Background Poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP)is the member of a family of enzymes that catalyze the addition of ADP-ribose units to proteins that mediate DNA repair pathways. Olaparib (KU-0059436; AZD2281) is a potent oral inhibitor of PARP currently in clinical development, which has selective antitumor activity in cancers, associated with BRCA1 and BRCA2 mutations. Gastric cancer is the most common cancer and the second leading cause of cancer deaths in Korea. New therapies including molecular targeting agents are eagerly awaited, and treatment strategies to overcome chemoresistance are also needed in the treatment of gastric cancer. Materials and Methods We studied the growth inhibitory effects of Olaparib on gastric cancer (GC) cells using clonogenic survival assays and studied the effect of combination with chemotherapeutic agents using MTS assays. Cell cycle analysis and molecular changes induced by olaparib were also performed. Results Olaparib showed marked growth inhibitory activity against the SNU 601 cell line, with IC50 value of 0.015 μM. In addition, 5 out of 11 GC cells (45%) were sensitive to olaparib with IC50s ≤ 2μM. Olaprib induced G2/M cell cycle arrest and apoptosis in sensitive GC cells. We identified synergistic growth inhibitory effects of Olaparib in combination with clinically relevant cytotoxic agents (5-FU, cisplatin, and oxaliplatin). Furthermore, Olaparib-induced apoptosis was associated with PARP cleavage and caspase-3 activation. Conclusion: Olaparib showed growth inhibitory activity against GC cells as a single agent and acted synergistically with cytotoxic agents. These results provide a rationale for the future clinical trials of olaparib combined with cytotoxic drugs in the treatment of gastric cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1775.