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: K J Bowman, A White, B T Golding, R J Griffin, N J Curtin
• Journal: British journal of cancer (Br J Cancer) Vol. 78 Issue 10 Pg. 1269-77 (Nov 1998) ISSN: 0007-0920 [Print] England
• PMID: 9823965 (Publication Type: Journal Article)

Chemical References

• 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

Topics

• 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, 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