Identification and characterization of three subtypes of radiation response in normal human urothelial cultures exposed to ionizing radiation

In an attempt to assess genetic variation underlying the variation in human responses to radiation exposure, measurements of apoptosis, necrosis and i nduction of key proteins were made in primary explant cultures of human nor mal urothelium and correlated with growth postexposure to a range of doses of Co-60, These data were validated by similar experiments using CBA/H and C57/BL6 mouse strains, known to exhibit genetically determined differences in response to radiation, The data for human tissues show a wide variation in response with three broad categories being identifiable, The commonest h ad a hypersensitive response involving considerable apoptosis in the low do se region, followed by 'induction' of a survival response at higher doses i nvolving the persistence of abnormal cells. The pattern of gene expression was consistent with suppression of apoptosis, The second category showed no induction of survival and considerable necrosis was seen in the progeny. T he rarest category showed an extremely hypersensitive low dose response and despite induction of a survival response, the sensitivity to higher doses was very severe. Considerable apoptosis and necrosis were seen in these cul tures. In the mouse experiments, strain CBA/H (mice known to exhibit geneti c instability post-irradiation) had lower levels of delayed cell death and apoptosis than C57/BL6 mice (which exhibit significantly less instability). It is concluded that there is a variation in response to radiation between human patient cultures which is detectable in this system and which is con sistent with a pattern of radiation-induced delayed death/apoptosis correla ting with long-term genomic stability. The mouse experiments demonstrate th e importance of genetic factors in determining these responses.