Evaluation of Novel Agents Which Target Neovasculature of Breast Tumors
Final rept. 1 Apr 2002-31 Mar 2006
M D ANDERSON CANCER CENTER HOUSTON TX
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The unique fusion toxin VEGF121rGel specifically kills both log-phase and confluent vascular endothelial cells expressing the KOR receptor for VEGF PNAS 997866 2002. We have discovered 22 unique genes consistently up-regulated in endothelial cells treated with VEGF121rGel confirmed by Western and RT-PCR. VEGF121rGel i.v. treatment against an orthotopic breast model resulted in significant delay of tumor growth by 50. In addition tumors completely regressed in 36 50 of treated mice. In the metastatic breast model treatment with VEGF121rGel reduced both the number and area of lung foci by 58 and 50 respectively. Immunohistochemical analysis demonstrated that VEGF121rGel targeted 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 VEGFrGel treated group had 10 vesselscolony compared to 23 in the control group. Metastatic foci had a 3 fold lower Ki-67 labeling index compared to control tumors. This suggests that VEGF121rGel has impressive anti-tumor activity in breast cancer. In addition VEGF121rGel prevented osteolytic lesions in a prostate cancer bone tumor model and inhibited new bone formation in an ex vivo model with murine calvaria. Thus VEGF121rGel may be useful in inhibiting breast cancer skeletal metastases.
- Medicine and Medical Research