mda7+Avastin preclinical..this is an oral
Abstract Number: 251
Presentation Title: Translational and functional inhibition of VEGF by Ad-mda7 and bevacizumab results in enhanced anti-tumor activity against lung cancer.
Presentation Start/End Time: Sunday, Apr 02, 2006, 8:00 AM -12:00 PM
Location: Exhibit Hall, Washington Convention Center
Poster Section: 24
Poster Board Number: 27
Author Block: Satoshi Inoue, Amanda Hartman, Cynthia D. Branch, Corazan Bucana, Sunil Chada, Rajagopal Ramesh. The University of Texas, Houston, TX, Introgen Therapeutics, Houston, TX
A humanized monoclonal antibody against VEGF, Bevacizumab (Avastin; Genentech, CA) has demonstrated reduced tumor angiogenesis and growth. However, Bevacizumab treatment does not induce complete tumor regression. Therefore, additional treatment strategies need to be incorporated in combination with Bevacizumab to achieve tumor regression. We have shown melanoma differentiation associated gene-7 (MDA-7) protein exerts a potent antiangiogenic activity in vitro and in vivo. In the present study we evaluated the therapeutic effects of Bevacizumab in combination with Ad-mda7 using lung cancer as a model.
Treatment of lung tumor cells (H1299, A549) with non-cytotoxic dose of Ad-mda7 (1000 vp/cell) or Bevacizumab showed inhibition of VEGF with no effect on tumor cell growth. However, treatment of tumor cells with Ad-mda7 plus Bevacizumab resulted in enhanced inhibition of VEGF as determined by ELISA. Furthermore, a significant (P < 0.05) inhibition of human umbilical vein endothelial cells (HUVEC) cell proliferation was observed when tissue culture supernatant from Ad-mda7 plus Bevacizumab-treated tumor cells was added to HUVEC compared to HUVEC proliferation treated with culture supernatant from Ad-mda7- or Bevacizumab-treated tumor cells. These results showed that both Ad-mda7 and Bevacizumab effectively inhibit VEGF albeit via different mechanisms. Ad-mda7 inhibited VEGF at a transcriptional level regulated by the Src pathway; Bevacizumab inhibited VEGF by preventing its binding to its receptors (VEGFR) expressed in HUVEC. We next conducted animal experiments using subcutaneous H1299 lung tumor xenograft model to determine whether Ad-mda7 combined with Bevacizumab enhances tumor growth suppression. Tumor-bearing mice were treated with PBS, Ad-luc, Ad-mda7, Bevacizumab, Bevacizumab plus Ad-luc or Bevacizumab plus Ad-mda7. Ad-luc or Ad-mda7 was administered intratumorally (5 X 109 vp/dose) and Bevacizumab intraperitoneally (5 mg/Kg). Treatment was given twice a week for a total of four weeks and tumor growth measured. A significant tumor growth inhibition was observed in mice that were treated with Ad-mda7 plus Bevacizumab compared to tumor growth inhibition in mice that were treated with Ad-mda7, Bevacizumab or Ad-luc plus Bevacizumab. Furthermore, in approximately 70% of the Ad-mda7 plus Bevacizumab-treated mice the tumors completely regressed. Tumor regression was not observed in other treatment groups. Molecular analysis of tumors showed Ad-mda7 plus Bevacizumab treatment enhanced tumor cell apoptosis, effectively inhibited VEGF and reduced angiogenesis as determined by western blotting and immunohistochemsitry. In conclusion, Ad-mda7 plus Bevacizmab treatment significantly increases the antitumor activity against human lung cancer cells and can be potent treatment strategy for advanced lung cancer.
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