11 research outputs found
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Regulation of soluble neuropilin 1, an endogenous angiogenesis inhibitor, in liver development and regeneration
Neuropilin-1 (NRP1) is a receptor for vascular endothelial growth factor (VEGF). A soluble isoform of Nrp1 (sNrp1) has not been described in the mouse. Our goal was to examine the expression of mouse sNrp1 during liver development and regeneration. sNrp1 was cloned from mouse liver. The expression of sNrp1 and VEGF was examined in mouse liver during postnatal development and regeneration using northern blot, western blot, in situ hybridization, and immunohistochemical analyses. HGF/NRP1 binding was examined in vitro. A novel 588-amino acid sNrp1 isoform was found to contain the ligand binding regions of Nrp1. The adult liver expressed more sNrp1 than full-length Nrp1. In vivo, hepatocytes constitutively expressed VEGF and sNrp1 in the quiescent state. sNrp1 was highly upregulated at P20, a time point coinciding with a plateau in liver and body weights. Following hepatectomy, endogenous levels of sNrp1 decreased during the rapid growth phase; and VEGF levels were highest just prior to and during the angiogenic phase. sNrp1 levels again rose 5-10 days post-hepatectomy, presumably to control regeneration. HGF protein bound NRP1 and binding was competed with sNRP1. We cloned a novel mouse sNrp1 isoform from liver and provide evidence that this endogenous angiogenesis inhibitor may regulate VEGF or HGF bioavailability during normal physiological growth and development as well as during liver regeneration
The Adnectin CT-322 is a novel VEGF receptor 2 inhibitor that decreases tumor burden in an orthotopic mouse model of pancreatic cancer
<p>Abstract</p> <p>Background</p> <p>Pancreatic cancer continues to have a 5-year survival of less than 5%. Therefore, more effective therapies are necessary to improve prognosis in this disease. Angiogenesis is required for tumor growth, and subsequently, mediators of angiogenesis are attractive targets for therapy. Vascular endothelial growth factor (VEGF) is a well-characterized mediator of tumor angiogenesis that functions primarily by binding and activating VEGF receptor 2 (VEGFR2). In this study, we evaluate the use of CT-322, a novel biologic (Adnectin). This small protein is based on a human fibronectin domain and has beneficial properties in that it is fully human, stable, and is produced in bacteria. CT-322 binds to and inhibits activation of VEGFR2.</p> <p>Methods</p> <p>The efficacy of CT-322 was evaluated <it>in vivo </it>using two orthotopic pancreatic tumor models. The first model was a human tumor xenograft where MiaPaCa-2 cells were injected into the tail of the pancreas of nude mice. The second model was a syngeneic tumor using Pan02 cells injected into pancreas of C57BL/6J mice. In both models, therapy was initiated once primary tumors were established. Mice bearing MiaPaCa-2 tumors were treated with vehicle or CT-322 alone. Gemcitabine alone or in combination with CT-322 was added to the treatment regimen of mice bearing Pan02 tumors. Therapy was given twice a week for six weeks, after which the animals were sacrificed and evaluated (grossly and histologically) for primary and metastatic tumor burden. Primary tumors were also evaluated by immunohistochemistry for the level of apoptosis (TUNEL), microvessel density (MECA-32), and VEGF-activated blood vessels (Gv39M).</p> <p>Results</p> <p>Treatment with CT-322 was effective at preventing pancreatic tumor growth and metastasis in orthotopic xenograft and syngeneic models of pancreatic cancer. Additionally, CT-322 treatment increased apoptosis, reduced microvessel density and reduced the number of VEGF-activated blood vessels in tumors. Finally, CT-322, in combination with gemcitabine was safe and effective at controlling the growth of syngeneic pancreatic tumors in immunocompetent mice.</p> <p>Conclusion</p> <p>We conclude that CT-322 is an effective anti-VEGFR2 agent and that further investigation of CT-322 for the treatment of pancreatic cancer is warranted.</p
A Novel Suspension Formulation Enhances Intestinal Absorption of Macromolecules Via Transient and Reversible Transport Mechanisms
Hormonal Regulation of Messenger Ribonucleic Acid Expression for Steroidogenic Factor-1, Steroidogenic Acute Regulatory Protein, and Cytochrome P450 Side-Chain Cleavage in Bovine Luteal Cells
Neuropilin-1 binds vascular endothelial growth factor 165, placenta growth factor-2, and heparin via its b1b2 domain
Molecular Identification of Adenylyl Cyclase 3 in Bovine Corpus Luteum and Its Regulation by Prostaglandin F2α-Induced Signaling Pathways1
Regulation of soluble neuropilin 1, an endogenous angiogenesis inhibitor, in liver development and regeneration
Safety and efficacy of oral octreotide in acromegaly: results of a multicenter phase III trial
A novel oral octreotide formulation was tested for efficacy and safety in a phase III, multicenter, open-label, dose-titration, baseline-controlled study in patients with acromegaly