RESUMEN
Although interferon-beta (IFN-beta) has been demonstrated to be effective in the treatment of multiple sclerosis (MS) patients, the mechanism(s) underlying its beneficial effects has not been uncovered yet. Until now, most of the effort in the study of the relevant mechanisms of IFN-beta has dealt with its ability to modulate the immune response. Only recently, it has been proposed that the beneficial effects of IFN-beta in MS patients could depend on its ability to modulate astrocyte function. In the present work, we have found that IFN-beta treatment promotes the survival of astrocytes through stimulation of the phosphatidylinositol 3-kinase (PI-3K)/Akt pathway. We propose that the beneficial effects of IFN-beta in MS therapy may depend, at least in part, on its capacity to protect astrocytes against the apoptotic cell death that occurs in the early steps of the pathogenesis of MS.
Asunto(s)
Astrocitos/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , Interferón beta/farmacología , Esclerosis Múltiple/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Proteínas Serina-Treonina Quinasas , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Astrocitos/enzimología , Supervivencia Celular/fisiología , Células Cultivadas , Sistema Nervioso Central/enzimología , Sistema Nervioso Central/fisiopatología , Medio de Cultivo Libre de Suero/farmacología , Inhibidores Enzimáticos/farmacología , Feto , Interferón beta/uso terapéutico , Esclerosis Múltiple/enzimología , Esclerosis Múltiple/fisiopatología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas/efectos de los fármacos , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: To assess management patterns and outcome in patients with glioblastoma multiforme (GBM) treated during 2008-2010 in Spain. METHODS: Retrospective analysis of clinical, therapeutic, and survival data collected through filled questionnaires from patients with histologically confirmed GBM diagnosed in 19 Spanish hospitals. RESULTS: We identified 834 patients (23% aged >70 years). Surgical resection was achieved in 66% of patients, although the extent of surgery was confirmed by postoperative MRI in only 41%. There were major postoperative complications in 14% of patients, and age was the only independent predictor (Odds ratio [OR], 1.03; 95% confidence interval [CI],1.01-1.05; P = .006). After surgery, 57% received radiotherapy (RT) with concomitant and adjuvant temozolomide, 21% received other regimens, and 22% were not further treated. In patients treated with surgical resection, RT, and chemotherapy (n = 396), initiation of RT ≤42 days was associated with longer progression-free survival (hazard ratio [HR], 0.8; 95% CI, 0.64-0.99; P = .042) but not with overall survival (HR, 0.79; 95% CI, 0.62-1.00; P = .055). Only 32% of patients older than 70 years received RT with concomitant and adjuvant temozolomide. The median survival in this group was 10.8 months (95% CI, 6.8-14.9 months), compared with 17.0 months (95% CI, 15.5-18.4 months; P = .034) among younger patients with GBM treated with the same regimen. CONCLUSIONS: In a community setting, 57% of all patients with GBM and only 32% of older patients received RT with concomitant and adjuvant temozolomide. In patients with surgical resection who were eligible for chemoradiation, initiation of RT ≤42 days was associated with better progression-free survival.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/mortalidad , Dacarbazina/análogos & derivados , Glioblastoma/mortalidad , Pautas de la Práctica en Medicina , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/epidemiología , Neoplasias Encefálicas/terapia , Terapia Combinada , Dacarbazina/uso terapéutico , Femenino , Estudios de Seguimiento , Glioblastoma/diagnóstico , Glioblastoma/epidemiología , Glioblastoma/terapia , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , Estudios Retrospectivos , España/epidemiología , Tasa de Supervivencia , Temozolomida , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: We have previously shown that interferon-beta (IFN-beta) is a potent promoter of astrocyte survival. Although the mechanism(s) by which IFN-beta promotes astrocyte survival have not been completely elucidated, it has been shown that IFN-beta directly stimulates survival signaling pathways. In the present report, we took advantage of the differences in the susceptibility of fetal and neonatal astrocytes to apoptosis to further investigate the mechanism(s) underlying the antiapoptotic effect of IFN-beta. METHODS: Primary monolayer cultures of cortical astrocytes were established from neonatal (3- to 6-day-old) or fetal (embryonic days: E15 or E17) Sprague-Dawley rat cerebral cortices. Apoptotic cell death was determined by fluorescent-microscopic analysis of staining patterns of cell DNA with Hoechst 33258, and determination of annexin V binding.Akt phosphorylation was detected by Western blottingusing a commercial kit that allows specific recognition of both non-phosphorylated and serine-phosphorylated Akt. RESULTS: In the present work, we have found that primary astrocytes obtained from neonatal rats are resistant to apoptosis induced by serum starvation, though cell death may be induced by combining serum starvation with sodium butyrate treatment. This effect is counteracted by IFN-beta treatment through a mechanism that involves phosphatidylinositol 3-kinase stimulation. CONCLUSIONS: IFN-beta can be considered as a neuroprotective agent and, therefore, part of its beneficial effects in multiple sclerosis (MS) treatment may depend on its capacity to protect astrocytes against the apoptotic cell death that occurs in the course of the MS lesions.