The influence of inhibitors of poly (ADP-ribose) polymerase on X-ray-induced potentially lethal damage repair

Br J Cancer Suppl. 1984;6:27-31.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Benzamides / pharmacology
  • Caffeine / pharmacology
  • Cell Survival / drug effects
  • Cell Survival / radiation effects*
  • Cells, Cultured
  • Cricetinae
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Female
  • NAD+ Nucleosidase / antagonists & inhibitors*
  • Niacinamide / pharmacology
  • Ovary
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Thymidine / pharmacology
  • Time Factors

Substances

  • Benzamides
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Niacinamide
  • Caffeine
  • 3-aminobenzamide
  • NAD+ Nucleosidase
  • Thymidine