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Potent VEGF
blockade causes regression of coopted vessels in a model of
neuroblastoma
Eugene S. Kim,
Anna Serur, Jianzhong Huang, Christina
A. Manley, Kimberly W. McCrudden, Jason
S. Frischer, Samuel Z. Soffer, Laurence
Ring, Tamara New, Stephanie Zabski,
John S. Rudge, Jocelyn Holash, George
D. Yancopoulos, Jessica J. Kandel and Darrell
J. Yamashiro
Divisions of Pediatric Surgery
[E.S.K., A.S., J.H., K.W.M., J.S.F., S.Z.S., J.J.K., D.J.Y.] and
Pediatric Oncology [C.A.M., L.R., T.N., D.J.Y.], College of
Physicians and Surgeons of Columbia University, New York, NY
10032; and Regeneron Pharmaceuticals, Incorporated, 777 Old Saw
Mill River Road, Tarrytown, NY 10591 [S.Z., J.S.R., J.Ho.,
G.D.Y.].
[DJY] To whom reprint requests should be addressed. E-mail: dy39@columbia.edu.
Communicated by P. Roy Vagelos, Merck & Co., Inc., Bedminster,
NJ and approved July 5, 2002 (received for review April 19, 2002).
Vascular endothelial growth factor
(VEGF) plays a key role in human tumor
angiogenesis.
We compared the effects of inhibitors of VEGF with
different specificities in a xenograft model of neuroblastoma.
Cultured human neuroblastoma NGP-GFP cells were implanted
intrarenally in nude mice.
Three anti-VEGF agents were tested: an anti-human VEGF165
RNA-based fluoropyrimidine aptamer; a monoclonal
anti-human VEGF antibody; and VEGF-Trap, a composite
decoy receptor based on VEGFR-1 and VEGFR-2 fused to an
Fc segment of IgG1.
A wide range of efficacy was observed, with high-dose
VEGF-Trap causing the greatest inhibition of tumor
growth (81% compared with controls).
We examined tumor angiogenesis and found that early in
tumor formation, cooption of host vasculature
occurs.
We postulate that this coopted vasculature serves as a
source of blood supply during the initial phase of
tumor growth.
Subsequently, control tumors undergo vigorous growth
and remodeling of vascular networks, which results in disappearance
of the coopted vessels.
However, if VEGF function is blocked, cooption of host
vessels may persist.
Persistent cooption, therefore, may represent a novel
mechanism by which neuroblastoma can partly evade
antiangiogenic therapy and may explain why experimental
neuroblastoma is less susceptible to VEGF blockade than a
parallel model of Wilms tumor.
However, more effective VEGF blockade, as achieved by
high doses of VEGF-Trap, can lead to regression of
coopted vascular structures.
These results demonstrate that cooption of host
vasculature is an early event in tumor formation, and that
persistence of this effect is related to the degree of blockade
of VEGF activity.
Copyright © 2002 by the National
Academy of Sciences
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