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. 2010 Dec 1;70(23):9886-94.
doi: 10.1158/0008-5472.CAN-10-1419. Epub 2010 Nov 30.

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

Marianne O Stefanini  1 , Florence T H Wu, Feilim Mac Gabhann, Aleksander S Popel
Affiliations

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

Marianne O Stefanini et al. Cancer Res. .

Abstract

Vascular endothelial growth factor (VEGF) is one of the most potent cytokines targeted in antiangiogenic 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 among 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.

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Conflict of interest statement

Conflict of Interest: The authors hereby declare no competing conflicts of interest.

Figures

Figure 1
Figure 1. Free VEGF concentration profiles following the intravenous injection of an anti-VEGF agent
A-B. Single injection (10 mg/kg), C-D. Daily injection of 1 mg/kg for 10 days (metronomic therapy). 1 pM VEGF equivalent to 24 pg/mL total blood. Solid line: normal tissue; dashed line: blood; dotted line: tumor.
Figure 2
Figure 2. Net inter-compartmental flows of VEGF, anti-VEGF and VEGF/anti-VEGF complex
Solid line: normal tissue; dotted line: tumor. Black: free VEGF; light gray: anti-VEGF agent; dark gray: VEGF/anti-VEGF complex (also total VEGF).
Figure 3
Figure 3. Relative VEGF distribution profiles in normal, blood and tumor tissues
Percentage of VEGF bound to the anti-VEGF agent, free, bound to the receptors and sequestered in the extracellular matrix. From top to bottom: normal tissue, blood, tumor. Light gray: VEGF bound to anti-VEGF (VEGF/anti-VEGF complex); white: VEGF bound to the extracellular matrix; dark gray: VEGF bound to receptors; black: unbound VEGF.
Figure 4
Figure 4. VEGF receptor occupancy profiles
Percentage of ligated and unligated receptors. A. VEGFR1, B. VEGFR2, C. NRP1. Solid line: normal tissue; dotted line: tumor. Black: single injection; gray: metronomic therapy.
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References

    1. Gaur P, Bose D, Samuel S, Ellis LM. Targeting tumor angiogenesis. Semin Oncol. 2009;36(2 Suppl 1):S12–9. - PubMed
    1. Kut C, Mac Gabhann F, Popel AS. Where is VEGF in the body? A meta-analysis of VEGF distribution in cancer. Br J Cancer. 2007;97(7):978–85. - PMC - PubMed
    1. Grothey A, Galanis E. Targeting angiogenesis: progress with anti-VEGF treatment with large molecules. Nat Rev Clin Oncol. 2009;6(9):507–18. - PubMed
    1. Gordon MS, Margolin K, Talpaz M, et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol. 2001;19(3):843–50. - PubMed
    1. Segerstrom L, Fuchs D, Backman U, Holmquist K, Christofferson R, Azarbayjani F. The anti-VEGF antibody bevacizumab potently reduces the growth rate of high-risk neuroblastoma xenografts. Pediatr Res. 2006;60(5):576–81. - PubMed

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