Evaluation of Novel Agents Which Target Neovasculature of Breast Tumors
Abstract
The unique fusion toxin VEGF(sub 121)/rGel can specifically kill both log-phase and confluent vascular endothelial cells expressing the KDR receptor for vEGF(PNAs 99:7866,2002). We have discovered 22 unique genes consistently upregulated in endothelial cells treated with VEGF(sub 121)/rGel(confirmed by Western and RT-PCR).VEGF(sub 121)/rGel(i.v.) treatment had a dramatic cytotoxic effect in both orthotopic and metastatic human breast tumor models. Against the orthotopic model, tumor growth was significantly delayed by-50%. In addition, tumors completely regressed in 3/6 (50%) of treated mice. In the metastatic breast model, treatment with VEGF(sub 121)/rGel reduced both the number and area of lung foci by 58% and 50% respectively and we demonstrated VEGF(sub 121)/rGel(by IHC) on lung tumor vasculature but not normal vasculature. In addition, the number of blood vessels per mm2 in metastatic foci was 198 +/- 37 versus 388 +/- 21 for treated and control respectively. Approximately 62% of metastatic colonies from the VEGF/rGel treated group had <10 vessels/colony compared to 23% in the control group. The flk-1 receptor on blood vessel endothelium was intensely expressed on control tumors, but not expressed on treated tumors. Netastatic foci had a 3 fold lower Ki-67 labeling index compared to control tumors. This suggests that VEGF(sub 121)/rGel has impressive antitumor activity in breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2005
- Accession Number
- ADA439833
Entities
People
- Michael Rosenblum
Organizations
- The University of Texas MD Anderson Cancer Center