Background

[PubMed]

Vascular endothelial growth factor (VEGF) consists of at least six isoforms of various number of amino acids (121, 145, 165, 183, 189 and 206) produced through alternative splicing (1). VEGF₁₂₁, VEGF₁₆₅ and VEGF₁₈₉ are the major forms secreted by most cell types. They are active as homodimers linked by disulfide bonds. VEGF₁₆₅ is the best-characterized VEGF species. VEGF is a potent angiogenic factor inducing proliferation, sprouting, migration, and tube formation of endothelial cells. There are three high affinity tyrosine kinase 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 beta cells also express VEGF receptors (1).

VEGF receptors were found to be overexpressed in various tumor cells and tumor-associated endothelial cells (2). Inhibition of VEGF receptor function has been shown to inhibit pathological angiogenesis and tumor growth and metastasis (3, 4). [¹²³I]VEGF₁₆₅ was developed as a SPECT tracer for imaging solid tumors and angiogenesis (5).

Synthesis

[PubMed]

VEGF₁₆₅ was labeled with sodium [¹²³I]iodide by electrophilic radioiodination using the chloramine-T method (5). This method gave a radiochemical yield of >25% and a radiochemical purity of >97% in a specific activity of 42.3 mCi/nmol (1.66 GBq/nmol).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

[¹²³I]VEGF₁₆₅ (0.001 nm) induced proliferation of human umbilical vein endothelial cells (HUVECs) and A431 mammary carcinoma cells to a similar extent as unlabeled VEGF₁₆₅ (5). Two classes of high-affinity [¹²³I]VEGF₁₆₅-binding sites (B_max1 = 518 sites/cell, K_d1 = 26 pm and B_max2 = 6,100 sites/cell, K_d2 = 2.07 nm) were found on the cell surfaces of HUVECs. In contrast, one class of binding site (B_max = 1,290-3,540 sites/cell and K_d = 88-167 pM) was found on various human cell lines such as HMC-1 mast cells, A431 mammary carcinoma, HEP-G2 hepatoma, HEP-1 hepatic endothelioma, and U937 monocyte cells as well as many human primary tumors (5). No specific binding sites were detected in undifferentiated adenocarcinoma cells as compared with differentiated adenocarcinoma cells (B_max = 15.6 fmol/10⁷ cells, K_d = 143 pm) (6). Tumor cells expressed a significantly higher number of [¹²³I]VEGF₁₆₅ binding sites on their cell surfaces than normal blood cells and adjacent normal tissues (5).

Animal Studies

Human Studies

[PubMed]

[¹²³I]VEGF₁₆₅ (184 ± 18 MBq, 5 ± 0.5 mCi; 0.13 nmol) was administered intravenously to 18 patients with gastrointestinal tumors (8). SPECT images with [¹²³I]VEGF₁₆₅ were compared with computed tomography (CT) and magnetic resonance imaging (MRI). Binding of [¹²³I]VEGF₁₆₅ to primary tumors and metastases was visible shortly after injection. In patients with pancreatic adenocarcinoma, primary tumors were visualized by imaging in 7 of 9, lymph node metastases in 3 of 4, liver metastases in 3 of 6 and lung metastases in 1 of 3. Cholangiocarcinomas were visualized by imaging in 1 of 2 patients. Hepatocellular carcinomas were visible by imaging in 2 of 4 patients. [¹²³I]VEGF₁₆₅ images were weakly positive in one patient with abdominal schwannoma and in 1 patient with peritoneal carcinosis. A ring-shaped tracer accumulation around the necrotic tumors was observed. [¹²³I]VEGF₁₆₅ SPECT provided an overall specificity of 58% and CT/MRI provided a specificity of 95%.

Human dosimetry of [¹²³I]VEGF₁₆₅ was determined from blood samples and SPECT images in 9 patients with pancreatic adenocarcinoma after intravenous injection of 189 ± 17 MBq (5.1 ± 0.5 mCi). [¹²³I]VEGF₁₆₅ disappeared rapidly from the blood to 4% in 30 min postinjection (6).High uptake in the lungs, liver, kidneys and spleen was observed in 30 min. There was a rapid uptake of the tracer by the primary pancreatic adenocarcinoma (tumor/background ratios, 1.3 to 2.7) within 30 min by SPECT scans. The images were still visible at 3 h. The overall sensitivity of [¹²³I]VEGF₁₆₅ scintigraphy for detecting primary pancreatic tumors and their metastases was 64% (14 of 22 lesions) visualizing primary pancreatic adenocarcinoma in 7 of 9 patients (sensitivity, 78%). The effective dose was estimated to be 0.017 mSv/MBq (63 mrem/mCi). The organ that received the highest dose was the thyroid (0.058 mGy/MBq or 0.21 rad/mCi), followed by the spleen (0.046 mGy/MBq or 0.17 rad/mCi), urinary bladder (0.040 mGy/MBq or 0.15 rad/mCi), lungs (0.034 mGy/MBq or 0.13 rad/mCi) kidneys (0.033 mGy/MBq or 0.12 rad/mCi), and liver (0.029 mGy/MBq or 0.11 rad/mCi).

References

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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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Ferrara N. Vascular endothelial growth factor as a target for anticancer therapy. Suppl 1Oncologist. 2004; 9 :2–10. [PubMed: 15178810]

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Hicklin D.J. , Ellis L.M. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005; 23 (5):1011–27. [PubMed: 15585754]

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Li S. , Peck-Radosavljevic M. , Koller E. , Koller F. , Kaserer K. , Kreil A. , Kapiotis S. , Hamwi A. , Weich H.A. , Valent P. , Angelberger P. , Dudczak R. , Virgolini I. Characterization of (123)I-vascular endothelial growth factor-binding sites expressed on human tumour cells: possible implication for tumour scintigraphy. Int J Cancer. 2001; 91 (6):789–96. [PubMed: 11275981]

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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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Cornelissen B. , Oltenfreiter R. , Kersemans V. , Staelens L. , Frankenne F. , Foidart J.M. , Slegers G. In vitro and in vivo evaluation of [123I]-VEGF165 as a potential tumor marker. Nucl Med Biol. 2005; 32 (5):431–6. [PubMed: 15982572]

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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]