The influence of inhibitors of poly (ADP-ribose) polymerase on X-ray-induced potentially lethal damage repair.
Inhibition of repair of X-ray-induced potentially lethal damage (PLD) could enhance the curability of radioresistant tumours. We have studied the effect of inhibitors of the enzyme poly (ADP-ribose) polymerase on X-ray PLD repair. Four classes of inhibitors are known: aromatic amides (e.g., 3-aminobenzamide), thymidine, nicotinamides and methyl xanthines (e.g., caffeine). Plateau-phase Chinese hamster ovary (HA-1) cultures were exposed to 10mM concentrations of thymidine, nicotinamide, 3-aminobenzamide (3-ABA) and caffeine prior to irradiation to 12 Gy in air, and then incubated with drug at 37 degrees C for varying times (0-6 h) prior to subculture. Irradiated cells without drug exhibited a 5-6 fold increase in survival over the 6 h period compared to cultures plated immediately after irradiation. Although none of the compounds proved cytotoxic to unirradiated controls over the 6.5 h exposure, all of the compounds except thymidine reduced the capacity of the cells to repair PLD. The order of the inhibitory effect was caffeine greater than 3-ABA greater than nicotinamide, and the inhibition was concentration dependent for nicotinamide and 3-ABA. We also studied the effect of 3-ABA on the radiation response of exponentially growing cells. 5mM 3-ABA for 2 h post-irradiation resulted in a dose-multiplicative sensitization reducing the D0 from 0.88 Gy to 0.69 Gy, indicating an involvement of poly (ADP-ribose) polymerase in the radiosensitivity of exponentially growing as well as plateau-phase cells.
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects*; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005260:Female; D009244:NAD+ Nucleosidase / Q000037:antagonists & inhibitors*; D009536:Niacinamide / Q000494:pharmacology; D010053:Ovary; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013936:Thymidine / Q000494:pharmacology; D013997:Time Factors
D001549:Benzamides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009536:Niacinamide; D002110:Caffeine; C025160:3-aminobenzamide; D009244:NAD+ Nucleosidase; D013936:Thymidine