title: Assessment of tumor response to radiation and vascular targeting therapy in mice using quantitative ultrasound spectroscopy.
abstract: OBJECTIVE
  It is now recognized that the tumor vasculature is in part responsible for regulating tumor responses to radiation therapy. However, the extent to which radiation-based vascular damage contributes to tumor cell death remains unknown. In this work, quantitative ultrasound spectroscopy (QUS) methods were used to investigate the acute responses of tumors to radiation-based vascular treatments.
  
  
  METHODS
  Tumor xenografts (MDA-MB-231) were treated with single radiation doses of 2 or 8 Gy alone, or in combination with pharmacological agents that modulate vascular radiosensitivity. The midband fit, the slope, and the 0-MHz intercept QUS parameters were obtained from a linear-regression fit to the averaged power spectrum of frequency-dependent ultrasound backscatter and were used to quantify acute tumor responses following treatment administration. Power spectrums were extracted from raw volumetric radio-frequency ultrasound data obtained before and 24 h following treatment administration. These parameters have previously been correlated to tumor cell death. Staining using in situ end labeling, carbonic anhydrase 9 and cluster of differentiation 31 of tumor sections were used to assess cell death, oxygenation, and vasculature distributions, respectively.
  
  
  RESULTS
  Results indicate a significant midband fit QUS parameter increases of 3.2 ± 0.3 dBr and 5.4 ± 0.5 dBr for tumors treated with 2 and 8 Gy radiation combined with the antiangiogenic agent Sunitinib, respectively. In contrast, tumors treated with radiation alone demonstrated a significant midband fit increase of 4.4 ± 0.3 dBr at 8 Gy only. Preadministration of basic fibroblast growth factor, an endothelial radioprotector, acted to minimize tumor response following single large doses of radiation. Immunohistochemical analysis was in general agreement with QUS findings; an R(2) of 0.9 was observed when quantified cell death was correlated with changes in midband fit.
  
  
  CONCLUSIONS
  Results from QUS analysis presented in this study confirm that acute tumor response is linked to a vascular effect following high doses of radiation therapy. Overall, this is in agreement with previous reports suggesting that acute tumor radiation response is regulated by a vascular-driven response. Data also suggest that Sunitinib may enhance tumor radiosensitivity through a vascular remodeling process, and that QUS may be sensitive to changes in tissue properties associated with vascular remodeling. Finally, the work also demonstrates the ability of QUS methods to monitor response to radiation-based vascular strategies.
authors.affiliation: Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada; Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada; and Departments of Medical Biophysics and Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Ahmed
authors.initials: A
authors.lastname: El Kaffas
authors.affiliation: Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada; Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada; and Departments of Medical Biophysics and Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Ali
authors.initials: A
authors.lastname: Sadeghi-Naini
authors.affiliation: Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada; Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada; and Departments of Medical Biophysics and Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Omar
authors.initials: O
authors.lastname: Falou
authors.affiliation: Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada; Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada; and Departments of Medical Biophysics and Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: William Tyler
authors.initials: WT
authors.lastname: Tran
authors.affiliation: Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada and Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada.
authors.forename: Amr
authors.initials: A
authors.lastname: Hashim
authors.affiliation: Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Fernandes
authors.affiliation: Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada.
authors.forename: Anoja
authors.initials: A
authors.lastname: Giles
authors.affiliation: Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada; Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada; and Departments of Medical Biophysics and Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Czarnota
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010100:Oxygen / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D013057:Spectrum Analysis / Q000379:methods*; D000077210:Sunitinib; D016896:Treatment Outcome; D014463:Ultrasonography / Q000379:methods*
chemical_list: D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D005346:Fibroblast Growth Factors; D010100:Oxygen; D000077210:Sunitinib