Combination Antiangiogenic and Immunomodulatory Gene Therapy for Breast Cancer
Abstract
Inhibition of angiogenesis has been shown to be an effective strategy in cancer therapy in mice. However its widespread application has been hampered by difficulties in the large-scale production of the antiangiogenic proteins. This limitation may be resolved by in vivo delivery and expression of the antiangiogenic genes. We have constructed a recombinant adenovirus that expresses murine endostatin which resulted in a significant delay of tumor progression of JC breast carcinoma and Lewis lung carcinoma , and more importantly, in complete prevention of lung metastases formation in Lewis lung carcinoma. The inability to control pre-established tumors may be due to insufficient circulating: endostatin levels or to inadequate local endostatin concentrations, both of which have been shown to be important for the anti-tumor effect of endostatin. We now constructed a recombinant adenovirus expressing a murine Ig-endostatin fusion protein resulting in significantly higher circulating endostatin levels in vivo. This construct is now being tested in breast cancer models. Furthermore, we demonstrate that locally deposited endostatin is biological active with respect to inhibition of endothelial cell proliferation and induction of endothelial cell apoptosis. We are now constructing a new tumor-targeted version of endostatin to increase directly local endostatin concentrations in the tumor. In conclusion, the present study clearly demonstrates the potential of vector-mediated antiangiogenic gene therapy in cancer treatment. Changes in vector design, however, resulting in higher transgene expression levels, or tumor targeted delivery of endostatin may even lead to stronger anti-tumor activity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2001
- Accession Number
- ADA392557
Entities
People
- Bernhard Sauter
Organizations
- Icahn School of Medicine at Mount Sinai