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 induction of key proteins were made in primary explant cultures of human normal urothelium and correlated with growth post- exposure to a range of doses of (60)Co. 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 had a hypersensitive response involving considerable apoptosis in the low dose region, followed by 'induction' of a survival response at higher doses involving 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. The 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 cultures. In the mouse experiments, strain CBA/H (mice known to exhibit genetic 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 consistent with a pattern of radiation- induced delayed death/apoptosis correlating with long-term genomic stability. The mouse experiments demonstrate the importance of genetic factors in determining these responses.