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Inhibition of
Glioma Angiogenesis and Growth in Vivo by Systemic
Treatment with a Monoclonal Antibody against Vascular Endothelial
Growth Factor Receptor-2
Philip Kunkel, Ulrike
Ulbricht, Peter Bohlen, Marc A.
Brockmann, Regina Fillbrandt, Dimitrios
Stavrou, Manfred Westphal and Katrin
Lamszus
Departments of Neurosurgery [P. K.,
U. U., M. A. B., R. F., M. W.] and Neuropathology [D. S., K. L.],
University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany, and
ImClone Systems, Inc. [P. B.], New York, New York 10014.
[K.L.] To whom requests for reprints should addressed, at
Department of Neuropathology, University Hospital
Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg,
Germany. Phone: 49-40-42803-3763; Fax: 49-40-42803-4596; E-mail:
mailto:lamszus@uke.uni-hamburg.de.
Received 4/13/01; accepted 7/30/01.
Using an orthotopic intracerebral
model, we investigated whether systemic treatment with
DC101, a monoclonal antibody against vascular
endothelial growth factor receptor (VEGFR)-2, could inhibit
angiogenesis and the growth of human glioblastoma cells in
severe combined immunodeficient mice.
Intraperitoneal treatment with DC101, control IgG, or
PBS was initiated either on day 0 or, in another
series, on day 6 after tumor cell implantation, and
animals were killed ~2 weeks after tumor cell injection.
Tumor volumes in animals treated with DC101 were reduced by 59
and 81% compared with IgG and PBS controls, respectively (P
< 0.001), when treatment was initiated immediately, and similar
results were obtained when treatment started on day 6.
Microvessel density in tumors of DC101-treated animals was reduced
by at least 40% compared with animals treated with control IgG
or PBS (P < 0.01).
We observed a reduction in tumor cell proliferation and
an increase in apoptosis in DC101-treated animals (P
< 0.001).
However, in mice treated with DC101, we also noticed a
striking increase in the number and total area of small
satellite tumors clustered around, but distinct from,
the primary.
These satellites usually contained central vessel
cores, and tumor cells often had migrated over long distances
along the host vasculature to eventually reach the surface
and spread leptomeningeally.
We conclude that systemic antagonization of VEGFR-2 can
inhibit glioblastoma neovascularization and growth but
can lead to increased cooption of preexistent cerebral blood vessels.
Therefore, a combination of different treatment modalities which
also include anti-invasive therapy may be needed for an effective
therapy against glioblastoma, and the use of an antibody against
VEGFR-2 may be one effective component.
© 2001 American Association for
Cancer Research
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