Predicting Enhanced Cell Killing through PARP Inhibition

A, scheme of pol β-dependent BER initiated by a monofunctional (left) or bifunctional (right) DNA glycosylase showing formation of 5′- or 3′-blocking groups (circled), respectively, in repair intermediates. The specific interaction between PARP-1 and the 5′-dRP–containing intermediate is indicated. B, inhibitory effect of 4-AN (10 μmol/L) on PAR synthesis in MMS-treated mouse embryonic fibroblasts (MEF; 10 mmol/L for 20 minutes at 4°C) as measured by a commercial ELISA assay (Trevigen). C, sensitivity of wild-type MEFs to a 1-hour exposure to MMS (circles) and the sensitization obtained by cotreatment with 4-AN (10 μmol/L for 24 hours; squares). D, sensitivity of wild-type mouse fibroblasts to a 1-hour exposure to peroxynitrite (circles) and the absence of sensitization provided by cotreatment with 4-AN (10 μmol/L for 24 hours; squares). The plot was drawn to the same scale as in C. Cell sensitivity was obtained by growth inhibition assays as described previously (12). E, comparison of 4-AN–mediated fold-sensitization of wild-type MEFs to MMS (40-fold) and peroxynitrite (negligible).