Radiation-induced apoptosis and the adaptive response in human lymphocytes.

Apoptosis is a genetically programmed cell death process which can be activated in cells by a variety of toxic agents including ionizing radiation. It has generally been assumed that radiation-induced DNA damage is responsible for activating the apoptotic process; however, some recent data suggests that oxidative damage of the plasma membrane may be more important. It has previously been reported that pre-exposure of mitogen-stimulated lymphocytes to a low dose of ionizing radiation can reduce the extent of chromosomal damage induced by a subsequent high dose radiation exposure. This phenomena has been termed an "adaptive response" to ionizing radiation and has been proposed to involve the induction of a DNA repair process by the low dose radiation exposure. In the present study we investigated the possibility that pre-exposure of lymphocytes to a low dose of ionizing radiation could modify the extent of apoptosis induced by a subsequent radiation exposure. Our results demonstrate that when lymphocytes from various donors were pre-exposed to a 0.1-Gy (adapting) dose of ionizing radiation the extent of apoptosis induced by a subsequent 2-Gy (challenge) dose of radiation was either significantly enhanced (mean increase of 26.1 +/- 6.8%) or did not change. This sensitization effect was shown to be significantly greater when the adapting exposure was given 6 hours prior to the challenge exposure than when it was given immediately before suggesting that the sensitization effect involves an induced cellular response and does not simply result from an additivity of the lesions produced by the two radiation exposures. Furthermore, we show that this increased sensitivity to radiation-induced apoptosis could be triggered in cells pre-exposed to either a low dose of ionizing radiation or a low concentration of t-butyl hydroperoxide. On the other hand, these pretreatments did not affect the level of apoptosis induced by exposure to a high concentration of the membrane oxidizing agent t-butyl hydroperoxide. Since an increase in the elimination of genetically damaged cells by apoptosis could reduce the risk of cancer from exposure to radiation or other DNA damaging agents, this cellular sensitization for apoptosis may represent a novel adaptive response mechanism. (Abstract shortened by UMI.