RESUMEN
PURPOSE: To determine the effects of MRI-assayed vascular leakiness on the delivery of macromolecular therapeutics to tumors. MATERIALS AND METHODS: MDA-MB 435 tumors, subcutaneously implanted into nude rats were treated with a single dose of bevacizumab at levels of 0.1 mg (n = 5) or 1.0 mg (n = 10) or received saline (control animals, n = 8). After 24 hours, albumin-(Gd-DTPA) (30)-enhanced MRI was performed. Just prior to MRI, the cytotoxic drug vinorelbine was administered intravenously. Upon completion of the MR experiment, tumor vinorelbine concentrations were quantified by high performance liquid chromatography (HPLC). Vascular leakiness (K (PS)) was calculated based on the MRI data using a pharmacokinetic model. RESULTS: K (PS) was calculated as 3.70 +/- 1.12 (control tumors), 1.95 +/- 0.70 (0.1 mg group) and 0.75 +/- 0.46 microl min (-1)cm (-3) (1.0 mg group). K (PS) was significantly higher in the control group compared to the 1.0 mg bevacizumab group. Vinorelbine concentrations were measured as 409.4 +/- 109.7 (control tumors), 387.5 +/- 47.5 (0.1 mg group) and 250.7 +/- 71.9 (1.0 mg group). These differences were not significant. A moderate and significant correlation was found between K (PS) and Vinorelbine concentrations in tumors (r = 0.49, p < 0.05). CONCLUSION: MRI-assayed K (PS) based on dynamic MRI enhanced by albumin-(Gd-DTPA) (30) correlated significantly with vinorelbine accumulation in experimental xenograft tumors under angiogenesis inhibition. Thus, the MRI technique applied in our study could potentially help to predict accumulation of macromolecular cytotoxic drugs and to optimize individual therapeutic regimes in tumors.
Asunto(s)
Antineoplásicos Fitogénicos/farmacocinética , Permeabilidad Capilar/fisiología , Aumento de la Imagen , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Melanoma Experimental/irrigación sanguínea , Melanoma Experimental/metabolismo , Vinblastina/análogos & derivados , Ensayos Antitumor por Modelo de Xenoinjerto , Albúminas/farmacocinética , Inhibidores de la Angiogénesis/farmacología , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Bevacizumab , Línea Celular Tumoral , Medios de Contraste/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Gadolinio DTPA/farmacocinética , Humanos , Infusiones Intravenosas , Melanoma Experimental/tratamiento farmacológico , Tasa de Depuración Metabólica/fisiología , Microcirculación/fisiología , Ratas , Ratas Desnudas , Vinblastina/farmacocinética , VinorelbinaRESUMEN
The cerebral motor and cognitive behavior is obviously altered by chronic alcoholism, which generates significant morphological and biochemical changes. In turn, alcoholic withdrawal improves the cerebral blood supply, the psychological and motor behavior and the EEG appearance, especially in young alcoholics. Our study also underlines that alcoholic women develop a late improvement of the clinical and bioelectrical condition during the alcoholic withdrawal.
