PT  - JOURNAL ARTICLE
AU  - Horton, Julie K.
AU  - Wilson, Samuel H.
TI  - Predicting Enhanced Cell Killing through PARP Inhibition
AID  - 10.1158/1541-7786.MCR-12-0512
DP  - 2013 Jan 01
TA  - Molecular Cancer Research
PG  - 13--18
VI  - 11
IP  - 1
4099  - http://mcr.aacrjournals.org/content/11/1/13.short
4100  - http://mcr.aacrjournals.org/content/11/1/13.full
SO  - Mol Cancer Res2013 Jan 01; 11
AB  - 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. Mol Cancer Res; 11(1); 13–18. ©2012 AACR.