Date of Award

12-1-1996

Degree Type

Restricted Access Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Pharmacology and Neuroscience

Department

Graduate School of Biomedical Sciences

First Advisor

Abbot F. Clark

Second Advisor

Eugene E. Quist

Third Advisor

Thomas Yorio

Abstract

DeFaller, 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 <0.05, ANOVA). Pterygia recurred in 71% of the placebo group compared to 42% of the AL-3789 treated group (p<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.

Comments

DeFaller, 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 W 4 D313m 1996

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