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1.
Drug Dev Res ; 80(5): 666-679, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31112325

RESUMO

Inflammation is the response of the body to noxious stimuli such as infections, trauma, or injury. Experimental studies have shown that vanillic acid has anti-inflammatory effects. The objective of this study was to investigate the anti-inflammatory and antipyretic properties of the derivative of vanillic acid, isopropyl vanillate (ISP-VT), in mice. The results of this study indicated that ISP-VT reduced paw edema induced by carrageenan, dextran sulfate (DEX), compound 48/80, serotonin, bradykinin (BK), histamine (HIST), and prostaglandin E2 (PGE2). Furthermore, ISP-VT reduced recruitment of leukocytes and neutrophils and reduced its adhesion and rolling, and decreased myeloperoxidase enzyme activity (MPO), cytokine levels (tumor necrosis factor-α and interleukin-6), and vascular permeability. ISP-VT also significantly reduced the expression of cyclooxygenase-2 (COX-2) in subplantar tissue of mice. ISP-VT inhibited COX-2 selectively compared to the standard drug. Our results showed that although ISP-VT binds to COX-1, it is less toxic than indomethacin, as evidenced by MPO analysis of gastric tissue. Treatment with the ISP-VT significantly reduced rectal temperature in yeast-induced hyperthermia in mice. Our results showed that the main mechanism ISP-VT-induced anti-inflammatory activity is by inhibition of COX-2. In conclusion, our results indicate that ISP-VT has potential as an anti-inflammatory and antipyretic therapeutic compound.


Assuntos
Anti-Inflamatórios/administração & dosagem , Carragenina/efeitos adversos , Inibidores de Ciclo-Oxigenase/administração & dosagem , Inflamação/tratamento farmacológico , Fenóis/efeitos adversos , Ácido Vanílico/química , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anticorpos Monoclonais/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacologia , Modelos Animais de Doenças , Feminino , Inflamação/induzido quimicamente , Inflamação/metabolismo , Injeções Intraperitoneais , Masculino , Camundongos , Modelos Moleculares , Fenóis/síntese química , Fenóis/química , Fenóis/farmacologia , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia
2.
Biotechnol J ; 14(4): e1800352, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30485675

RESUMO

There is continual demand to maximize CHO cell culture productivity of a biotherapeutic while maintaining product quality. In this study, a comprehensive multi-omics analysis is performed to investigate the cellular response to the level of dosing of the amino acid cysteine (Cys) in the production of a monoclonal antibody (mAb). When Cys feed levels are insufficient, there is a significant decrease in protein titer. Multi-omics (metabolomics and proteomics, with support from RNAseq) is performed over the time course of the CHO bioprocess producing an IgG1 mAb in 5 L bioreactors. Pathway analysis reveals that insufficient levels of Cys in the feed lead to Cys depletion in the cell. This depletion negatively impacts antioxidant molecules, such as glutathione (GSH) and taurine, leading to oxidative stress with multiple deleterious cellular effects. In this paper, the resultant ER stress and subsequent apoptosis that affects cell viability and viable cell density has been considered. Key metabolic enzymes and metabolites are identified that can be potentially monitored as the process progresses and/or increased in the cell either by nutrient feeding or genetic engineering. This work reinforces the centrality of redox balance to cellular health and success of the bioprocess as well as the power of multi-omics to provide an in-depth understanding of the CHO cell biology during biopharmaceutical production.


Assuntos
Anticorpos Monoclonais/biossíntese , Técnicas de Cultura de Células , Meios de Cultura/farmacologia , Cisteína/farmacologia , Animais , Anticorpos Monoclonais/efeitos dos fármacos , Reatores Biológicos , Células CHO , Sobrevivência Celular/efeitos dos fármacos , Cricetinae , Cricetulus , Cisteína/química , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Glutationa/química , Imunoglobulina G/biossíntese , Imunoglobulina G/química , Estresse Oxidativo/efeitos dos fármacos , Proteômica , Taurina/química
3.
PLoS One ; 13(5): e0196800, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29723274

RESUMO

Glycan analysis may result in exploitation of glycan biomarkers and evaluation of heterogeneity of glycosylation of biopharmaceuticals. For N-linked glycan analysis, we investigated alkaline hydrolysis of the asparagine glycosyl carboxamide of glycoproteins as a deglycosylation reaction. By adding hydroxylamine into alkaline de-N-glycosylation, we suppressed the degradation of released glycans and obtained a mixture of oximes, free glycans, and glycosylamines. The reaction was completed within 1 h, and the mixture containing oximes was easily tagged with 2-aminobenzamide by reductive amination. Here, we demonstrated N-linked glycan analysis using this method for a monoclonal antibody, and examined whether this method could liberate glycans without degradation from apo-transferrin containing NeuAc and NeuGc and horseradish peroxidase containing Fuc α1-3 GlcNAc at the reducing end. Furthermore, we compared glycan recoveries between conventional enzymatic glycan release and this method. Increasing the reaction temperature and reaction duration led to degradation, whereas decreasing these parameters resulted in lower release. Considering this balance, we proposed to carry out the reaction at 80°C for 1 h for asialo glycoproteins from mammals and at 50°C for 1 h for sialoglycoproteins.


Assuntos
Anticorpos Monoclonais/química , Cromatografia Líquida , Glicoproteínas/química , Polissacarídeos/análise , Aminação , Animais , Anticorpos Monoclonais/efeitos dos fármacos , Apoproteínas/química , Apoproteínas/efeitos dos fármacos , Bovinos , Glicoproteínas/efeitos dos fármacos , Glicosilação , Peroxidase do Rábano Silvestre/química , Peroxidase do Rábano Silvestre/efeitos dos fármacos , Hidrólise , Hidroxilamina , Metilação , Oximas/isolamento & purificação , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Temperatura Ambiente , Fatores de Tempo , Transferrina/química , Transferrina/efeitos dos fármacos
4.
Rev. med. Rosario ; 84(1): 22-25, ene.-abr. 2018. ilus
Artigo em Espanhol | LILACS | ID: biblio-973330

RESUMO

Una paciente con osteoporosis había sido tratada por 4 años con ibandronato oral, luego por 1 año con ranelato de estroncio, y finalmente por 4 años con denosumab. En vista de la buena respuesta densitométrica este fármaco fue suspendido a fines de 2015. A los 14 meses la enferma tuvo lumbalgia aguda y se detectó hundimiento del platillo superior de L1, a lo que siguieron en rápida sucesión iguales lesiones en L2 y L3, y acuñamiento de D11 y D12. Se descartaron causas de osteoporosis secundaria. El plan terapéutico incluye corsé ortopédico, analgésicos, y teriparatida. En los dos últimos años se han publicado varios casos de este síndrome.


A patient with osteoporosis had been treated for 4 years with oral ibandronate, then for 1 year with strontium ranelate, and finally for 4 years with denosumab. In view of the good densitometric response to the latter, the drug was discontinued in December 2015. Fourteen months later the patient had acute low back pain; crushing of the upper plate of L1 was detected, followed by similar lesions in L2 and L3, and wedging of D11 and D12. Causes of secondary osteoporosis were ruled out. The therapeutic strategy includes a corset, analgesics, and teriparatide. In the last two years several cases of this syndrome have been reported.


Assuntos
Humanos , Feminino , Idoso de 80 Anos ou mais , Anticorpos Monoclonais , Anticorpos Monoclonais/efeitos dos fármacos , Osteoporose Pós-Menopausa/prevenção & controle , Fraturas da Coluna Vertebral/diagnóstico , Fraturas da Coluna Vertebral/prevenção & controle , Osteoprotegerina , Osteoprotegerina/efeitos dos fármacos , Resultado do Tratamento
5.
MAbs ; 9(7): 1155-1168, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28758834

RESUMO

Preferential interactions of weakly interacting formulation excipients govern their effect on the equilibrium and kinetics of several reactions of protein molecules in solution. Using vapor pressure osmometry, we characterized the preferential interactions of commonly used excipients trehalose, L-arginine.HCl and NaCl with three therapeutically-relevant, IgG1 monoclonal antibodies that have similar size and shape, but differ in their surface hydrophobicity and net charge. We further characterized the effect of these excipients on the reversible self-association, aggregation and viscosity behavior of these antibody molecules. We report that trehalose, L-arginine.HCl and NaCl are all excluded from the surface of the three IgG1 monoclonal antibodies, and that the exclusion behavior is linearly related to the excipient molality in the case of trehalose and NaCl, whereas a non-linear behavior is observed for L-arginine.HCl. Interestingly, we find that the magnitude of trehalose exclusion depends upon the nature of the protein surface. Such behavior is not observed in case of NaCl and L-arginine.HCl as they are excluded to the same extent from the surface of all three antibody molecules tested in this study. Analysis of data presented in this study provides further insight into the mechanisms governing excipient-mediated stabilization of mAb formulations.


Assuntos
Anticorpos Monoclonais/efeitos dos fármacos , Arginina/farmacologia , Imunoglobulina G/efeitos dos fármacos , Cloreto de Sódio/farmacologia , Trealose/farmacologia , Estabilidade de Medicamentos , Excipientes/farmacologia , Osmometria
6.
Ann Oncol ; 28(8): 1713-1729, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28407110

RESUMO

Background: There is increasing evidence that metastatic colorectal cancer (mCRC) is a genetically heterogeneous disease and that tumours arising from different sides of the colon (left versus right) have different clinical outcomes. Furthermore, previous analyses comparing the activity of different classes of targeted agents in patients with KRAS wild-type (wt) or RAS wt mCRC suggest that primary tumour location (side), might be both prognostic and predictive for clinical outcome. Methods: This retrospective analysis investigated the prognostic and predictive influence of the localization of the primary tumour in patients with unresectable RAS wt mCRC included in six randomized trials (CRYSTAL, FIRE-3, CALGB 80405, PRIME, PEAK and 20050181), comparing chemotherapy plus EGFR antibody therapy (experimental arm) with chemotherapy or chemotherapy and bevacizumab (control arms). Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) for patients with left-sided versus right-sided tumours, and odds ratios (ORs) for objective response rate (ORR) were estimated by pooling individual study HRs/ORs. The predictive value was evaluated by pooling study interaction between treatment effect and tumour side. Results: Primary tumour location and RAS mutation status were available for 2159 of the 5760 patients (37.5%) randomized across the 6 trials, 515 right-sided and 1644 left-sided. A significantly worse prognosis was observed for patients with right-sided tumours compared with those with left-sided tumours in both the pooled control and experimental arms for OS [HRs = 2.03 (95% CI: 1.69-2.42) and 1.38 (1.17-1.63), respectively], PFS [HRs = 1.59 (1.34-1.88) and 1.25 (1.06-1.47)], and ORR [ORs = 0.38 (0.28-0.50) and 0.56 (0.43-0.73)]. In terms of a predictive effect, a significant benefit for chemotherapy plus EGFR antibody therapy was observed in patients with left-sided tumours [HRs = 0.75 (0.67-0.84) and 0.78 (0.70-0.87) for OS and PFS, respectively] compared with no significant benefit for those with right-sided tumours [HRs = 1.12 (0.87-1.45) and 1.12 (0.87-1.44) for OS and PFS, respectively; P value for interaction <0.001 and 0.002, respectively]. For ORR, there was a trend (P value for interaction = 0.07) towards a greater benefit for chemotherapy plus EGFR antibody therapy in the patients with left-sided tumours [OR = 2.12 (1.77-2.55)] compared with those with right-sided tumours [OR = 1.47 (0.94-2.29)]. Exclusion of the unique phase II trial or the unique second-line trial had no impact on the results. The predictive effect on PFS may depend of the type of EGFR antibody therapy and on the presence or absence of bevacizumab in the control arm. Conclusion: This pooled analysis showed a worse prognosis for OS, PFS and ORR for patients with right-sided tumours compared with those with left-sided tumours in patients with RAS wt mCRC and a predictive effect of tumour side, with a greater effect of chemotherapy plus EGFR antibody therapy compared with chemotherapy or chemotherapy and bevacizumab, the effect being greatest in patients with left-sided tumours. These predictive results should be interpreted with caution due to the retrospective nature of the analysis, which was carried out on subpopulations of patients included in these trials, and because none of these studies contemplated a full treatment sequence strategy.


Assuntos
Anticorpos Monoclonais/efeitos dos fármacos , Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/efeitos dos fármacos , Cetuximab/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Genes ras , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Metástase Neoplásica , Panitumumabe , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
7.
Clin Cardiol ; 40(7): 503-511, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28326559

RESUMO

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) downregulates low-density lipoprotein (LDL) receptors, thereby leading to a rise in circulating LDL cholesterol (LDL-C). RG7652 is a fully human monoclonal antibody against PCSK9. This placebo-controlled, phase 1 ascending-dose study in healthy subjects evaluated the safety of RG7652 and its efficacy as a potential LDL-C-lowering drug. HYPOTHESIS: Anti-PCSK9 antibody therapy safely and effectively reduces LDL-C. METHODS: Subjects (N = 80) were randomized into 10 cohorts. Six sequential single-dose cohorts received 10, 40, 150, 300, 600, or 800 mg of RG7652 via subcutaneous injection. Four multiple-dose cohorts received 40 or 150 mg of RG7652 once weekly for 4 weeks, either with or without statin therapy (atorvastatin). RESULTS: Adverse events (AEs) were generally mild; the most common AEs were temporary injection-site reactions. No serious AEs, severe AEs, AEs leading to study-drug discontinuation, or dose-limiting toxicities were reported. RG7652 monotherapy reduced mean LDL-C levels by up to 64% and as much as 100 mg/dL at week 2; the effect magnitude and duration increased with dose (≥57 days following a single RG7652 dose ≥300 mg). Exploratory analyses showed reduced oxidized LDL, lipoprotein(a), and lipoprotein-associated phospholipase A2 with RG7652. Antidrug antibody against RG7652 tested positive in 2 of 60 (3.3%) RG7652-treated and in 4 of 20 (20.0%) placebo-treated subjects. Simultaneous atorvastatin administration did not appear to impact the pharmacokinetic profile or lipid-lowering effects of RG7652. CONCLUSIONS: Overall, RG7652 elicited substantial and sustained dose-related LDL-C reductions with an acceptable safety profile and minimal immunogenicity.


Assuntos
Anticorpos Monoclonais/administração & dosagem , LDL-Colesterol/sangue , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/efeitos dos fármacos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/administração & dosagem , Atorvastatina/administração & dosagem , Biomarcadores/sangue , LDL-Colesterol/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/imunologia , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9/imunologia , Pró-Proteína Convertase 9/metabolismo , Resultado do Tratamento , Adulto Jovem
10.
J Biotechnol ; 218: 53-63, 2016 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-26654938

RESUMO

Industrial fed-batch cultivation of mammalian cells is used for the production of therapeutic proteins such as monoclonal antibodies. Besides medium ensuring initial growth, feeding is necessary to improve growth, viability and antibody production. Established processes include a slight acidic main feed and a separate alkaline feed containing l-tyrosine and l-cysteine. Since l-cysteine is not stable at neutral pH, a new derivative, S-sulfocysteine, was tested in neutral pH feeds. In small scale fed-batch processes, the S-sulfocysteine process yielded a comparable maximum viable cell density, prolonged viability and increased titer compared to the two feed system. Bioreactor experiments confirmed the increase in specific productivity. In depth characterization of the monoclonal antibody indicated no change in the glycosylation, or charge variant pattern whereas peptide mapping experiments were not able to detect any integration of the modified amino acid in the sequence of the monoclonal antibody. Finally, the mechanism of action of S-sulfocysteine was investigated, and results pointed out the anti-oxidative potential of the molecule, mediated through an increase in superoxide dismutase enzyme levels and in the total intracellular glutathione pool. Finally, we propose that the increase in specific productivity obtained in the S-sulfocysteine process results from the anti-oxidative properties of the molecule.


Assuntos
Antioxidantes/farmacologia , Técnicas de Cultura Celular por Lotes/métodos , Meios de Cultura , Cisteína/análogos & derivados , Aminoácidos/metabolismo , Animais , Anticorpos Monoclonais/biossíntese , Anticorpos Monoclonais/efeitos dos fármacos , Anticorpos Monoclonais/metabolismo , Antioxidantes/metabolismo , Reatores Biológicos , Células CHO , Cricetinae , Cricetulus , Cisteína/metabolismo , Cisteína/farmacologia , Glutationa/metabolismo , Glicosilação/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Mapeamento de Peptídeos , Tirosina/metabolismo
11.
Biotechnol Prog ; 31(2): 460-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25504679

RESUMO

Alternate sugars such as galactose and fructose are metabolized at a slower rate than glucose and result in lower accumulation of lactate. While low lactate accumulation is desirable, we report that complete substitution of glucose with these sugars results in an increase in M5 high mannose glycans. Surprisingly, this increase is much higher when the culture is supplemented with manganese: for example, when cells are cultured with galactose, M5 high mannose glycan content increased from 5% at 1 nM Mn(2+) in the basal medium to 32% with 16 µM Mn(2+) supplementation. When galactose is supplemented with glucose maintained at low concentrations, a small reduction in high mannose glycans is seen. In control cultures with glucose, the high mannose content was however <2% in this range of Mn(2+) concentration. By varying Mn(2+) and glucose supplementation levels, with or without galactose, we systematically demonstrate that Mn(2+) concentration and glucose availability, together, significantly affect the high mannose glycan content. To our knowledge, this is the first report that shows that the effect of Mn(2+) on high mannose glycan content depends on glucose availability. At each Mn(2+) supplementation level evaluated, galactosylation percentages were highest for cultures where galactose was supplemented with glucose at non-limiting concentration.


Assuntos
Anticorpos Monoclonais/metabolismo , Manganês/farmacologia , Manose/metabolismo , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/efeitos dos fármacos , Biotecnologia , Células CHO , Cricetinae , Cricetulus , Meios de Cultura/química , Meios de Cultura/metabolismo , Glicosilação/efeitos dos fármacos , Hexoses/metabolismo
12.
Biotechnol Prog ; 30(5): 1103-13, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25044865

RESUMO

Protein phase behavior characterization is a multivariate problem due to the high amount of influencing parameters and the diversity of the proteins. Single influences on the protein are not understood and fundamental knowledge remains to be obtained. For this purpose, a systematic screening method was developed to characterize the influence of fluid phase conditions on the phase behavior of proteins in three-dimensional phase diagrams. This approach was applied to three monoclonal antibodies to investigate influences of pH, protein and salt concentrations, with five different salts being tested. Although differences exist between the antibodies, this extensive study confirmed the general applicability of the Hofmeister series over the broad parameter range analyzed. The influence of the different salts on the aggregation (crystallization and precipitation) probability was described qualitatively using this Hofmeister series, with a differentiation between crystallization and precipitation being impossible, however.


Assuntos
Anticorpos Monoclonais/química , Biotecnologia/métodos , Anticorpos Monoclonais/efeitos dos fármacos , Anticorpos Monoclonais/metabolismo , Cristalização , Ensaios de Triagem em Larga Escala , Concentração de Íons de Hidrogênio , Íons/farmacologia , Agregados Proteicos/efeitos dos fármacos , Projetos de Pesquisa , Cloreto de Sódio/química , Cloreto de Sódio/farmacologia , Sulfatos/química , Sulfatos/farmacologia
13.
J Am Coll Cardiol ; 63(23): 2541-2548, 2014 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-24694531

RESUMO

OBJECTIVES: This study sought to evaluate the efficacy and safety of subcutaneous evolocumab compared with oral ezetimibe in hypercholesterolemic patients who are unable to tolerate effective statin doses. BACKGROUND: Statin intolerance, which is predominantly due to muscle-related side effects, is reported in up to 10% to 20% of patients. Evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), demonstrated marked reductions in plasma low-density lipoprotein cholesterol (LDL-C) in a phase 2 study in statin-intolerant patients. METHODS: The GAUSS-2 (Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects) trial was a 12-week, double-blind study of randomized patients (2:2:1:1) to evolocumab 140 mg every two weeks (Q2W) or evolocumab 420 mg once monthly (QM) both with daily oral placebo or subcutaneous placebo Q2W or QM both with daily oral ezetimibe 10 mg. Co-primary endpoints were percent change from baseline in LDL-C at the mean of weeks 10 and 12, and at week 12. RESULTS: Three hundred seven patients (age 62 ± 10 years; LDL-C 193 ± 59 mg/dl) were randomized. Evolocumab reduced LDL-C from baseline by 53% to 56%, corresponding to treatment differences versus ezetimibe of 37% to 39% (p <0.001). Muscle adverse events occurred in 12% of evolocumab-treated patients and 23% of ezetimibe-treated patients. Treatment-emergent adverse events and laboratory abnormalities were comparable across treatment groups. CONCLUSIONS: Robust efficacy combined with favorable tolerability makes evolocumab a promising therapy for addressing the largely unmet clinical need in high-risk patients with elevated cholesterol who are statin intolerant. (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-2; NCT01763905).


Assuntos
Anticorpos Monoclonais/efeitos dos fármacos , Colesterol/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertases/antagonistas & inibidores , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados , Apoptose , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Tolerância a Medicamentos , Feminino , Seguimentos , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/imunologia , Masculino , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/imunologia , Serina Endopeptidases/imunologia , Resultado do Tratamento , Adulto Jovem
14.
Curr Opin Oncol ; 25(6): 615-24, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24097103

RESUMO

PURPOSE OF REVIEW: With recent advances in DNA sequencing technology, recurrent genomic alterations can be identified in tumor samples from patients with metastatic breast cancer (MBC) to enrich clinical trials testing targeted therapies. This review provides an overview of clinically relevant genomic alterations in MBC and summarizes the recent clinical data from early phase trials of novel targeted treatments. RECENT FINDINGS: The clinical development of personalized treatment includes targeted agents directed against PI3K/mTOR, fibroblast growth factor receptor (FGFR), human epidermal growth factor receptor 2 (HER2), DNA repair, and cell cycle pathways. PI3K/mTOR pathway drugs are active in endocrine and trastuzumab-resistant disease. Drugs targeted at PI3K/mTOR, FGFR, and poly(ADP-ribose) polymerase show early signs of efficacy in MBC subpopulations enriched with relevant pathway aberrancies. Regimens combining targeted agents with either endocrine, anti-HER2, or chemotherapy treatments are also being studied in hormone receptor-defined and HER2-defined or pathway-enriched subgroups. SUMMARY: A new approach to personalized medicine for MBC that involves molecular screening for clinically relevant genomic alterations and genotype-targeted treatments is emerging. Clinical trials are needed to determine whether rare subpopulations of MBC benefit from genotype-targeted treatments.


Assuntos
Anticorpos Monoclonais/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Neoplasias da Mama/patologia , Reparo do DNA/efeitos dos fármacos , Terapia de Alvo Molecular , Medicina de Precisão , Neoplasias da Mama/tratamento farmacológico , Receptores ErbB/efeitos dos fármacos , Feminino , Humanos , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Poli(ADP-Ribose) Polimerases/efeitos dos fármacos , Medicina de Precisão/métodos , Medicina de Precisão/tendências , Receptor ErbB-2/efeitos dos fármacos , Receptor ErbB-2/genética , Serina-Treonina Quinases TOR/efeitos dos fármacos , Serina-Treonina Quinases TOR/genética , Resultado do Tratamento
15.
Leuk Lymphoma ; 54(2): 229-41, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22897729

RESUMO

The prognosis of patients with multiple myeloma (MM) has radically changed over the past two decades mostly due to the introduction of novel pharmacologic treatments such as thalidomide, bortezomib and lenalidomide. These drugs were the first new anti-myeloma agents since the 1950s, and represented a landmark step in the race for the cure of MM and the paradigm of effectiveness of bench-to-bedside research. Compared to a median overall survival of 2-3 years in the mid-1950s, patients with MM have nowadays an expected median survival of 7-8 years. Novel agents have not only extended the life expectancy of patients with MM, but also shed light on the necessity of further understanding the biology of MM in order to design more effective, less toxic therapies. Basic research has provided a critical mass of information about the molecular and cellular biology of MM, particularly the pivotal pathogenetic role of the bone marrow niche. Several novel drugs, designed to specifically target MM in the context of its microenvironment, are currently in clinical trials and hold great promise for improving the MM treatment armamentarium and overcoming resistance. In this article we review the biological basis of effectiveness of anti-myeloma agents with an emphasis on experimental drugs.


Assuntos
Antineoplásicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais/efeitos dos fármacos , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/farmacologia , Remodelação Óssea/efeitos dos fármacos , Humanos , Hipóxia , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Terapia de Alvo Molecular , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico , Biossíntese de Proteínas/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Resposta a Proteínas não Dobradas/efeitos dos fármacos
16.
Postepy Hig Med Dosw (Online) ; 66: 855-67, 2012 Nov 15.
Artigo em Polonês | MEDLINE | ID: mdl-23175342

RESUMO

Deregulation of cellular signal transduction, caused by gene mutations, has been recognized as a basic factor of cancer initiation, promotion and progression. Thus, the ability to control the activity of overstimulated signal molecules by the use of appropriate inhibitors became the idea of targeted cancer therapy, which has provided an effective tool to normalize the molecular disorders in malignant cells and to treat certain types of cancer. The molecularly targeted drugs are divided into two major pharmaceutical classes: monoclonal antibodies and small-molecule kinase inhibitors. This review presents a summary of their characteristics, analyzing their chemical structures, specified molecular targets, mechanisms of action and indications for use. Also the molecules subjected to preclinical trials or phase I, II and III clinical trials evaluating their efficiency and safety are presented. Moreover, the article discusses further perspectives for development of targeted therapies focusing on three major directions: systematic searching and discovery of new targets that are oncogenic drivers, improving the pharmacological properties of currently known drugs, and developing strategies to overcome drug resistance. Finally, the role of proper pharmacodiagnostics as a key to rational anticancer therapy has been emphasized since the verification of reliable predictive biomarkers is a basis of individualized medicine in oncology. 


Assuntos
Antineoplásicos/uso terapêutico , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Medicina de Precisão/métodos , Transdução de Sinais/efeitos dos fármacos , Animais , Anticorpos Monoclonais/efeitos dos fármacos , Antineoplásicos/química , Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Neoplasias/genética , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/genética
17.
J Hepatobiliary Pancreat Sci ; 19(4): 342-53, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22678429

RESUMO

Biliary tract carcinoma (BTC) is a lethal malignancy. This lethality is essentially attributed to both slow carcinogenesis occurring under complex pathological circumstances and to the asymptomatic growth of BTC infiltrating the surrounding structures by varying routes. The disease is therefore usually detected at an advanced stage with a high frequency of distant organ metastasis. To date, conventional chemotherapy and radiation therapy have been notably ineffective against BTC. For an improved treatment outcome of BTC and prolonged survival, there is now a real and urgent need to focus on developing novel and potent therapeutic strategies aimed at exploiting select molecular targets associated with tumor proliferation, invasion, and/or metastasis that would impact in a significant way on clinical outcome. The outcomes of recent studies, by the analysis of BTC cells, BTC animal models, and clinical specimens of BTC patients, have revealed, in detail, the molecular mechanism of carcinogenesis and tumor progression of BTC, and these studies have exploited select molecular targets that could significantly impact the clinical outcome. In the near future, the development of new molecular targeting drugs with potent efficacy against BTC, and the performance of randomized clinical trials of these drugs are urgent and essential for the treatment of patients with BTC.


Assuntos
Neoplasias do Sistema Biliar/tratamento farmacológico , Terapia de Alvo Molecular , Animais , Anticorpos Monoclonais/efeitos dos fármacos , Neoplasias do Sistema Biliar/metabolismo , Neoplasias do Sistema Biliar/prevenção & controle , Western Blotting , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Receptores ErbB/fisiologia , Neoplasias da Vesícula Biliar/metabolismo , Humanos , Invasividade Neoplásica , Proteínas Tirosina Quinases/antagonistas & inibidores , Receptores de Somatomedina/metabolismo , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/metabolismo
18.
Sci Total Environ ; 424: 130-42, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22425172

RESUMO

Intensive farming of potatoes in Prince Edward Island (PEI) relies on the repeated and widespread application of fertilizers and pesticides. In PEI the main potato farming areas are in close proximity and drain directly to estuaries. Runoff from high agricultural activity watersheds could impact benthic organism health in the depositional zone of downstream estuaries. The estuarine filter feeder Mya arenaria (soft-shell clam) could be particularly vulnerable to both particle-adsorbed and water soluble contaminants. M. arenaria is susceptible to haemocytic leukemia. In May 2009, we established that heavily proliferated leukemia (HPL) prevalence was generally higher in PEI estuaries located downstream of high intensity potato farming (Dunk and Wilmot estuaries) watersheds than in estuaries downstream of lower intensity areas. Using Mab-1E10 based immunocytochemistry we observed that leukemic haemocytes from the Dunk and Wilmot estuaries were 1E10 negative whereas those from the Ox/Sheep estuary (low potato farming intensity) were 1E10 positive. The expression of genes in the p53 tumour suppressor pathway enabled us to differentiate groups of leukemic and normal M. arenaria, validating our diagnoses. In October 2009, we confirmed that HPL prevalence was elevated in the Dunk and Wilmot estuaries compared to reference (Souris River). Moreover, leukemia prevalence declined with distance from the river mouths along transects through the Dunk and Wilmot estuaries. The pesticides ß-endosulfan and α-endosulfan were detected in surface sediments from the Dunk and Wilmot estuaries, but not in sediments from either the Souris River or several other lower intensity potato farming watersheds. Our study provides evidence of an association between intensity of potato farming and prevalence of clam leukemia at downstream estuaries in PEI.


Assuntos
Endossulfano/análise , Hemócitos/efeitos dos fármacos , Inseticidas/análise , Mya/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Agricultura , Animais , Anticorpos Monoclonais/efeitos dos fármacos , Ecossistema , Endossulfano/toxicidade , Monitoramento Ambiental , Cromatografia Gasosa-Espectrometria de Massas , Regulação da Expressão Gênica , Sedimentos Geológicos/análise , Proteínas de Choque Térmico HSP70/metabolismo , Hemócitos/citologia , Hemócitos/imunologia , Immunoblotting , Imuno-Histoquímica , Inseticidas/toxicidade , Camundongos , Mya/citologia , Mya/imunologia , Mya/metabolismo , Coelhos , Reação em Cadeia da Polimerase em Tempo Real , Estações do Ano , Solanum tuberosum , Especificidade da Espécie , Proteína Supressora de Tumor p53/metabolismo , Poluentes Químicos da Água/análise
20.
Clin Orthop Relat Res ; 469(8): 2207-14, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21562893

RESUMO

BACKGROUND: Currently, antiresorptive therapy in the treatment and prevention of osteoporosis includes bisphosphonates, estrogen replacement, selective estrogen receptor modulators (raloxifene), and denosumab (a human antibody that inactivates RANKL). The original paradigm driving the development of antiresorptive therapy was that inhibition of bone resorption would allow bone formation to continue and correct the defect. However, it is now clear increases in bone density account for little of the antifracture effect of these treatments. QUESTIONS/PURPOSES: We examined the antifracture benefit of antiresorptives deriving from bone quality changes. METHODS: We searched the archive of nearly 30,000 articles accumulated over more than 40 years in our research center library using a software program (Refman™). Approximately 250 publications were identified in locating the 69 cited here. RESULTS: The findings document antiresorptive agents are not primarily anabolic. All cause a modest increase in bone density due to a reduction in the bone remodeling space; however, the majority of their efficacy is due to suppression of the primary cause of osteoporosis, ie, excessive bone remodeling not driven by mechanical need. All of them improve some element(s) of bone quality. CONCLUSIONS: Antiresorptive therapy reduces risk of fracture by improving bone quality through halting removal of bone tissue and the resultant destruction of microarchitecture of bone and, perhaps to some extent, by improving the intrinsic material properties of bone tissue. Information presented here may help clinicians to improve selection of patients for antiresorptive therapy by avoiding them in cases clearly not due to excessive bone remodeling.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Osso e Ossos/efeitos dos fármacos , Anticorpos Monoclonais/efeitos dos fármacos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Conservadores da Densidade Óssea/uso terapêutico , Remodelação Óssea/fisiologia , Osso e Ossos/fisiologia , Denosumab , Difosfonatos/farmacologia , Difosfonatos/uso terapêutico , Humanos , Menopausa/fisiologia , Ligante RANK/efeitos dos fármacos , Ligante RANK/farmacologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico
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