title: Out-of-field cell survival following exposure to intensity-modulated radiation fields.
abstract: OBJECTIVE
  To determine the in-field and out-of-field cell survival of cells irradiated with either primary field or scattered radiation in the presence and absence of intercellular communication.
  
  
  METHODS
  Cell survival was determined by clonogenic assay in human prostate cancer (DU145) and primary fibroblast (AGO1552) cells following exposure to different field configurations delivered using a 6-MV photon beam produced with a Varian linear accelerator.
  
  
  RESULTS
  Nonuniform dose distributions were delivered using a multileaf collimator (MLC) in which half of the cell population was shielded. Clonogenic survival in the shielded region was significantly lower than that predicted from the linear quadratic model. In both cell lines, the out-of-field responses appeared to saturate at 40%-50% survival at a scattered dose of 0.70 Gy in DU-145 cells and 0.24 Gy in AGO1522 cells. There was an approximately eightfold difference in the initial slopes of the out-of-field response compared with the α-component of the uniform field response. In contrast, cells in the exposed part of the field showed increased survival. These observations were abrogated by direct physical inhibition of cellular communication and by the addition of the inducible nitric oxide synthase inhibitor aminoguanidine known to inhibit intercellular bystander effects. Additional studies showed the proportion of cells irradiated and dose delivered to the shielded and exposed regions of the field to impact on response.
  
  
  CONCLUSIONS
  These data demonstrate out-of-field effects as important determinants of cell survival following exposure to modulated irradiation fields with cellular communication between differentially irradiated cell populations playing an important role. Validation of these observations in additional cell models may facilitate the refinement of existing radiobiological models and the observations considered important determinants of cell survival.
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom. k.butterworth@qub.ac.uk
authors.forename: Karl T
authors.initials: KT
authors.lastname: Butterworth
authors.forename: Conor K
authors.initials: CK
authors.lastname: McGarry
authors.forename: Colman
authors.initials: C
authors.lastname: Trainor
authors.forename: Joe M
authors.initials: JM
authors.lastname: O'Sullivan
authors.forename: Alan R
authors.initials: AR
authors.lastname: Hounsell
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Prise
mesh_terms: D024201:Bystander Effect / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects*; D005347:Fibroblasts / Q000502:physiology / Q000528:radiation effects*; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D016014:Linear Models; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D010315:Particle Accelerators; D017785:Photons / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D011835:Radiation Protection; D050397:Radiotherapy, Intensity-Modulated / Q000379:methods*; D012542:Scattering, Radiation; D014410:Tumor Stem Cell Assay / Q000379:methods
chemical_list: D006146:Guanidines; D052247:Nitric Oxide Synthase Type II; C004479:pimagedine