title: Chemopotentiation of temozolomide, irinotecan, and cisplatin activity by CEP-6800, a poly(ADP-ribose) polymerase inhibitor.
abstract: 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 G(2)/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.
authors.affiliation: Cephalon, Inc., West Chester, Pennsylvania 19380, USA.
authors.forename: Sheila J
authors.initials: SJ
authors.lastname: Miknyoczki
authors.forename: Susan
authors.initials: S
authors.lastname: Jones-Bolin
authors.forename: Sonya
authors.initials: S
authors.lastname: Pritchard
authors.forename: Kathryn
authors.initials: K
authors.lastname: Hunter
authors.forename: Hugh
authors.initials: H
authors.lastname: Zhao
authors.forename: Weihua
authors.initials: W
authors.lastname: Wan
authors.forename: Mark
authors.initials: M
authors.lastname: Ator
authors.forename: Ronald
authors.initials: R
authors.lastname: Bihovsky
authors.forename: Robert
authors.initials: R
authors.lastname: Hudkins
authors.forename: Sankar
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Andres
authors.initials: A
authors.lastname: Klein-Szanto
authors.forename: Craig
authors.initials: C
authors.lastname: Dionne
authors.forename: Bruce
authors.initials: B
authors.lastname: Ruggeri
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D000077146:Irinotecan; D007700:Kinetics; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000077204:Temozolomide; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; C481203:CEP-6800; D004791:Enzyme Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000077146:Irinotecan; D003606:Dacarbazine; D002945:Cisplatin; D002166:Camptothecin; D000077204:Temozolomide