Predicting enhanced cell killing through PARP inhibition

摘要

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 singlenucleotide base excision repair (BER) pathway. An intermediate of this process has a single-nucleotide gap in double-stranded DNA containing the 50-deoxyribose phosphate (dRP) group at one margin. This 50-dRP group is removed by the lyase activity of pol b prior to gap filling; then completion of repair is by DNA ligation. PARP-1 binds to and is activated by the 50-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.