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Cephalon, Inc., West Chester, Pennsylvania 19380

¹ To whom requests for reprints should be addressed, at Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380. Phone: (610) 738-6509; Fax: (610) 738-6643

Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear zinc finger DNA-binding protein that is implicated in the repair of DNA damage. Inhibition of PARP-1 through genetic knockouts causes cells to become hypersensitive to various chemotherapeutic agents. We tested the chemopotentiating ability of the PARP-1 inhibitor, CEP-6800, when used in combination with temozolomide (TMZ), irinotecan (camptothecin or SN38), and cisplatin against U251MG glioblastoma, HT29 colon carcinoma, and Calu-6 non-small cell lung carcinoma xenografts and cell lines, respectively. Exposure of tumor cells to TMZ, camptothecin (or SN38), and cisplatin before, or in the presence of, CEP-6800 significantly increased the onset and the magnitude of DNA damage, the duration for cells to effect repair, and the onset, duration, or fraction of cells arrested at the G₂/M boundary. In addition, in vivo biochemical efficacy studies with CEP-6800 showed that it was able to attenuate irinotecan- and TMZ-induced poly(ADP-ribose) accumulation in LoVo and HT29 xenografts, respectively. Treatment of CEP 6800 (30 mg/kg) with TMZ (17 and 34 mg/kg) resulted in 100% complete regression of U251MG tumors by day 28 versus 60% complete regression caused by TMZ alone. CEP-6800 (30 mg/kg) in combination with irinotecan (10 mg/kg) resulted in a 60% inhibition of HT29 tumor growth versus irinotecan alone by day 33. The combination therapy of cisplatin (5 mg/kg) with CEP-6800 (30 mg/kg) caused a 35% reduction in Calu-6 tumor growth versus cisplatin alone by day 28. These data suggest that CEP-6800 could be used as a chemopotentiating agent with a variety of clinically effective chemotherapeutic agents.

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