title: Variations in the Processing of DNA Double-Strand Breaks Along 60-MeV Therapeutic Proton Beams.
abstract: OBJECTIVE
  To investigate the variations in induction and repair of DNA damage along the proton path, after a previous report on the increasing biological effectiveness along clinically modulated 60-MeV proton beams.
  
  
  METHODS
  Human skin fibroblast (AG01522) cells were irradiated along a monoenergetic and a modulated spread-out Bragg peak (SOBP) proton beam used for treating ocular melanoma at the Douglas Cyclotron, Clatterbridge Centre for Oncology, Wirral, Liverpool, United Kingdom. The DNA damage response was studied using the 53BP1 foci formation assay. The linear energy transfer (LET) dependence was studied by irradiating the cells at depths corresponding to entrance, proximal, middle, and distal positions of SOBP and the entrance and peak position for the pristine beam.
  
  
  RESULTS
  A significant amount of persistent foci was observed at the distal end of the SOBP, suggesting complex residual DNA double-strand break damage induction corresponding to the highest LET values achievable by modulated proton beams. Unlike the directly irradiated, medium-sharing bystander cells did not show any significant increase in residual foci.
  
  
  CONCLUSIONS
  The DNA damage response along the proton beam path was similar to the response of X rays, confirming the low-LET quality of the proton exposure. However, at the distal end of SOBP our data indicate an increased complexity of DNA lesions and slower repair kinetics. A lack of significant induction of 53BP1 foci in the bystander cells suggests a minor role of cell signaling for DNA damage under these conditions.
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Chaudhary
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Thomas I
authors.initials: TI
authors.lastname: Marshall
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom; Centre for Plasma Physics, School of Mathematics and Physics, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Currell
authors.affiliation: Douglas Cyclotron, Clatterbridge Cancer Centre, Bebbington, Wirral, United Kingdom.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Kacperek
authors.affiliation: National Physical Laboratory, Teddington, United Kingdom. Electronic address: giuseppe.schettino@npl.co.uk.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Schettino
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Prise
mesh_terms: D024201:Bystander Effect; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000528:radiation effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D018499:Linear Energy Transfer; D011522:Protons; D011829:Radiation Dosage; D011836:Radiation Tolerance; D012062:Relative Biological Effectiveness; D000071857:Tumor Suppressor p53-Binding Protein 1; D014965:X-Rays
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011522:Protons; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1