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2.
Antivir Ther ; 19(5): 479-90, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24448487

RESUMEN

BACKGROUND: Daclatasvir (DCV; BMS-790052) is a picomolar inhibitor of HCV non-structural protein 5A (NS5A) and has demonstrated efficacy in patients chronically infected with HCV. METHODS: In the double-blind, randomized studies AI444021 and AI444022, 71 Japanese patients chronically infected with HCV genotype 1 (predominantly genotype 1b) received DCV (10 mg or 60 mg) plus peginterferon alfa-2b or alfa-2a and ribavirin. Virological failure occurred in 14% (5/36) of treatment-naive patients and 54% (19/35) of prior alfa/ribavirin non-responders. Resistance testing was performed on baseline samples and samples with HCV RNA≥1,000 IU/ml at week 1 through post-treatment week 24. RESULTS: Baseline NS5A resistance-associated polymorphisms had less impact on virological response rates than IL28B genotype. All patients with virological failure had NS5A DCV-resistant variants at the time of failure. The predominant NS5A variants were L31V/M/I plus Y93H; this combination was detected in 100% (5/5) of treatment-naive patients and 74% (14/19) of non-responders with failure. Emergent resistance variants in prior non-responders (four viral breakthroughs, one relapse) were more varied with novel combinations such as L31F-ΔP32 and L28M-R30Q-A92K detected. Significant loss in DCV antiviral activity was generally only seen with ≥ two resistance-associated NS5A substitutions. All DCV-resistant variants were still detected at end of study. CONCLUSIONS: Virological failure in HCV genotype 1b treatment-naive Japanese patients receiving DCV plus alfa-2a/ribavirin or alfa-2b/ribavirin was associated with enrichment of NS5A resistance variants L31V/M-Y93H. In prior non-responders, emergent variants associated with failure also included NS5A-A92K or NS5A-ΔP32. As with L31-Y93 variants, these variants persisted.


Asunto(s)
Antivirales/uso terapéutico , Genotipo , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Imidazoles/uso terapéutico , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Ribavirina/uso terapéutico , Adulto , Anciano , Antivirales/administración & dosificación , Antivirales/efectos adversos , Carbamatos , Farmacorresistencia Viral , Quimioterapia Combinada , Femenino , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/genética , Hepatitis C Crónica/virología , Humanos , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interferón-alfa/efectos adversos , Interferones , Interleucinas/genética , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Mutación , Fenotipo , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Pirrolidinas , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Ribavirina/administración & dosificación , Ribavirina/efectos adversos , Resultado del Tratamiento , Valina/análogos & derivados , Carga Viral , Adulto Joven
3.
Int J Oncol ; 22(2): 345-51, 2003 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-12527933

RESUMEN

Introduction of genes encoding immuno-stimulatory cytokines into cancer cells is known to enhance antitumor immunity. CD40 ligand (CD40L, CD154) and fms-like tyrosine kinase 3 ligand (Flt3L) are recently identified cytokines, which have been demonstrated to stimulate antitumor immunity in several cancer models. However little is known about antitumor activity of Ftl3L and CD40L against hepatocellular carcinoma (HCC). In the present study, we constructed replication-defective adenoviruses expressing Flt3L and CD40L and examined their therapeutic efficacy on mouse HCC, MH134 cells. Subcutaneous injection of MH134 cells genetically engineered to express Flt3L and/or CD40L developed tumors in all the syngeneic immunocompetent mice, but tumor growth was significantly delayed as compared to control mice. Partial inhibition of this antitumor effect in athymic nude mice suggests that both innate and adaptive immunity appear to play a role. It was shown by immunodepletion of NK cells with anti-asialo-GM1 antibody that the effector cells involved in innate immunity are NK cells. In a therapeutic setting, however, injection of adenovirus expressing Flt3L or CD40L into pre-established MH134 tumors exhibited no efficacy. These data demonstrate that Flt3L and CD40L induce significant, but only weak, antitumor immunity against MH134 cells presumably through both innate and adaptive immunity. Our results suggest that immuno-gene therapy with Flt3L and CD40L may need adjuvant modalities to achieve strong immune response.


Asunto(s)
Ligando de CD40/fisiología , Terapia Genética , Inmunoterapia , Neoplasias Hepáticas Experimentales/prevención & control , Proteínas de la Membrana/fisiología , Animales , Ligando de CD40/genética , ADN Complementario/genética , Virus Defectuosos/genética , Vectores Genéticos/genética , Vectores Genéticos/uso terapéutico , Células HeLa , Humanos , Inmunidad Innata , Inyecciones Subcutáneas , Células Asesinas Naturales/inmunología , Neoplasias Hepáticas Experimentales/inmunología , Neoplasias Hepáticas Experimentales/patología , Neoplasias Hepáticas Experimentales/terapia , Mastadenovirus/genética , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C3H , Ratones Desnudos , Trasplante de Neoplasias , Proteínas Recombinantes de Fusión/fisiología , Células Tumorales Cultivadas/trasplante
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