Targeting active angiogenesis, which is a major hallmark of malignant gliomas, is a potential therapeutic approach. For effective inhibition of tumor-induced neovascularization, antiangiogenic compounds have to be delivered in sufficient quantities over a sustained period of time. The short biological half-life of many antiangiogenic inhibitors and the impaired intratumoral blood flow create logistical difficulties that make it necessary to optimize drug delivery for the treatment of malignant gliomas. In this study, we compared the effects of endostatin delivered by daily systemic administration or local intracerebral microinfusion on established intracranial U87 human glioblastoma xenografts in nude mice. Noninvasive magnetic resonance imaging methods were used to assess treatment effects and additional histopathological analysis of tumor volume, microvessel density, proliferation, and apoptosis rate were performed. Three weeks of local intracerebral microinfusion of endostatin (2 mg/kg/day) led to 74% (P < 0.05) reduction of tumor volumes with decreased microvessel densities (33.5%, P < 0.005) and a 3-fold increased tumor cell apoptosis (P < 0.002). Systemic administration of a 10-fold higher amount of endostatin (20 mg/kg/day) did not result in a reduction of tumor volume nor in an increase of tumor cell apoptosis despite a significant decrease of microvessel densities (26.9%, P < 0.005). Magnetic resonance imaging was used to successfully demonstrate treatment effects. The local microinfusion of human endostatin significantly increased survival when administered at 2 mg/kg/day and was prolonged further when the dose was increased to 12 mg/kg/day. Our results indicate that the local intracerebral microinfusion of antiangiogenic compounds is an effective way to overcome the logistical problems of inhibiting glioma-induced angiogenesis.
Antiangiogenic therapy by local intracerebral microinfusion improves treatment efficiency and survival in an orthotopic human glioblastoma model / N.O. Schmidt, M. Ziu, G. Carrabba, C. Giussani, L. Bello, Y. Sun, K. Schmidt, M. Albert, P.M. Black, R.S. Carroll. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - 10:4(2004 Feb 15), pp. 1255-1262.
|Titolo:||Antiangiogenic therapy by local intracerebral microinfusion improves treatment efficiency and survival in an orthotopic human glioblastoma model|
|Parole Chiave:||Magnetic Resonance Imaging; Animals; Glioblastoma; Ki-67 Antigen; Apoptosis; Humans; Caspase 3; Mice, Nude; Mice; Cell Line, Tumor; Endostatins; Caspases; Angiogenesis Inhibitors; Antigens, CD31; Cell Survival; Neoplasm Transplantation; Brain Neoplasms; Xenograft Model Antitumor Assays; Telencephalon; Microcirculation; Glioma; Time Factors; Cell Division|
|Settore Scientifico Disciplinare:||Settore MED/27 - Neurochirurgia|
|Data di pubblicazione:||15-feb-2004|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1158/1078-0432.CCR-03-0052|
|Appare nelle tipologie:||01 - Articolo su periodico|