Engineered Autologous Stromal Cells for the Delivery of Kringle 5, a Potent Endothelial Cell Specific Inhibitor, for Anti-Angiogenic Breast Cancer Therapy
Abstract
Glioblastoma multiforme is one of the most highly vascularized tumors in humans. Therefore, the development of a potent antiangiogenic gene therapy strategy for brain cancer represents an attractive alternative to existing therapeutic interventions and circumvents the existing pitfalls associated with direct recombinant antiangiogenic protein delivery. Several potent inhibitors of the angiogenic process are known. Amongst them, angiostatin, is a cleavage product of human plasminogen encompassing the first four N-terminal kringle structures. Of particular interest is the fifth kringle (KS) of plasminogen that has been found to enhance the angiostatic potency of angiostatin. We propose that the KS domain may serve as a potent angiostatic agent on its own and that it may act as a usefully therapeutic transgene within a cancer gene therapy strategy. To test this hypothesis, we have developed a KS expressing retroviral vector and have characterized the angiostatic activity of the de novo produced KS peptide in vitro and tested its efficacy in vivo using an orthotopic brain cancer model. Upon intracerebral implantation of lO% U87-GFP (n=S) and U87-KS-GFP (n=S) glioma cells in nude mice, hematoxylin and eosin-stained brain timue sections reveal that U87-K-GFP-implanted mice possess significantly reduced tumor volumes as compared to the mock implanted mice 32 days post-implantation. This evidence suggests that soluble KS peptide holds promise as an attractive anti- angiogenic therapeutic agent within a cancer gene therapy setting.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2004
- Accession Number
- ADA432977
Entities
People
- Sabrina R. Perri