Browsing by Subject "Angiogenesis"
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Item Mechanism of Action and Clinical Efficacy of AL-3789, an Angiostatic Steroid(1996-12-01) Defaller, Joseph M.; Clark, Abbot F.; Quist, Eugene E.; Yorio, ThomasDeFaller, Joseph M., Mechanism of Action and Clinical Efficacy of AL-3789, an Angiostatic Steroid. Doctor of Philosophy (Pharmacology), December, 1996, 115 pp., 11 tables, 31 illustrations, reference list, 115 titles. Angiogenesis, the growth of new blood vessels, is important in cancerous tumor growth, diabetes, and degenerative diseases. During angiogenesis, proliferating vascular endothelial cells from blood vessels secrete proteinases, including urokinase (uPA) and stromelysin-1 (MMP-3), which dissolve the extracellular matrix and allow them to migrate and form new blood vessels. In this investigation the angiostatic effects of AL-3789, an angiostatic steroid, were investigated in in vitro human cell models and human clinical trials. The angiostatic mechanism of action of this agent at 10^-5 molar concentration was demonstrated to include: 1) inhibition of lipopolysaccharide-induced uPA and MMP-3 production by human microvascular endothelial cells (HMVEC-L), 2) dose-dependent inhibition of HMVEC-L proliferation, and 3) alteration in the expression of approximately 1% of HMVEC-L proteins visualized by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). These protein changes are similar in magnitude to those caused by glucocorticoids, which act via an intracellular/intranuclear glucocorticoid receptor. The clinical efficacy of AL-3789 in preventing re-neovascularization and recurrence of malignant pterygia following surgical excision in humans was demonstrated by topical ocular dosing of a 1.0% suspension three times daily in a double-masked, randomized, prospective, placebo-controlled trial. Pterygium is a chronic condition in which neovascularized fibrotic tissue grows over the cornea to eventually obstruct the visual axis in some patients. Computer image analysis of serial photographs for each patient following surgery showed a re-neovascularization growth rate following pterygium excision of 1.58 mm^2/week for patients treated with placebo compared to 0.78 mm^2/week exhibited by the AL-3789 treated group (p [less than] 0.05, ANOVA). Pterygia recurred in 71% of the placebo group compared to 42% of the AL-3789 treated group (p [less than] 0.05, Chi-square contingency test). In conclusion, the angiostatic steroid AL-3789 inhibits neovascularization in part by decreasing vascular endothelial cell proliferation and proteinase (urokinase and stromelysin-1) secretion. AL-3789 treatment significantly inhibits re-neovascularization and recurrence rates following malignant pterygium excision in humans.Item Serum exosomal-annexin A2 is associated with African-American triple-negative breast cancer and promotes angiogenesis(BioMed Central Ltd., 2020-01-28) Chaudhary, Pankaj; Gibbs, Lee D.; Maji, Sayantan; Lewis, Cheryl M.; Suzuki, Sumihiro; Vishwanatha, Jamboor K.BACKGROUND: Limited information is available on biomarker(s) for triple-negative breast cancer (TNBC) that can address the higher incidence and aggressiveness of TNBC in African-American (AA) women. Our previous studies have demonstrated annexin A2 (AnxA2) association with exosomes which promotes angiogenesis and metastasis. Therefore, our goal was to examine the expression and function of exosomal-annexin A2 (exo-AnxA2) derived from the serum samples of breast cancer patients. METHODS: The expression of serum exo-AnxA2 and its association with clinicopathological features of the breast cancer patients were determined. The role of serum exo-AnxA2 to promote angiogenesis was determined by an in vivo Matrigel plug assay. RESULTS: Our results show that the expression of serum exo-AnxA2 in breast cancer patients (n = 169; 83.33 +/- 2.040 ng/mL, P < 0.0001) is high compared to non-cancer females (n = 68; 34.21 +/- 2.238 ng/mL). High expression of exo-AnxA2 levels in breast cancer was significantly associated with tumor grade (P < 0.0001), poor overall survival (hazard ratio (HR) 2.802; 95% confidence intervals (CI) = 1.030-7.620; P = 0.0353), and poor disease-free survival (HR 7.934; 95% CI = 1.778-35.398; P = 0.0301). The expression of serum exo-AnxA2 levels was significantly elevated in TNBC (n = 68; 109.1 +/- 2.905 ng/mL; P < 0.0001) in comparison to ER(+) (n = 50; 57.35 +/- 1.545 ng/mL), HER2(+) (n = 59; 78.25 +/- 1.146 ng/mL), and non-cancer females (n = 68; 34.21 +/- 2.238 ng/mL). Exo-AnxA2 showed diagnostic values with a maximum AUC as 1.000 for TNBC, 0.8304 for ER(+), and 0.9958 for HER2(+) compared to non-cancer females. The expression of serum exo-AnxA2 was significantly elevated in AA women with TNBC (n = 29; 118.9 +/- 4.086 ng/mL, P < 0.0001) in comparison to Caucasian-American TNBC (n = 27; 97.60 +/- 3.298 ng/mL) patients. Our in vivo results suggest a role of serum exo-AnxA2 in angiogenesis and its association with aggressiveness of TNBC in AA women. CONCLUSIONS: Our results demonstrated that the expression of serum exo-AnxA2 is high in AA women with TNBC and promotes angiogenesis. These findings suggest that exo-AnxA2 holds promise as a potential prognosticator of TNBC and may lead to an effective therapeutic option.