title: Dose-dependent response of tumor vasculature to radiation therapy in combination with Sunitinib depicted by three-dimensional high-frequency power Doppler ultrasound.
abstract: OBJECTIVE
  Large doses of radiation (8-20 Gy) preferentially target tumor vasculature. This vascular response is suggested to regulate tumor response to radiotherapy. Here, we investigate the relative contributions of direct cell killing by radiation versus tumor cell death due to radiation effects on the vasculature. We also examine Sunitinib's mechanism of action as a tumor radiosensitizer.
  
  
  METHODS
  MDA-MB-231 xenografts were treated with radiation doses of 2-16 Gy alone, or in combination with bFGF (endothelial radio-protector) or Sunitinib as pharmacological modulators of the vasculature. Sunitinib was orally administered for 2 weeks at 30 mg/kg before radiotherapy; bFGF was intravenously injected 1 h prior to irradiation. Three-dimensional high-frequency power Doppler ultrasound was used to assess relative changes in tumor vasculature. Immunohistochemistry, clonogenic and tumor growth assays were used to quantify tumor response.
  
  
  RESULTS
  Significant reductions in power Doppler signal of up to 50 % were observed for 8 and 16 Gy treatments, along with a dose-dependent increase in cell death. No significant change in power Doppler signal and minimal tumor cell death were noted for tumors treated with radiation and bFGF. Treatments where Sunitinib was combined with radiation demonstrated a significant increase in flow signal at doses equal or greater than 8 Gy. This was accompanied with a significant increase in cell death when compared to radiation or Sunitinib alone.
  
  
  CONCLUSIONS
  We confirm that tumor response to high doses of radiation is regulated by its vasculature. We also posit that the response observed when radiation is combined with Sunitinib is linked to a vascular "normalization" effect.
authors: Department of Radiation Oncology, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON, M4N 3M5, Canada.
authors: Ahmed
authors: A
authors: El Kaffas
authors: Anoja
authors: A
authors: Giles
authors: Gregory J
authors: GJ
authors: Czarnota
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D007211:Indoles / Q000627:therapeutic use*; D051379:Mice; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000532:radiotherapy; D011758:Pyrroles / Q000627:therapeutic use*; D000077210:Sunitinib; D018608:Ultrasonography, Doppler
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib