Inhibitors of poly (ADP-ribose) synthesis enhance radiation response by differentially affecting repair of potentially lethal versus sublethal damage.
The effect of nicotinamide and m-aminobenzamide, representative inhibitors of poly(ADP-ribose) synthesis, on the survival of V79 Chinese hamster cells following ionizing radiation was studied in plateau- and log-phase cultures. In plateau-phase, after an acute dose of X-rays, nicotinamide partially inhibited the repair of potentially lethal damage that occurs when the plating of such cells is delayed. The incompleteness of the inhibition was attributed to the slowness of the uptake of nicotinamide by unfed plateau-phase cells. Postirradiation incubation of log-phase cells with either of these inhibitors caused a pronounced enhancement of the radiation response which was reflected mainly by a reduction of the shoulder on the survival curve. However, the ability of such treated cells to repair sublethal damage was hardly affected as demonstrated by the reappearance of the shouldered survival curve during a fractionation interval. NAD levels in irradiated cells were rapidly reduced. This reduction was somewhat slower in a radiation sensitive mutant and was almost completely blocked in the presence of m-aminobenzamide. Another treatment that enhances the radiation response, i.e., incubation in D2O medium, facilitated the rate of NAD depletion in irradiated cells. We conclude that inhibitors of poly(ADP-ribose) synthesis inhibit the repair of potentially lethal damage in plateau-phase as well as in log-phase cells with little if any effect on the repair of sublethal damage. Poly(ADP-ribose) appears, therefore, to have a role in the repair of radiation damage that is potentially lethal in mammalian cells.
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects*; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004307:Dose-Response Relationship, Radiation; D009243:NAD / Q000378:metabolism; D009536:Niacinamide / Q000494:pharmacology*; D009702:Nucleoside Diphosphate Sugars / Q000096:biosynthesis*; D011064:Poly Adenosine Diphosphate Ribose / Q000096:biosynthesis*; D013997:Time Factors
D001549:Benzamides; D009702:Nucleoside Diphosphate Sugars; D009243:NAD; D009536:Niacinamide; D011064:Poly Adenosine Diphosphate Ribose; C025160:3-aminobenzamide