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Recombinant Human Vascular Endothelial Growth Inhibitor (VEGI-192)
(Cat. No.: C038)
Background:
Vascular endothelial growth inhibitor (VEGI; TNFSF-15) is a new member of the tumor necrosis factor family. VEGI is predominantly an endothelial cell-specific gene, and recombinant VEGI is a potent inhibitor of endothelial cell proliferation, angiogenesis and tumor growth. VEGI exerts two activities on endothelial cells: early G1 arrest of G0/G1-cells responding to growth stimuli, and programmed death of proliferating cells. These activities are highly specific to endothelial cells. VEGI is also able to regulate the expression of several important genes involved in angiogenesis. These findings are consistent with the view that VEGI functions as an autocrine cytokine to inhibit angiogenesis and stabilize the vasculature.
Description:
Recombinant human VEGI-192 produced in E. coli is a single, non-glycosylated polypeptide chain containing 192 amino acids and having a molecular mass of 21858 Dalton.
Quality Control:
Biological Activity: The ED50 as determined by the dose-dependant inhibition of the proliferation of HUVEC (Human Umbilical Vein Endothelial Cells) is less then 5μg/ml.
Purity: Greater than 95.0% as determined by:
(a) Analysis by RP-HPLC.
(b) Analysis by reducing and non-reducing SDS-PAGE Silver Stained gel.
Amino-Acid Sequence: The sequence of the first five N-terminal amino acids was determined and was found to be Met-Gln-Leu-Thr-Lys.
Endotoxin: Less than 0.1 ng/µg (1 IEU/µg) of rHuVEGI.
Formulation:
The protein was lyophilized after extensive dialysis against 0.5M NaCl, 50mM Tris-HCl buffer, pH 7.5.
Storage:
Lyophilized VEGI-192 although stable at room temperature for 3 weeks, should be stored desiccated below -18°C. Upon reconstitution VEGI-192 should be stored at 4°C between 2-7 days and for future use below -18°C. For long-term storage it is recommended to add a carrier protein (0.1% HSA or BSA).
Please avoid freeze-thaw cycles.
Reconstitution:
It is recommended to reconstitute the lyophilized VEGI-192 in sterile 18MΩ-cm H2O not less than 100µg/ml, which can then be further diluted to other aqueous solutions.
Latest Publications:
1: J Neuroinflammation 2008 ;Vol 5
VEGF receptor antagonist Cyclo-VEGI reduces inflammatory reactivity and vascular leakiness and is neuroprotective against acute excitotoxic striatal insult.
[Abstract] BACKGROUND: Excitotoxic brain insult is associated with extensive neuronal damage but could also cause inflammatory reactivity and vascular remodeling. The effects of the vascular endothelial growth factor (VEGF) inhibitor, Cyclo-VEGI on expression of VEGF, microgliosis and astrogliosis, blood-brain barrier (BBB) integrity and neuronal viability have been studied following intra-striatal injection of the excitotoxin, quinolinic acid (QUIN). The purpose of this study was to examine VEGF-dependent inflammatory responses in excitotoxin-injected brain and their dependence on pharmacological antagonism of VEGF receptors. METHODS: Single and double immunofluorescence staining of cellular (microglia, astrocyte, neuron) responses and dye and protein infiltration of
blood-brain barrier have been applied in the absence, and presence, of pharmacological modulation using a VEGF receptor antagonist, Cyclo-VEGI. Dunn-Bonferroni statistical analysis was used to measure for significance between animal groups. RESULTS: Detailed analysis, at a single time point of 1 d post-QUIN injection, showed excitotoxin-injected striatum to exhibit marked increases in microgliosis (ED1 marker), astrogliosis (GFAP marker) and VEGF expression, compared with PBS injection. Single and double immunostaining demonstrated significant effects of Cyclo-VEGI treatment of QUIN-injected striatum to inhibit microgliosis (by 38%), ED1/VEGF (by 42%) and VEGF striatal immunoreactivity (by 43%); astrogliosis and GFAP/VEGF were not significantly altered with Cyclo-VEGI treatment. Leakiness of
BBB was indicated by infiltration of Evans blue dye and plasma protein fibrinogen into QUIN-injected striatum with barrier permeability restored by 62% (Evans blue permeability) and 49% (fibrinogen permeability) with Cyclo-VEGI application. QUIN-induced toxicity was demonstrated with loss of striatal neurons (NeuN marker) and increased neuronal damage (Fluoro-Jade marker) with significant neuroprotection conferred by Cyclo-VEGI treatment (33% increase in NeuN and 38% decrease in Fluoro-Jade). CONCLUSION: An antagonist for VEGF receptor-mediated signaling, Cyclo-VEGI, has shown efficacy in a broad spectrum of activity against striatal excitotoxic insult including inhibition of microgliosis, reduction in leakiness of BBB and parenchymal infiltration of plasma fibrinogen and in conferring
significant protection for striatal neurons. Antagonism of VEGF-mediated activity, possibly targeting VEGF receptors on reactive microglia, is suggested as a neuroprotective mechanism against inflammatory reactivity and a novel strategy to attenuate acute excitotoxic damage.
2: Angiogenesis 2006 ;Vol 9(2)
Reduced vascular endothelial growth inhibitor (VEGI) expression is associated with poor prognosis in breast cancer patients.
[Abstract] Vascular endothelial growth inhibitor (VEGI) is a novel anti-angiogenic cytokine that belongs to the tumour necrosis factor (TNF) superfamily. Very little is known about the significance of VEGI in cancer. Our study analysed VEGI expression in relation to breast cancer patient clinical parameters. The VEGI expression profile was assessed qualitatively (RT-PCR), quantitatively (real-time Quantitative-PCR), and immuno-histochemically (IHC), in a panel of 24 human normal and cancer cell lines and in a cohort of 151 mammary tissue samples (n = 33 normal breast tissue; n = 118 breast cancer tissue) with a 6-year median follow-up. Patients who had died of breast cancer or had local recurrence of the disease expressed significantly lower levels of VEGI in comparison
to the elevated levels in the disease free patients. High levels of VEGI were associated with an increased chance of patient survival. Importantly, patients with breast tumours expressing reduced levels of VEGI had a poorer prognosis than those patients expressing high levels of VEGI. However, no significant correlations were observed between VEGI expression and tumour grade, TNM classification, or nodal involvement. In conclusion, VEGI is aberrantly expressed in human breast cancer tissues. VEGI displays prognostic relevance as breast cancer patients with an overall poor prognosis express significantly lower levels of VEGI compared to those with a favourable prognosis.
3: Int J Mol Med 2006 Jun;Vol 17(6)
Comparative integromics on Angiopoietin family members.
[Abstract] Angiopoietin-1 (ANGPT1), Angiopoietin-4 (ANGPT4), VEGF, FGF2, FGF4, HGF, Ephrin, IL8 and CXCL12 (SFD1) are pro-angiogenic factors (angiogenic activators), while Angiopoietin-2 (ANGPT2), Angiostatin, Endostatin, Tumstatin, Canstatin, THBS1, THBS2, TNFSF15 (VEGI) and Vasohibin (VASH1) are anti-angiogenic factors (angiogenic inhibitors). ANGPT1 and ANGPT2 are ligands for TIE family receptor tyrosine kinases, TIE1 and TIE2 (TEK). Angiopoietin family consists of ANGPT1, ANGPT2, ANGPT4, ANGPTL1 (ANGPT3), ANGPTL2, ANGPTL3 (ANGPT5), ANGPTL4, ANGPTL5, ANGPTL6 and ANGPTL7. TCF/LEF binding sites within the promoter region of human Angiopoietin family members were searched for by using bioinformatics and human intelligence (Humint). Because four TCF/LEF-binding sites were
identified within the human ANGPTL7 promoter, comparative genomics analyses on ANGPTL7 orthologs were further performed. ANGPTL7 gene at human chromosome 1p36.22 was located within intron 28 of FRAP1 gene encoding mTOR protein. Chimpanzee ANGPTL7 gene, consisting of five exons, was located within NW_101546.1 genome sequence. Chimpanzee ANGPTL7 showed 99.4% and 86.1% total-amino-acid identity with human ANGPTL7 and mouse Angptl7, respectively. Human ANGPTL7 mRNA was expressed in neural tissues, keratoconus cornea, trabecular meshwork, melanotic melanoma and uterus endometrial cancer, while mouse Angptl7 mRNA was expressed in four-cell embryo, synovial fibroblasts, thymus, uterus and testis. Four TCF/LEF-binding sites within human ANGPTL7 promoter were conserved in chimpanzee ANGPTL7 promoter;
however, only an unrelated TCF/LEF-binding site occurred in mouse and rat Angptl7 promoters. Human ANGPTL7, characterized as potent target gene of WNT/ beta-catenin signaling pathway, is a pharmacogenomics target in the fields of oncology and regenerative medicine.
4: Pharm Res 2005
Aug;Vol 22(8)
Design, synthesis, and evaluation of original carriers for targeting vascular endothelial growth factor receptor interactions.
[Abstract] PURPOSE: Angiogenesis is a key event in tumor growth and metastasis, chronic inflammatory disease, and cardiovascular disease. It is controlled by positive and negative regulators, which include vascular endothelial growth factor (VEGF) as the most active of these. VEGF/VEGF receptors are important targets not only for therapy but also for imaging. Based on the structural study of VEGF, we developed a novel cyclopeptide (cyclo-VEGI) that exhibits powerful antitumor properties. We herein report the design of novel molecules derived from cyclo-VEGI as potential targeting agents in cancer and other angiogenesis-related diseases. METHODS: We performed selective chemical modification of the most active VEGF-derived cyclopeptide (cyclo-VEGI). Original hydrophilic
linkers were synthesized and coupled to cyclo-VEGI. These reactions provide nanocarriers for delivery. The inhibitory effect of the different compounds on VEGF binding was evaluated in competition assays with 125I-VEGF. A fluorescent cyclo-VEGI peptide was synthezised to assess direct binding and internalization of cyclo-VEGI. RESULTS: Chemical modifications of cyclo-VEGI do not diminish the biological activity of cyclo-VEGI as measured in competition assays; in fact, it is even increased. Moreover there is a strong cellular accumulation of the fluorescent-labeled cyclo-VEGI. Conjugates synthesized in this study may be useful leads to design delivery systems for targeting approaches in cancer and other angiogenesis-related diseases. CONCLUSION: The modified cyclo-VEGIs may have a wide range
of applications and represent a useful tool to develop delivery/carrier systems for therapeutic targeting or imaging.
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