Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Más filtros

Banco de datos
Tipo de estudio
Tipo del documento
País de afiliación
Intervalo de año de publicación
1.
Biochem Biophys Res Commun ; 382(2): 430-3, 2009 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-19285960

RESUMEN

Drosophila melanogaster multisubstrate deoxyribonucleoside kinase (Dm-dNK) can additionally sensitize human cancer cell lines towards the anti-cancer drug gemcitabine. We show that this property is based on the Dm-dNK ability to efficiently phosphorylate gemcitabine. The 2.2A resolution structure of Dm-dNK in complex with gemcitabine shows that the residues Tyr70 and Arg105 play a crucial role in the firm positioning of gemcitabine by extra interactions made by the fluoride atoms. This explains why gemcitabine is a good substrate for Dm-dNK.


Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Desoxicitidina/análogos & derivados , Drosophila melanogaster/enzimología , Resistencia a Antineoplásicos , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Animales , Antimetabolitos Antineoplásicos/química , Antimetabolitos Antineoplásicos/metabolismo , Línea Celular Tumoral , Desoxicitidina/química , Desoxicitidina/metabolismo , Desoxicitidina/farmacología , Humanos , Fosfotransferasas (Aceptor de Grupo Alcohol)/química , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Conformación Proteica , Relación Estructura-Actividad , Especificidad por Sustrato , Gemcitabina
2.
Neuro Oncol ; 12(6): 549-58, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20154339

RESUMEN

The prognosis for malignant gliomas remains poor, and new treatments are urgently needed. Targeted suicide gene therapy exploits the enzymatic conversion of a prodrug, such as a nucleoside analog, into a cytotoxic compound. Although this therapeutic strategy has been considered a promising regimen for central nervous system (CNS) tumors, several obstacles have been encountered such as inefficient gene transfer to the tumor cells, limited prodrug penetration into the CNS, and inefficient enzymatic activity of the suicide gene. We report here the cloning and successful application of a novel thymidine kinase 1 (TK1) from the tomato plant, with favorable characteristics in vitro and in vivo. This enzyme (toTK1) is highly specific for the nucleoside analog prodrug zidovudine (azidothymidine, AZT), which is known to penetrate the blood-brain barrier. An important feature of toTK1 is that it efficiently phosphorylates its substrate AZT not only to AZT monophosphate, but also to AZT diphosphate, with excellent kinetics. The efficiency of the toTK1/AZT system was confirmed when toTK1-transduced human glioblastoma (GBM) cells displayed a 500-fold increased sensitivity to AZT compared with wild-type cells. In addition, when neural progenitor cells were used as delivery vectors for toTK1 in intracranial GBM xenografts in nude rats, substantial attenuation of tumor growth was achieved in animals exposed to AZT, and survival of the animals was significantly improved compared with controls. The novel toTK1/AZT suicide gene therapy system in combination with stem cell-mediated gene delivery promises new treatment of malignant gliomas.


Asunto(s)
Genes Transgénicos Suicidas/genética , Terapia Genética/métodos , Glioma/genética , Glioma/terapia , Solanum lycopersicum/enzimología , Timidina Quinasa/genética , Animales , Línea Celular Tumoral , Glioma/patología , Humanos , Solanum lycopersicum/genética , Proteínas de Plantas/genética , Proteínas de Plantas/uso terapéutico , Ratas , Ratas Desnudas , Timidina Quinasa/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA