Adeno-Associated Virus and Other Potential Vectors for Angiostatin and Endostatin Gene Therapy
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ADENO-ASSOCIATED VIRUS AND OTHER POTENTIAL VECTORS FOR ANGIOSTATIN AND ENDOSTATIN GENE THERAPY Josephine Tuong Nguyen
Department of Diagnostic Radiology Beth Israel Deaconess Medical Center Boston Massachusetts, 02115, U.S.A.
1. INTRODUCTION Recently, evidence has gathered that inhibiting angiogenesis, the process by which
new vessels are generated from existing ones, may have significant advantages over conventional cancer chemotherapy, including nontoxicity, lack of drug resistance, and broadspectrum efficacy against tumors of varied origins. To date, the demonstration of these benefits has relied solely on the administration of purified anti-angiogenic proteins into mouse models. A major hindrance to the clinical applicability of anti-angiogenic proteins lies in the current lack of the means to generate and administer these proteins in large enough quantities to achieve an effective dose over the lengths of time that would be needed to keep tumors suppressed in human subjects. Gene transfer using the appropriate vector may offer a single modality which can both generate and simply administer these proteins over the entire course needed to achieve anti-angiogenic cancer therapy.
2. ANTI-ANGIOGENESIS CANCER THERAPY The inhibition of angiogenesis can control tumor growth, as was first proposed many years ago (Folkman, 1971) and recently demonstrated in many animal studies. This feat requires the subversion of autocrine and paracrine forces which act on tumors to generate angiogenic factors as growth threatens to deplete energy supply. Whether angiogenesis proceeds depends on the relative intratumoral levels of negative and positive regulators (Folkman, 1995). To meet the energy demand of growth, many tumors expand their blood supply by secreting angiogenic factors, among which include vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), plateletderived growth factor (PDGF), insulin-like growth factor-1 (IGF-1). When the relative concentrations of anti- and pro-angiogenesis substances within a tumor change so that Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib Kluwer Academic/Plenum Publishers, New York, 2000.
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the pro-angiogenesis forces prevail, the switch of a tumor’s phenotype from dormant to angiogenic is said to occur, whereby blood vessel formation, tumor growth, and metastasis accelerate (Folkman, 1995). Indeed, angiogenesis correlates with growth and metastatic potential in many types of tumor. By contrast, in dormancy, sufficient ambient concentrations of angiogenesis inhibitors keep tumor growth in check. Among the most potent of these natural angiogenesis inhibitors are angiostatin and endostatin. Antiangiogenesis cancer therapy is achieved by raising the concentration of inhibitors such as these to a high enough level to inhibit angiogenesis and tumor growth. Anti-angiogenesis therapy complements conventional chemotherapy because each attacks a different major cellular compartment in a tumor. The tumor cell and the
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