Post-irradiation sensitization with the ADP-ribosyltransferase inhibitor 3-acetamidobenzamide.
In recent years several lines of evidence have indicated that nuclear ADP-ribosyltransferase (ADPRT) activity is involved in DNA repair, although the requirement of ADPRT activity for cell survival has only been demonstrated in certain cases. We have investigated further the possible role of ADP-ribosylation in the response of cells to ionizing radiation, using 3-acetamidobenzamide (3-AAB), a highly effective inhibitor of ADPRT. With this compound we have demonstrated that marked enhancement of cell killing is observed if ADP-ribosylation is inhibited to a sufficient extent during the post-irradiation repair period, using concentrations of 3-AAB which are not toxic towards unirradiated cells. The critical period within which the inhibitor was effective was the first 90 min post-irradiation, and the half life of the recoverable radiation damage involved was estimated as approximately 20 min. Treatment with 3-AAB slowed the rate at which DNA strand breaks were repaired but did not prevent the ultimate repair of breaks, within the limits of resolution of the alkaline unwinding method used to determine DNA strand breakage. Although the majority of breaks were ultimately repaired, the frequency of radiation-induced sister chromatid exchanges and chromosome aberrations was increased, indicating that more genomic rearrangement had taken place, possibly as a consequence of the persistence of breaks when ADPRT activity was inhibited by 3-AAB during the post-irradiation repair period. It is suggested that the increased frequency of transposition and recombination which these observations reflect is likely to be associated with an increased risk of lethal mutations, some possibly involving chromosomal aberrations.
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects*; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D004247:DNA / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008223:Lymphoma / Q000201:enzymology / Q000235:genetics; D051379:Mice; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors*; D010100:Oxygen; D011065:Poly(ADP-ribose) Polymerases; D012854:Sister Chromatid Exchange / Q000528:radiation effects; D013997:Time Factors
D001549:Benzamides; D000246:Adenosine Diphosphate Ribose; C040561:3-acetamidobenzamide; D004247:DNA; D011065:Poly(ADP-ribose) Polymerases; D009713:Nucleotidyltransferases; D010100:Oxygen