DNA damage, poly (ADP-ribosyl)ation and apoptotic cell death as a potential common pathway of cytotoxic drug action.
Although various anti-cancer drugs have widely differing primary modes of action, the mechanisms of cell death appear similar but are not well understood. To investigate this problem we exposed cultured human leukemic T-lymphoblasts to 1-hr pulse doses of an alkylating agent (mafosfamide) and a topoisomerase II inhibitor (etoposide) that cause delayed cell death. The effects of these drugs on nucleotide content, poly (ADP-ribosyl)ation and DNA strand breakage were assessed. Both drugs caused DNA strand breakage, and although the pattern differed, this seemed to be the major mechanism by which cells were killed. The degree and time course of the NAD and ATP depletion that mafosfamide and etoposide caused were similar. Both drugs caused a nadir in cellular nucleotide levels 2 hr after exposure but between 2 and 6 hr there was a partial recovery. This correlates with the time course of the DNA damage they caused and appeared to result from poly (ADP-ribosyl)ation. Both drugs were shown to cause apoptotic cell death associated with endonucleolytic DNA fragmentation. We suggest that DNA damage, as a primary or secondary effect, associated with poly (ADP-ribosyl)ation and apoptotic cell death may be a common pathway of cytotoxic drug action.
Marks
D I
DI
Department of Haematology and Medical Oncology, Royal Melbourne Hospital, Parkville, Victoria, Australia.
Fox
R M
RM
D000255:Adenosine Triphosphate / Q000032:analysis; D001711:Biotransformation; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D009243:NAD / Q000032:analysis; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects
D009243:NAD; C048341:mafosfamide; D005047:Etoposide; D000255:Adenosine Triphosphate; D003520:Cyclophosphamide; D011065:Poly(ADP-ribose) Polymerases