Background

[PubMed]

Vascular endothelial growth factor (VEGF) consists of at least six isoforms of various numbers of amino acids (121, 145, 165, 183, 189, and 206 amino acids) produced through alternative splicing (1). VEGF₁₂₁, VEGF₁₆₅, and VEGF₁₈₉ are the forms secreted by most cell types and are active as homodimers linked by disulfide bonds. VEGF₁₂₁ does not bind to heparin like the other VEGF species do (2). VEGF is a potent angiogenic factor that induces proliferation, sprouting, migration, and tube formation of endothelial cells. There are three high-affinity tyrosine kinase VEGF receptors (VEGFR-1, Flt-1; VEGFR-2, KDR/Flt-1; and VEGFR-3, Flt-4) on endothelial cells. Several types of non-endothelial cells such as hematopoietic stem cells, melanoma cells, monocytes, osteoblasts, and pancreatic β cells also express VEGF receptors (1).

VEGF is overexpressed in various tumor cells and tumor-associated endothelial cells (3). Inhibition of VEGF receptor function has been shown to inhibit pathological angiogenesis as well as tumor growth and metastasis (4, 5). Radiolabeled VEGF has been developed as a single-photon emission computed tomography tracer for imaging solid tumors and angiogenesis in humans (6-8). However, several studies have shown that cancer treatments (photodynamic therapy, radiotherapy, and chemotherapy) can lead to increased tumor VEGF expression and subsequently to more aggressive disease (9, 10). Therefore, it is important to measure VEGF levels in the tumors to design better anti-cancer treatment protocols. Bevacizumab is a humanized antibody against VEGF-A. It binds to all VEGF isoforms. Bevacizumab is approved for clinical use in metastatic colon carcinoma and non-small cell lung cancer. Nagengast et al. (11) prepared ⁸⁹Zr-N-succinyldesferrioxamine-bevacizumab (⁸⁹Zr-bevacizumab) for imaging VEGF expression in nude mice bearing SKOV-3 human ovarian tumor xenografts.

Synthesis

[PubMed]

N-Succinyldesferrioxamine (N-sucDf) B-tetrafluorophenol and bevacizumab were incubated in sodium carbonate buffer (pH 9.5) for 30 min at room temperature (11). N-sucDf-Bevacizumab was isolated from the incubation mixture with ultrafiltration. There were 1.5–2.5 chelate groups per antibody. N-sucDf-Bevacizumab was mixed with ⁸⁹Zr-oxalate. The mixture was incubated for 45 min at room temperature. ⁸⁹Zr-Bevacizumab had a radiochemical purity of >99% and a specific activity 8.8 MBq/nmol (0.24 mCi/nmol) with a labeling yield of 98 ± 0.7%. ⁸⁹Zr-Bevacizumab was stable for 7 d at 4°C in ammonium acetate and at 37°C in serum. ⁸⁹Zr-Bevacizumab resulted in 54.0 ± 3.7% binding to VEGF. Bevacizumab (≥500-fold) almost completely blocked ⁸⁹Zr-bevacizumab binding to <5%.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

No publication is currently available.

Animal Studies

Human Studies

[PubMed]

No publication is currently available.

References

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Cohen T. , Gitay-Goren H. , Sharon R. , Shibuya M. , Halaban R. , Levi B.Z. , Neufeld G. VEGF121, a vascular endothelial growth factor (VEGF) isoform lacking heparin binding ability, requires cell-surface heparan sulfates for efficient binding to the VEGF receptors of human melanoma cells. J Biol Chem. 1995; 270 (19):11322–6. [PubMed: 7744769]

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Soria J.C. , Fayette J. , Armand J.P. Molecular targeting: targeting angiogenesis in solid tumors. Suppl 4Ann Oncol. 2004; 15 :iv223–7. [PubMed: 15477311]

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Li S. , Peck-Radosavljevic M. , Kienast O. , Preitfellner J. , Hamilton G. , Kurtaran A. , Pirich C. , Angelberger P. , Dudczak R. Imaging gastrointestinal tumours using vascular endothelial growth factor-165 (VEGF165) receptor scintigraphy. Ann Oncol. 2003; 14 (8):1274–7. [PubMed: 12881392]

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Li S. , Peck-Radosavljevic M. , Kienast O. , Preitfellner J. , Havlik E. , Schima W. , Traub-Weidinger T. , Graf S. , Beheshti M. , Schmid M. , Angelberger P. , Dudczak R. Iodine-123-vascular endothelial growth factor-165 (123I-VEGF165). Biodistribution, safety and radiation dosimetry in patients with pancreatic carcinoma. Q J Nucl Med Mol Imaging. 2004; 48 (3):198–206. [PubMed: 15499293]

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Gorski D.H. , Beckett M.A. , Jaskowiak N.T. , Calvin D.P. , Mauceri H.J. , Salloum R.M. , Seetharam S. , Koons A. , Hari D.M. , Kufe D.W. , Weichselbaum R.R. Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res. 1999; 59 (14):3374–8. [PubMed: 10416597]

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Solban N. , Selbo P.K. , Sinha A.K. , Chang S.K. , Hasan T. Mechanistic investigation and implications of photodynamic therapy induction of vascular endothelial growth factor in prostate cancer. Cancer Res. 2006; 66 (11):5633–40. [PubMed: 16740700]

11.

Nagengast W.B. , de Vries E.G. , Hospers G.A. , Mulder N.H. , de Jong J.R. , Hollema H. , Brouwers A.H. , van Dongen G.A. , Perk L.R. , Lub-de Hooge M.N. In vivo VEGF imaging with radiolabeled bevacizumab in a human ovarian tumor xenograft. J Nucl Med. 2007; 48 (8):1313–9. [PubMed: 17631557]