title: Potentiation of anti-cancer agent cytotoxicity by the potent poly(ADP-ribose) polymerase inhibitors NU1025 and NU1064.
abstract: 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.
authors.affiliation: Cancer Research Unit, University of Newcastle upon Tyne, Medical School, UK.
authors.forename: K J
authors.initials: KJ
authors.lastname: Bowman
authors.forename: A
authors.initials: A
authors.lastname: White
authors.forename: B T
authors.initials: BT
authors.lastname: Golding
authors.forename: R J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: N J
authors.initials: NJ
authors.lastname: Curtin
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000633:toxicity*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology; D016923:Cell Death; D004249:DNA Damage / Q000187:drug effects*; D019175:DNA Methylation; D004260:DNA Repair; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005720:Gamma Rays; D007939:Leukemia L1210 / Q000473:pathology; D051379:Mice; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000577:Amides; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; C115774:NU 1025; C115773:NU 1064; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines; D001761:Bleomycin; D003606:Dacarbazine; D011065:Poly(ADP-ribose) Polymerases; C010243:5-(3-methyl-1-triazeno)imidazole-4-carboxamide