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Theranostics ; 6(10): 1477-90, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27446484

RESUMO

We investigated a therapeutic strategy for recurrent malignant gliomas using mesenchymal stem cells (MSC), expressing cytosine deaminase (CD), and prodrug 5-Fluorocytosine (5-FC) as a more specific and less toxic option. MSCs are emerging as a novel cell therapeutic agent with a cancer-targeting property, and CD is considered a promising enzyme in cancer gene therapy which can convert non-toxic 5-FC to toxic 5-Fluorouracil (5-FU). Therefore, use of prodrug 5-FC can minimize normal cell toxicity. Analyses of microarrays revealed that targeting DNA damage and its repair is a selectable option for gliomas after the standard chemo/radio-therapy. 5-FU is the most frequently used anti-cancer drug, which induces DNA breaks. Because dihydropyrimidine dehydrogenase (DPD) was reported to be involved in 5-FU metabolism to block DNA damage, we compared the survival rate with 5-FU treatment and the level of DPD expression in 15 different glioma cell lines. DPD-deficient cells showed higher sensitivity to 5-FU, and the regulation of DPD level by either siRNA or overexpression was directly related to the 5-FU sensitivity. For MSC/CD with 5-FC therapy, DPD-deficient cells such as U87MG, GBM28, and GBM37 showed higher sensitivity compared to DPD-high U373 cells. Effective inhibition of tumor growth was also observed in an orthotopic mouse model using DPD- deficient U87MG, indicating that DPD gene expression is indeed closely related to the efficacy of MSC/CD-mediated 5-FC therapy. Our results suggested that DPD can be used as a biomarker for selecting glioma patients who may possibly benefit from this therapy.


Assuntos
Antineoplásicos/uso terapêutico , Citosina Desaminase/metabolismo , Di-Hidrouracila Desidrogenase (NADP)/análise , Flucitosina/uso terapêutico , Glioma/terapia , Células-Tronco Mesenquimais/enzimologia , Pró-Fármacos/uso terapêutico , Transplante de Células-Tronco/métodos , Animais , Biomarcadores/análise , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Camundongos , Prognóstico , Recidiva , Resultado do Tratamento
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