Inducible Anti-Angiogenic Gene Therapy
Abstract
Clinical studies have indicated that high breast tumor levels of plasminogen activator inhibitor-i (PAl-i; SERPINEl) are associated with an increased risk for metastasis, decreased patient survival, tumor angiogenesis and overall poor prognosis. Since PAl-i is required for both the initiation of tumor-dependent angiogenesis and inhibition of capillary regression, a targeted molecular genetic approach was utilized to ablate PAl-i synthesis in endothelial cells using antisense PAl-i constructs and dominant-negative approaches. Such targeting provided proof-of-principle that reduced PAl-i synthesis and inhibited capillary network formation by immortalized endothelial cells. Adaptation of this inethodology to primary endothelial cells provided a means to "tag" cells with a PAl-1-GEP chimeric protein and confirmed that such engineered cells were capable of being incorporated into a hybrid capillary network in vitro. Importantly, use of a dominant-negative version of USF-1, a HLH-LZ transcription factor important in PAT-i gene control, also attenuated PAl-i expression in response to growth factor stimulation. Collectively, these results suggest that combinational approaches (PAT-i antisense/dominant-negative nSF-i) may form the basis for more efficient breast cancer anti-angiogenic gene therapy.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2004
- Accession Number
- ADA427186
Entities
People
- Paul J. Higgins
Organizations
- Albany Medical College