title: Enhancement of radiation response with bevacizumab.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF) plays a critical role in tumor angiogenesis. Bevacizumab is a humanized monoclonal antibody that neutralizes VEGF. We examined the impact on radiation response by blocking VEGF signaling with bevacizumab.
  
  
  METHODS
  Human umbilical vein endothelial cell (HUVEC) growth inhibition and apoptosis were examined by crystal violet assay and flow cytometry, respectively. In vitro HUVEC tube formation and in vivo Matrigel assays were performed to assess the anti-angiogenic effect. Finally, a series of experiments of growth inhibition on head and neck (H&N) SCC1 and lung H226 tumor xenograft models were conducted to evaluate the impact of bevacizumab on radiation response in concurrent as well as sequential therapy.
  
  
  RESULTS
  The anti-angiogenic effect of bevacizumab appeared to derive not only from inhibition of endothelial cell growth (40%) but also by interfering with endothelial cell function including mobility, cell-to-cell interaction and the ability to form capillaries as reflected by tube formation. In cell culture, bevacizumab induced a 2 ~ 3 fold increase in endothelial cell apoptosis following radiation. In both SCC1 and H226 xenograft models, the concurrent administration of bevacizumab and radiation reduced tumor blood vessel formation and inhibited tumor growth compared to either modality alone. We observed a siginificant tumor reduction in mice receiving the combination of bevacizumab and radiation in comparison to mice treated with bevacizumab or radiation alone. We investigated the impact of bevacizumab and radiation treatment sequence on tumor response. In the SCC1 model, tumor response was strongest with radiation followed by bevacizumab with less sequence impact observed in the H226 model.
  
  
  CONCLUSIONS
  Overall, these data demonstrate enhanced tumor response when bevacizumab is combined with radiation, supporting the emerging clinical investigations that are combining anti-angiogenic therapies with radiation.
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA. txh@medicine.wisc.edu
authors.forename: Tien
authors.initials: T
authors.lastname: Hoang
authors.forename: Shyhmin
authors.initials: S
authors.lastname: Huang
authors.forename: Eric
authors.initials: E
authors.lastname: Armstrong
authors.forename: Jens C
authors.initials: JC
authors.lastname: Eickhoff
authors.forename: Paul M
authors.initials: PM
authors.lastname: Harari
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects*; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D011838:Radiation-Sensitizing Agents; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab