The Novel Poly(ADP-Ribose) Polymerase Inhibitor, AG14361, Sensitizes Cells to Topoisomerase I Poisons by Increasing the Persistence of DNA Strand Breaks

Poly(ADP-ribose) polymerase (PARP) inhibitors enhance DNA topoisomerase I (topo I) poison-induced cytotoxicity and antitumor activity in vitro and in vivo , but the mechanism has not been defined. We investigated the role of PARP-1 in the response to topo I poisons using PARP-1 −/− and PARP-1 +/+ mouse embryonic fibroblasts and the potent PARP-1 inhibitor, AG14361 ( K i < 5 nmol/L). PARP-1 −/− mouse embryonic fibroblasts were 3-fold more sensitive to topotecan than PARP-1 +/+ mouse embryonic fibroblasts (GI 50 , 21 and 65 nmol/L, respectively). AG14361 caused a >3-fold sensitization of PARP-1 +/+ cells to topotecan compared with a