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Local delivery of
anti-angiogenic compounds to human orthotopic glioblastoma xenografts improves
treatment efficacy and survival
Mateo Ziu, Nils O. Schmidt, Yanping Sun, Mitchell Albert,
Peter M. Black, Rona S. Carroll
Harvard Medical School/Brigham and Women's
Hospital & Children's Hospital, Boston, MA
Targeting active angiogenesis which is a major hallmark of
malignant gliomas, is a potential adjuvant therapeutic approach.
For effective inhibition of tumor-induced neovascularisation, anti-angiogenic
compounds have to be delivered in sufficient quantities over a sustained period
of time.
The short biological half-life of many anti-angiogenic proteins creates
logistical difficulties which make it necessary to develop an optimized drug
delivery system for the treatment of malignant gliomas.
We evaluated the effects of systemic administration of murine endostatin via
i.p. injections (20mg/kgBW/d) and continuous intracerebral administration via
osmotic mini-pumps (2mg/kgBW/d) on established intracranial U87 human
glioblastoma xenografts in nude mice (n=45).
Noninvasive MRI methods were used to monitor tumor growth.
Histopathological analysis of tumor volume, microvessel density (CD31),
proliferation (Ki-67) and apoptotic index (Caspase3 activation) were
performed.
Three weeks of local intracerebral anti-angiogenic treatment with endostatin
(2mg/kgBW/d) led to a 74% (p<0.05) reduction of tumor volumes with decreased
microvessel densities (31%, p<0.05) and a 3-fold increased tumor cell
apoptosis (p<0.01).
Systemic administration of a 10-fold higher amount of endostatin (20mg/kg BW/d)
did not result in a reduction of tumor volume or increase in tumor cell
apoptosis despite a significant decrease of microvessel densities (27%,
p<0.01).
In a separate study we assessed the efficacy of locally delivered human
endostatin on the survival of nude mice bearing orthotopic U87 glioblastoma
xenografts (n=47).
Continuous and local delivery of human endostatin (2mg/mgBW/d) resulted in a
prolonged survival rate compared to control mice (PBS) and could further be
enhanced by using higher concentrations of endostatin (12mg/kgBW/d).
Our results indicate that the continuous intratumoral delivery of
anti-angiogenic compounds is an effective way to overcome the logistical
problems of inhibiting glioma-induced angiogenesis and should be considered for
further clinical evaluation.
Copyright © 2003 American Association for Cancer Research. All rights reserved.
Source: http://aacr03.agora.com/planner/displayabstract.asp?presentationid=6541
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