title: The VEGFR Inhibitor Cediranib Improves the Efficacy of Fractionated Radiotherapy in a Colorectal Cancer Xenograft Model.
abstract: OBJECTIVE
  Radiotherapy (RT) increases local tumor control in locally advanced rectal cancer, but complete histological response is seen in only a minority of cases. Antiangiogenic therapy has been proposed to improve RT efficacy by "normalizing" the tumor microvasculature. Here, we examined whether cediranib, a pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, improves microvascular function and tumor control in combination with RT in a mouse colorectal cancer (CRC) model.
  
  
  METHODS
  CRC xenografts (HT29) were grown subcutaneously in mice. Animals were treated for 5 consecutive days with vehicle, RT (1.8 Gy daily), cediranib (6 mg/kg po), or combined therapy (cediranib 2 h prior to radiation). Tumor volume was measured with calipers. Vascular changes were analyzed by dynamic contrast-enhanced MRI, oxygenation and interstitial fluid pressure probes and histology. To investigate vascular changes more in detail, a second set of mice were fitted with titanium dorsal skinfold window chambers, wherein a HT29 tumor cell suspension was injected. In vivo fluorescence microscopy was performed before and after treatment (same treatment protocol).
  
  
  RESULTS
  In vivo microscopy analyses showed that VEGFR inhibition with cediranib led to a "normalization" of the vessel wall, with decreased microvessel permeability (p < 0.0001) and tortuosity (p < 0.01), and a trend to decreased vessel diameters. This seemed to lead to lower tumor hypoxia rates in the cediranib and combination groups compared to the control and RT groups. This led to an increased tumor control in the combination group compared to controls or monotherapy (p < 0.0001).
  
  
  CONCLUSIONS
  The combination of RT with cediranib enhances tumor control in a CRC xenograft mouse model. Microvascular analyses suggest that cediranib leads to vascular normalization and improved oxygenation.
authors.affiliation: Laboratory of Experimental Surgery, Department of Surgery, Ghent University Hospital, Ghent, Belgium.
authors.forename: Elodie
authors.initials: E
authors.lastname: Melsens
authors.forename: Bert
authors.initials: B
authors.lastname: Verberckmoes
authors.forename: Natacha
authors.initials: N
authors.lastname: Rosseel
authors.forename: Christian
authors.initials: C
authors.lastname: Vanhove
authors.forename: Benedicte
authors.initials: B
authors.lastname: Descamps
authors.forename: Piet
authors.initials: P
authors.lastname: Pattyn
authors.forename: Wim
authors.initials: W
authors.lastname: Ceelen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D019073:HT29 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D055806:Microvessels / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D059016:Tumor Microenvironment / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D007211:Indoles
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D040262:Receptors, Vascular Endothelial Growth Factor; C500926:cediranib; D007211:Indoles
keywords: Angiogenesis; Cediranib; Colorectal cancer; In vivo microscopy; Radiotherapy