Two pathways for the induction of apoptosis in human lymphocytes.
OBJECTIVE
To assess the roles of cell membranes and DNA as targets in radiation-induced apoptosis.


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.
Cregan
S P
SP
Atomic Energy of Canada Ltd, Chalk River Laboratories, Ontario.
Smith
B P
BP
Brown
D L
DL
Mitchel
R E
RE
D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D004247:DNA / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects / Q000528:radiation effects; D008214:Lymphocytes / Q000502:physiology*; D013997:Time Factors; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
D016166:Free Radical Scavengers; D004247:DNA; D020122:tert-Butylhydroperoxide; D003513:Cycloheximide