Antiangiogenic Therapy by Local Intracerebral Microinfusion Improves Treatment Efficiency and Survival in an Orthotopic Human Glioblastoma Model

Abstract

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.

Improved Therapeutic Effectiveness by Combining Recombinant CXC Chemokine Ligand 10 with Cisplatin in Solid Tumors

“…The inhibition of angiogenesis by CXCL10, therefore, is complementary to antitumor treatments, as was seen in our experiments. The other agents, including soluble vascular endothelial growth factor receptor (44), angiostatin (45), endostatin (46,47), etc., has been also reported to inhibit tumor angiogenesis, to induce apoptosis, and to suppress tumor growth. The molecular mechanisms underlying the inhibition of angiogenesis, which in turn result in the induction of apoptosis in tumor cells by these agents, have yet to be elucidated fully (48).…”

Primary neural stem/progenitor cells expressing endostatin or cytochrome P450 for gene therapy of glioblastoma

“…34 Our finding of an antiendothelial effect over the range of endostatin concentrations achieved in NSC-conditioned medium is especially important in light of recent reports of a biphasic dose-reponse curve for the therapeutic efficacy of endostatin. 48,49 The concentrations of endostatin released into the medium correlate with the systemic concentrations of about 200 ng ml À1 endostatin reportedly sufficient to induce tumor suppression in mice.…”

“…34 After transduction, we established several clones by limiting dilution. A clone displaying bright fluorescence and a doubling time identical to that of the respective parental cells was used throughout the experiments (Figure 4).…”

Antitumor activity of 7-O-succinyl macrolactin A tromethamine salt in the mouse glioma model

“…The human U87MG xenograft model is the standard method for glioblastoma animal models (34)(35)(36); however, tumor invasion in this model is not as extensive as spontaneous glioblastomas in humans (37)(38)(39)(40)(41)(42)(43) . To the best of our knowledge, it is currently unknown how SMA salt is regulated in glioblastoma.…”