Combined anti-angiogenic therapy against VEGF and integrin alphaVbeta3 in an orthotopic model of ovarian cancer.

Abstract

PURPOSE:

We tested the efficacy of dual targeting of vascular endothelial growth factor (VEGF) and the alpha(V)beta(3) integrin in orthotopic mouse models of ovarian cancer.

RESULTS:

In the SKOV3ip1 model, both single-agent bevacizumab and etaracizumab reduced tumor growth by 52-63% (p < 0.05), while combined therapy reduced growth by 63-74% compared to either agent alone (p < 0.05). Furthermore, bevacizumab/paclitaxel was superior to paclitaxel alone (weight reduction by 53%, p < 0.05), but etaracizumab/paclitaxel was not. Combining all three agents was more effective than either agent with paclitaxel (p < 0.05). Significantly, both bevacizumab and etaracizumab each sensitized the taxane-resistant SKOV3TRip2 cells to paclitaxel, reducing growth by 56-73% (p < 0.05). Both agents decreased proliferation and microvessel density, and increased apoptosis, alone and in combination with paclitaxel. In the HeyA8 model, there was significantly reduced growth with bevacizumab treatment, but not with etaracizumab, and combination therapy was not superior to bevacizumab alone.

EXPERIMENTAL DESIGN:

In vivo therapy experiments were conducted in chemo-sensitive (SKOV3ip1, HeyA8) and -resistant (SKOV3TRip2) ovarian cancer models. VEGF was targeted with bevacizumab and alpha(V)beta(3) with etaracizumab. Mice were treated with each agent alone, together, or in combination with paclitaxel for assessment of tumor growth. Tumor specimens were tested for proliferative index, microvessel density and apoptosis.

CONCLUSIONS:

Bevacizumab and etaracizumab are more effective in combination than individually in some ovarian cancer models, but not all. Both can sensitize taxane-resistant ovarian cancer cells to paclitaxel, though bevacizumab was superior to etaracizumab in this regard. Further study of this dual anti-angiogenic therapy is warranted.

• Authors: Tae Jin Kim, Charles N Landen, Yvonne G Lin, Lingegowda S Mangala, Chunhua Lu, Alpa M Nick, Rebecca L Stone, William M Merritt, Guillermo Armaiz-Pena, Nicholas B Jennings, Robert L Coleman, David A Tice, Anil K Sood
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 8 Issue 23 Pg. 2263-72 (Dec 2009) ISSN: 1555-8576 [Electronic] United States
• PMID: 19829059 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Angiogenesis Inhibitors
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Integrin alphaVbeta3
• RNA, Messenger
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse
• Bevacizumab
• etaracizumab
• Paclitaxel

Topics

• Angiogenesis Inhibitors (therapeutic use)
• Animals
• Antibodies, Monoclonal (administration & dosage)
• Antibodies, Monoclonal, Humanized
• Apoptosis
• Bevacizumab
• Blotting, Western
• Cell Proliferation
• Disease Models, Animal
• Drug Therapy, Combination
• Female
• Fluorescent Antibody Technique
• Immunoenzyme Techniques
• Immunoprecipitation
• Integrin alphaVbeta3 (antagonists & inhibitors, genetics, metabolism)
• Mice
• Mice, Nude
• Ovarian Neoplasms (drug therapy, metabolism)
• Paclitaxel (administration & dosage)
• RNA, Messenger (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, genetics, metabolism)