Role of Angiogenesis in the Etiology and Prevention of Ovarian Cancer
Final rept. 1 Oct 1999-30 Sep 2004
MINNESOTA UNIV MINNEAPOLIS
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Ovarian cancer growth and its dissemination into the peritoneal cavity are dependent on angiogenesis. Therefore, angiogenesis inhibitors can be used in the prevention and treatment of ovarian cancers. One of the objectives of Project 1 is the development of a genetically reengineered angiostatic protein, endostatin. A mutant endostatin containing a single amino acid substitution at position 125 P125A-endostatin was found to be more active than the native protein. P125A endostatin was further modified to incorporate vascular targeting sequence, RGD, so that the bioavailability can be increased at the tumor vasculature. Modified endostatins were evaluated for antiangiogenic and antitumor activities in model systems. Genetic modifications significantly improved the biological activity of endostatin. Synthetic peptides corresponding to the mutation site were made to characterize the mechanism of enhanced antiangiogenic activity. Since a slow release formulation was more effective than the bolus injections, a gene therapy approach was developed to deliver the mutant endostatin to inhibit ovarian cancer growth.
- Anatomy and Physiology
- Medicine and Medical Research