NDLI: Increase of plasma VEGF after intravenous administration of bevacizumab is predicted by a pharmacokinetic model

Content Provider	PubMed Central
Author	Stefanini, Marianne O. Wu, Florence T. H. Mac Gabhann, Feilim Popel, Aleksander S.
Abstract	Vascular endothelial growth factor (VEGF) is one of the most potent cytokines targeted in anti-angiogenic therapies. Bevacizumab, a recombinant humanized monoclonal antibody to VEGF, is being used clinically in combination with chemotherapy for colorectal, non-small cell lung and breast cancers, and as a single agent for glioblastoma, and is being tested for other types of cancer in numerous clinical trials. It has been reported that the intravenous injection of bevacizumab leads to an increase of plasma VEGF concentration in cancer patients. The mechanism responsible for this counterintuitive increase has not been elucidated, although several hypotheses have been proposed. We use a multiscale systems biology approach to address this problem. We have constructed a whole-body pharmacokinetic model comprising three compartments: blood, normal tissue and tumor tissue. Molecular interactions between VEGF-A family members, their major receptors, the extracellular matrix, and an anti-VEGF ligand are considered for each compartment. Diffusible molecules extravasate, intravasate, are removed from the healthy tissue through the lymphatics, and are cleared from the blood. Our model reproduces the experimentally-observed increase of plasma VEGF following intravenous administration of bevacizumab, and predicts this increase to be a consequence of inter-compartmental exchange of VEGF, the anti-VEGF agent and the VEGF/anti-VEGF complex. Our results suggest that a fraction of the anti-VEGF drug extravasates, allowing the agent to bind the interstitial VEGF. When the complex intravasates (via a combination of lymphatic drainage and microvascular transport of macromolecules) and dissociates in the blood, VEGF is released and the VEGF concentration increases in the plasma. These results provide a new hypothesis on the kinetics of VEGF and on the VEGF distribution in the body caused by anti-angiogenic therapies, as well as their mechanisms of action and could help in designing anti-angiogenic therapies.
Related Links	http://dx.doi.org/10.1158/0008-5472.can-10-1419
Ending Page	9894
Page Count	9
Starting Page	9886
File Format	PDF
ISSN	00085472
e-ISSN	15387445
Journal	Cancer research
Issue Number	23
Volume Number	70
Language	English
Publisher Date	2010-12-01
Access Restriction	Open
Subject Keyword	Cancer Research Oncology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology

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