Two pathways for the induction of apoptosis in human lymphocytes

Purpose: To assess the roles of cell membranes and DNA as targets in radiation-induced apoptosis. Materials and methods: Peripheral blood lymphocytes from normal human donors were exposed to different types of apoptosis-inducing agents. Several measures of apoptosis were used to compare the kinetics of the processes induced, as well as to correlate the processes with DNA damage and membrane oxidation. Results: Two kinetically distinct processes were observed. DNA-damaging agents, such as ionizing radiation, bleomycin, cisplatin and the topoisomerase inhibitor m-amsacrine, induced apoptosis by a kinetically slow process initiated by DNA damage and dependent on protein synthesis, but which did not correlate with membrane oxidation. Conversely, the agents t-butyl hydroperoxide and cumene hydroperoxide induced apoptosis by a kinetically fast process independent of protein synthesis and which did correlate with membrane oxidation. Conclusions: Slowly repaired or unrepairable DNA lesions, such as some of those produced by ionizing radiation exposure, trigger apoptosis by a kinetically slow process. This slow apoptotic pathway is distinct from a Fast process not induced by radiation but which is induced by membrane-oxidizing agents.