title: Lymphoid and fibroblastic cell lineages from radiosensitive cancer patients: molecular analysis of DNA double strand break repair by major non-homologous end-joining sub-pathways.
abstract: OBJECTIVE
  Radiation therapy (RT) is used in the treatment of approximately half of all cancer patients. Although there have been great improvements in tumor localization and the technical accuracy of RT delivery, some RT patients still have idiosyncratic hypersensitivity to ionizing radiation (IR) in their normal tissues. Although much effort has been expended in the search for assays that could detect radiosensitive individuals prior to treatment and facilitate tailored therapy; a suitable and clinically practical predictive assay has yet to be realized. Since DNA double-strand breaks (DSB) are a major lesion caused by IR, we hypothesized that radiation hypersensitive individuals might be deficient in the repair of such lesions.
  
  
  METHODS
  To test this hypothesis we quantitatively and functionally characterized DSB repair of the two major non-homologous end-joining (NHEJ) sub-pathways in a pilot study using a plasmid repair reconstitution assay in lymphoblastoid and fibroblast cell lines from radiosensitive cancer patients and controls. Experiments using well-characterized mammalian DSB repair mutants demonstrated the ability of the assay to distinguish NHEJ sub-pathways. The proportion of direct end-joining repair compared with that of microhomology-directed repair was used as a functional end-point of DSB repair competence in the different cell lines.
  
  
  RESULTS
  We found that the overall level of NHEJ sub-pathway repair competency was similar in cell lines from radiosensitive patients and controls.
  
  
  CONCLUSIONS
  These data suggest that this assay in these cell lineages has limited usefulness as a predictive screen for the endogenous DNA DSB repair competency of radiosensitive cancer patients' cells but can usefully characterize major cellular DSB repair phenotypes.
authors.affiliation: Divisions of Radiation Oncology Research, Peter MacCallum Cancer Centre, Australian National University and Canberra Hospital, Yamba Drive, Canberra, ACT 2604, Australia. michael.mckay@act.gov.au
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McKay
authors.forename: Nimali
authors.initials: N
authors.lastname: Withana
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Davey
authors.forename: Danial
authors.initials: D
authors.lastname: Bishop
authors.forename: Michael
authors.initials: M
authors.lastname: Chao
authors.forename: Carl N
authors.initials: CN
authors.lastname: Sprung
mesh_terms: D016022:Case-Control Studies; D019070:Cell Lineage; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects*; D004260:DNA Repair / Q000235:genetics / Q000528:radiation effects*; D005347:Fibroblasts / Q000528:radiation effects*; D006801:Humans; D008221:Lymphoid Tissue / Q000166:cytology / Q000528:radiation effects*; D009369:Neoplasms / Q000235:genetics / Q000473:pathology* / Q000532:radiotherapy; D011836:Radiation Tolerance / Q000235:genetics*; D011839:Radiation, Ionizing