Inducible Anti-Angiogenic Gene Therapy
Abstract
Clinical studies indicate that high breast tumor levels of plasminogen activator inhibitor 1 (PAI-1) are associated with an increased metastatic risk, decreased survival, tumor angiogenesis; and overall poor prognosis. Since PAI-1 is required for tumor angiogenesis and inhibition of capillary regression, a targeted genetic approach was used to ablate PAI-1 synthesis in endothelial cells employing antisense PAI-1 and dominant-negative Constructs. Such targeting provided proof of principle that reduced PAI-1 synthesis inhibited capillary network formation by immortalized endothelial cells. Transfection of a dominant-negative version of USF-1, a bHLH-LZ protein important in PAI-1 transcription, also attenuated PAI-1 expression in response to angiogenic growth factors by inhibiting formation of functional USF-1 complexes on the PAI-1 promoter. Cell lines were created that were inducible for dominant-negative USF expression upon removal of doxycycline. These results suggest that combinational approaches targeting PAI-1 transcripts and its control network may form the basis for efficient breast cancer anti-angiogenic therapy.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2005
- Accession Number
- ADA437209
Entities
People
- Paul J. Higgins
Organizations
- Albany Medical College