Two pathways for the induction of apoptosis in human lymphocytes

Purpose: To assess the roles of cell membranes and DNA as targets in radiat ion-induced apoptosis. Materials and methods: Peripheral blood lymphocytes from normal human donor s were exposed to different types of apoptosis-inducing agents. Several mea sures of apoptosis were used to compare the kinetics of the processes induc ed, as well as to correlate the processes with DNA damage and membrane oxid ation. Results: Two kinetically distinct processes were observed. DNA-damaging age nts, such as ionizing radiation, bleomycin, cisplatin and the topoisomerase inhibitor m-amsacrine, induced apoptosis by a kinetically slow process ini tiated by DNA damage and dependent on protein synthesis, but which did not correlate with membrane oxidation. Conversely, the agents t-butyl hydropero xide and cumene hydroperoxide induced apoptosis by a kinetically fast proce ss independent of protein synthesis and which did correlate with membrane o xidation. Conclusions: Slowly repaired or unrepairable DNA lesions, such as some of t hose produced by ionizing radiation exposure, trigger apoptosis by a kineti cally slow process. This slow apoptotic pathway is distinct from a Fast pro cess not induced by radiation but which is induced by membrane-oxidizing ag ents.