PMID]:21713721
[Au] Autor:Borde JP; Offensperger WB; de With K
[Ad] Endereço:Klinik für Gastroenterologie, Hepatologie und Infektiologie, Ortenauklinik Offenburg-Gengenbach.
[Ti] Título:[Diagnosis and treatment of pneumocystis jirovecii pneumonia].
[Ti] Título:Aktuelle Diagnostik und Therapie der Pneumocystis-jirovecii-Pneumonie..
[So] Source:Dtsch Med Wochenschr;136(27):1426-30, 2011 Jul.
[Is] ISSN:1439-4413
[Cp] País de publicação:Germany
[La] Idioma:ger
[Mh] Termos MeSH primário: Pneumocystis carinii
Pneumonia por Pneumocystis/diagnóstico
[Mh] Termos MeSH secundário: Infecções Oportunistas Relacionadas com a AIDS/diagnóstico
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico
Infecções Oportunistas Relacionadas com a AIDS/patologia
Anti-Infecciosos/efeitos adversos
Anti-Infecciosos/uso terapêutico
Antifúngicos/efeitos adversos
Antifúngicos/uso terapêutico
Atovaquona/efeitos adversos
Atovaquona/uso terapêutico
Líquido da Lavagem Broncoalveolar/microbiologia
Diagnóstico Diferencial
Equinocandinas/efeitos adversos
Equinocandinas/uso terapêutico
Seres Humanos
Lipopeptídeos
Pulmão/patologia
Infecções Oportunistas/diagnóstico
Infecções Oportunistas/tratamento farmacológico
Infecções Oportunistas/patologia
Pentamidina/efeitos adversos
Pentamidina/uso terapêutico
Pneumonia por Pneumocystis/tratamento farmacológico
Pneumonia por Pneumocystis/patologia
Tomografia Computadorizada por Raios X
Combinação Trimetoprima e Sulfametoxazol/efeitos adversos
Combinação Trimetoprima e Sulfametoxazol/uso terapêutico
Trimetrexato/efeitos adversos
Trimetrexato/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Anti-Infective Agents); 0 (Antifungal Agents); 0 (Echinocandins); 0 (Lipopeptides); 673LC5J4LQ (Pentamidine); 8064-90-2 (Trimethoprim, Sulfamethoxazole Drug Combination); F0XDI6ZL63 (caspofungin); UPN4ITI8T4 (Trimetrexate); Y883P1Z2LT (Atovaquone)
[Em] Mês de entrada:1108
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:110630
[St] Status:MEDLINE
[do] DOI:10.1055/s-0031-1281532


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[PMID]:21123874
[Au] Autor:Dawson A; Tulloch LB; Barrack KL; Hunter WN
[Ad] Endereço:Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD15EH, Scotland.
[Ti] Título:High-resolution structures of Trypanosoma brucei pteridine reductase ligand complexes inform on the placement of new molecular entities in the active site of a potential drug target.
[So] Source:Acta Crystallogr D Biol Crystallogr;66(Pt 12):1334-40, 2010 Dec.
[Is] ISSN:1399-0047
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pteridine reductase (PTR1) is a potential target for drug development against parasitic Trypanosoma and Leishmania species. These protozoa cause serious diseases for which current therapies are inadequate. High-resolution structures have been determined, using data between 1.6 and 1.1 Šresolution, of T. brucei PTR1 in complex with pemetrexed, trimetrexate, cyromazine and a 2,4-diaminopyrimidine derivative. The structures provide insight into the interactions formed by new molecular entities in the enzyme active site with ligands that represent lead compounds for structure-based inhibitor development and to support early-stage drug discovery.
[Mh] Termos MeSH primário: Domínio Catalítico
Oxirredutases/química
Trypanosoma brucei brucei/enzimologia
[Mh] Termos MeSH secundário: Cristalografia por Raios X
Glutamatos/química
Guanina/análogos & derivados
Guanina/química
Ligantes
Modelos Moleculares
NADP/química
NADP/metabolismo
Oxirredutases/metabolismo
Pemetrexede
Ligação Proteica
Triazinas/química
Trimetrexato/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Glutamates); 0 (Ligands); 0 (Triazines); 04Q9AIZ7NO (Pemetrexed); 53-59-8 (NADP); 5Z93L87A1R (Guanine); CA49Y29RA9 (cyromazine); EC 1.- (Oxidoreductases); EC 1.1.1.33 (pteridine reductase); UPN4ITI8T4 (Trimetrexate)
[Em] Mês de entrada:1103
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:101203
[St] Status:MEDLINE
[do] DOI:10.1107/S0907444910040886


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[PMID]:20056487
[Au] Autor:Nzila A; Okombo J; Becker RP; Chilengi R; Lang T; Niehues T
[Ad] Endereço:Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Programme, Kilifi, Kenya. anzila@kilifi.kemri-wellcome.org
[Ti] Título:Anticancer agents against malaria: time to revisit?
[So] Source:Trends Parasitol;26(3):125-9, 2010 Mar.
[Is] ISSN:1471-5007
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The emergence of artemisinin resistance could adversely impact the current strategy for malaria treatment; thus, new drugs are urgently needed. A possible approach to developing new antimalarials is to find new uses for old drugs. Some anticancer agents such as methotrexate and trimetrexate are active against malaria. However, they are commonly perceived to be toxic and thus not suitable for malaria treatment. In this opinion article, we examine how the toxicity of anticancer agents is just a matter of dose or 'only dose makes the poison', as coined in Paracelsus' law. Thus, the opportunity exists to discover new antimalarials using the anticancer pharmacopoeia.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Malária/tratamento farmacológico
[Mh] Termos MeSH secundário: Antimaláricos/uso terapêutico
Antineoplásicos/toxicidade
Seres Humanos
Metotrexato/uso terapêutico
Metotrexato/toxicidade
Trimetrexato/uso terapêutico
Trimetrexato/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antimalarials); 0 (Antineoplastic Agents); UPN4ITI8T4 (Trimetrexate); YL5FZ2Y5U1 (Methotrexate)
[Em] Mês de entrada:1004
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:100109
[St] Status:MEDLINE
[do] DOI:10.1016/j.pt.2009.12.002


  9 / 361 MEDLINE  
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[PMID]:20036963
[Au] Autor:Peterson JJ
[Ad] Endereço:Drug Development Sciences Department, Research Statistics Unit (UP-4315), GlaxoSmithKline Pharmaceuticals, Rand D, 1250 So Collegeville Road, Collegeville, Pennsylvania 19426, USA. john.peterson@gsk.com
[Ti] Título:A review of synergy concepts of nonlinear blending and dose-reduction profiles.
[So] Source:Front Biosci (Schol Ed);2:483-503, 2010 Jan 01.
[Is] ISSN:1945-0524
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:This article presents a case-study review of synergy concepts of nonlinear blending and dose-reduction profiles. "Strong nonlinear blending" is a novel concept that provides a flexible paradigm for the assessment of combination drug synergy that is applicable to any shaped combination-drug dose-response surface; issues of varying relative potency, partial inhibitors, potentiation, or coalism pose no problems at all. Dose-reduction profiles are overlay plots created to show how much each drug can be reduced in amount and yet achieve the same efficacy as larger amounts of each drug used individually. This review applies these synergy concepts to two data sets from a previously published experiment. The previous publication had claimed a high degree of Loewe synergy for one of the data sets. However, a more penetrating analysis shows that with regard to strong nonlinear blending there is no reason to blend (for purposes of response enhancement) the two compounds studied. However, the dose-reduction profile plots show how Loewe synergy is present and provide further insight to the interaction of the two compounds (on the dose-concentration scale).
[Mh] Termos MeSH primário: Relação Dose-Resposta a Droga
Combinação de Medicamentos
Sinergismo Farmacológico
Modelos Teóricos
[Mh] Termos MeSH secundário: Ácido Fólico
Glutamatos/farmacologia
Pirimidinas/farmacologia
Trimetrexato/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (AG 2034); 0 (Drug Combinations); 0 (Glutamates); 0 (Pyrimidines); 935E97BOY8 (Folic Acid); UPN4ITI8T4 (Trimetrexate)
[Em] Mês de entrada:1009
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:091229
[St] Status:MEDLINE


  10 / 361 MEDLINE  
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[PMID]:20036904
[Au] Autor:Lee JJ; Lin HY; Liu DD; Kong M
[Ad] Endereço:Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Unit 1411, 1515 Holcombe Boulevard, Houston, Texas 77030-1402, USA.
[Ti] Título:Emax model and interaction index for assessing drug interaction in combination studies.
[So] Source:Front Biosci (Elite Ed);2:582-601, 2010 Jan 01.
[Is] ISSN:1945-0508
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Applying the Emax model in a Lowe additivity model context, we analyze data from a combination study of trimetrexate (TMQ) and AG2034 (AG) in media of low and high concentrations of folic acid (FA). The Emax model provides a sufficient fit to the data. TMQ is more potent than AG in both low and high FA media. At low TMQ:AG ratios, when a smaller amount of the more potent drug (TMQ) is added to a larger amount of the less potent drug (AG), synergy results. When the TMQ:AG ratio reaches 0.4 or larger in low FA medium, or when the TMQ:AG ratio reaches 1 or larger in high FA medium, synergy is weakened and drug interaction becomes additive. In general, synergistic effect in a dilution series is stronger at higher doses that produce stronger effects (closer to 1-Emax) than at lower dose levels that produce weaker effects (closer to 1). The two drugs are more potent in the low compared to the high FA medium. Drug synergy, however, is stronger in the high FA medium.
[Mh] Termos MeSH primário: Desenho de Drogas
Interações Medicamentosas
Ácido Fólico/metabolismo
Glutamatos/farmacologia
Pirimidinas/farmacologia
Trimetrexato/farmacologia
[Mh] Termos MeSH secundário: Interpretação Estatística de Dados
Relação Dose-Resposta a Droga
Combinação de Medicamentos
Glutamatos/metabolismo
Pirimidinas/metabolismo
Trimetrexato/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (AG 2034); 0 (Drug Combinations); 0 (Glutamates); 0 (Pyrimidines); 935E97BOY8 (Folic Acid); UPN4ITI8T4 (Trimetrexate)
[Em] Mês de entrada:1007
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:091229
[St] Status:MEDLINE



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