Potentiation of anti-cancer agent cytotoxicity by the potent poly(ADP-ribose) polymerase inhibitors NU1025 and NU1064

Br J Cancer. 1998 Nov;78(10):1269-77. doi: 10.1038/bjc.1998.670.


The ability of the potent poly(ADP-ribose) polymerase (PARP) inhibitor, NU1025 (8-hydroxy-2-methyl-quinazolin-4-[3H]one) to potentiate the cytotoxicity of a panel of mechanistically diverse anti-cancer agents was evaluated in L1210 cells. NU1025 enhanced the cytotoxicity of the DNA-methylating agent MTIC, gamma-irradiation and bleomycin 3.5-, 1.4- and 2-fold respectively. The cytotoxicities of the thymidylate synthase inhibitor, nolatrexed, and the cytotoxic nucleoside, gemcitabine, were not increased. Potentiation of MTIC cytotoxicity by a delayed exposure to NU1025 was equally effective as by a simultaneous exposure to NU1025, indicating that the effects of NU1025 were mediated by an inhibition of the cellular recovery. The recovery from potentially lethal gamma-irradiation damage cytotoxicity in plateau-phase cells was also inhibited by NU1025. Investigation of DNA strand breakage and repair in gamma-irradiated cells by alkaline elution demonstrated that NU1025 caused a marked retardation of DNA repair. A structurally different PARP inhibitor, NU1064 (2-methylbenzimidazole-4-carboxamide), also potentiated the cytotoxicity of MTIC, to a similar extent to NU1025. NU1064 potentiated a sublethal concentration of a DNA methylating agent in a concentration-dependent manner. Collectively, these data suggest that the most suitable cytotoxic agents for use in combination with PARP inhibitors are methylating agents, bleomycin and ionizing radiation, but not anti-metabolites.

MeSH terms

  • Amides / pharmacology*
  • Animals
  • Antimetabolites, Antineoplastic / pharmacology
  • Antineoplastic Agents / toxicity*
  • Antineoplastic Agents, Alkylating / pharmacology
  • Benzimidazoles / pharmacology*
  • Bleomycin / pharmacology
  • Cell Death
  • DNA Damage / drug effects*
  • DNA Methylation
  • DNA Repair*
  • Dacarbazine / analogs & derivatives
  • Dacarbazine / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Enzyme Inhibitors / toxicity*
  • Gamma Rays*
  • Leukemia L1210 / pathology
  • Mice
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Quinazolines / pharmacology*
  • Tumor Cells, Cultured


  • Amides
  • Antimetabolites, Antineoplastic
  • Antineoplastic Agents
  • Antineoplastic Agents, Alkylating
  • Benzimidazoles
  • Enzyme Inhibitors
  • NU 1025
  • NU 1064
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Quinazolines
  • Bleomycin
  • Dacarbazine
  • Poly(ADP-ribose) Polymerases
  • 5-(3-methyl-1-triazeno)imidazole-4-carboxamide