Late radiation morbidity: incidence in a south-east Scottish cohort and investigation into abnormalities in DNA double-strand break repair and damage response
Late normal tissue injury is dose -limiting for radiation therapy of cancer. The molecular
mechanisms of this injury are unknown. However, almost all radiosensitive animals and
cell lines are deficient in some aspect of DNA repair. We have derived EBV- transformed
cell lines from five patients with late radiation injury to determine whether there was any
evidence of reduced activity or expression of the enzymes active in non -homologous
recombination, the major mammalian repair pathway for DNA double -strand breaks
which cause radiation -induced cell death. Two of these cell lines exhibit post- radiation
viability intermediate between normal controls and a cell line from an individual with
ataxia -telangiectasia. DNA -dependent protein kinase activity in vitro was reduced 8-10 - fold in these two cell lines compared to normal controls. The primary tumours from one
of these patients, and a post- radiation cervix biopsy form the second, exhibited no
immunoreactivity with a polyclonal antibody against the catalytic subunit of the DNA - dependent protein kinase (DNA -PKcs). Immunoblotting showed normal levels of Ku70,
Ku80 and XRCC4, and the presence of DNA -PKcs, in both cell lines. This suggests that
the DNA -dependent protein kinase might be an important factor in determining the
predisposition of radiotherapy patients to late radiation injury
