Bevacizumab-Induced Transient Remodeling of the Vasculature in Neuroblastoma Xenografts Results in Improved Delivery and Efficacy of Systemically Administered Chemotherapy
Purpose: Dysfunctional tumor vessels can be a significant barrier to effective cancer therapy. However, increasing evidence suggests that vascular endothelial growth factor (VEGF) inhibition can effect transient “normalization” of the tumor vasculature, thereby improving tumor perfusion and, consequ...
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Published in | Clinical cancer research Vol. 13; no. 13; pp. 3942 - 3950 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Association for Cancer Research
01.07.2007
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Subjects | |
Online Access | Get full text |
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Summary: | Purpose: Dysfunctional tumor vessels can be a significant barrier to effective cancer therapy. However, increasing evidence suggests
that vascular endothelial growth factor (VEGF) inhibition can effect transient “normalization” of the tumor vasculature, thereby
improving tumor perfusion and, consequently, delivery of systemic chemotherapy. We sought to examine temporal changes in tumor
vascular function in response to the anti-VEGF antibody, bevacizumab.
Experimental Design: Established orthotopic neuroblastoma xenografts treated with bevacizumab were evaluated at serial time points for treatment-associated
changes in intratumoral vascular physiology, penetration of systemically administered chemotherapy, and efficacy of combination
therapy.
Results: After a single bevacizumab dose, a progressive decrease in tumor microvessel density to <30% of control was observed within
7 days. Assessment of the tumor microenvironment revealed a rapid, sustained decrease in both tumor vessel permeability and
tumor interstitial fluid pressure, whereas intratumoral perfusion, as assessed by contrast-enhanced ultrasonography, was improved,
although this latter change abated by 1 week. Intratumoral drug delivery mirrored these changes; penetration of chemotherapy
was improved by as much as 81% when given 1 to 3 days after bevacizumab, compared with when both drugs were given concomitantly,
or 7 days apart. Finally, administering topotecan to tumor-bearing mice 3 days after bevacizumab resulted in greater tumor
growth inhibition (36% of control size) than with monotherapy (88% bevacizumab, 54% topotecan) or concomitant administration
of the two drugs (44%).
Conclusions: Bevacizumab-mediated VEGF blockade effects alterations in tumor vessel physiology that allow improved delivery and efficacy
of chemotherapy, although careful consideration of drug scheduling is required to optimize antitumor activity. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.CCR-07-0278 |