title: Predicting enhanced cell killing through PARP inhibition.
abstract: PARP inhibitors show promise as combination and single agents in cancer chemotherapy. Here, we evaluate results obtained with mouse fibroblasts and the common laboratory PARP inhibitor 4-amino-1,8-naphthalimide (4-AN) and analyze the potential for enhanced cytotoxicity following the combination of a DNA-damaging agent and a PARP inhibitor. Methylated DNA bases are repaired by the monofunctional glycosylase-initiated single-nucleotide base excision repair (BER) pathway. An intermediate of this process has a single-nucleotide gap in double-stranded DNA containing the 5'-deoxyribose phosphate (dRP) group at one margin. This 5'-dRP group is removed by the lyase activity of pol β prior to gap filling; then completion of repair is by DNA ligation. PARP-1 binds to and is activated by the 5'-dRP group-containing intermediate, and poly(ADP-ribos)ylation is important for efficient repair. 4-AN-mediated sensitization to the methylating chemotherapeutic agent temozolomide is extreme, producing a level of cytotoxicity not seen with either agent alone. In contrast, with agents producing oxidative DNA damage repaired by bifunctional glycosylase-initiated BER, there is only weak sensitization by cotreatment with PARP inhibitor. Other clinically used DNA-damaging agents repaired by different DNA repair pathways also reveal minimal 4-AN-mediated sensitization. This information has potentially important implications for strategic use of PARP inhibitors in chemotherapy.
authors.affiliation: Laboratory of Structural Biology, National Institute of Environmental Health Sciences, 111 T.W. Alexander Dr., MD F1-12, Research Triangle Park, NC 27709, USA.
authors.forename: Julie K
authors.initials: JK
authors.lastname: Horton
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Wilson
mesh_terms: D015057:1-Naphthylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004249:DNA Damage; D004260:DNA Repair; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D053644:Naphthalimides / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D053644:Naphthalimides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D015363:Quinolones; C086538:4-amino-1,8-naphthalimide; D015057:1-Naphthylamine; D011065:Poly(ADP-ribose) Polymerases