Influence of non-toxic doses of bevacizumab and ranibizumab on endothelial functions and inhibition of angiogenesis.
OBJECTIVE
Ranibizumab (Lucentis) is an antibody fragment developed against all fragments of vascular endothelial growth factor (VEGF) that was approved by the FDA for treating age-related macular degeneration (AMD). Bevacizumab, a full-length anti-VEGF antibody approved for use in colon cancer, is non-FDA approved at this time but it is widely used for treating AMD. The purpose of this study was to compare the influence of Bevacizumab and Ranibizumab on angiogenesis in an in vitro model.


METHODS
A model consisting of H5V cells derived from murine hearts capillary endothelial cells (ECs) was used. The H5V cells were treated with three concentrations of Bevacizumab and Ranibizumab (0.125 mg/mL, 0.25 mg/mL, and 0.50 mg/mL) for 24 hr before all experiments. The effects of Bevacizumab and Ranibizumab on EC proliferation were compared by 3H-thymidine incorporation essay. Toxic effects and the safety of each drug in clinical concentrations were assessed by annexin 5 staining. The effects of the drugs on ECs functions were assessed by their ability to adhere to fibronectin and by evaluation of the cells' tube formation capacity on matrigel.


RESULTS
Both Bevacizumab and Ranibizumab equally suppressed the adhesive properties of ECs to fibronectin, and similarly inhibited ECs' proliferation capacity in a dose-dependent manner. Both Bevacizumab and Ranibizumab inhibited the ECs' tube formation capacity on matrigel, and were equally safe.


CONCLUSIONS
Ranibizumab and Bevacizumab at low, non-toxic doses similarly inhibit several properties of the angiogenesis process. Inhibition of ECs adhesion to fibronectin and tube formation capacity does not seem to be directly related to the anti-angiogenic effects as indicated by inhibition of VEGF. Further studies for delineating the exact mechanism of action of Ranibizumab and Bevacizumab in angiogenesis are warranted.
Barzelay
Aya
A
Tel Aviv Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Lowenstein
Anat
A
George
Jacob
J
Barak
Adiel
A
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D002448:Cell Adhesion / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003331:Coronary Vessels / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D000069579:Ranibizumab; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
D020533:Angiogenesis Inhibitors; D017304:Annexin A5; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D005353:Fibronectins; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000069579:Ranibizumab