Chemopotentiation of temozolomide, irinotecan, and cisplatin activity by CEP-6800, a poly(ADP-ribose) polymerase inhibitor
| Autor: | Sheila J, Miknyoczki, Susan, Jones-Bolin, Sonya, Pritchard, Kathryn, Hunter, Hugh, Zhao, Weihua, Wan, Mark, Ator, Ronald, Bihovsky, Robert, Hudkins, Sankar, Chatterjee, Andres, Klein-Szanto, Craig, Dionne, Bruce, Ruggeri |
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| Rok vydání: | 2003 |
| Předmět: |
Lung Neoplasms
Time Factors Mice Nude Antineoplastic Agents Enzyme-Linked Immunosorbent Assay Poly(ADP-ribose) Polymerase Inhibitors Irinotecan Heterocyclic Compounds 4 or More Rings Cell Line Mice Cell Line Tumor Temozolomide Animals Humans Enzyme Inhibitors Antineoplastic Agents Alkylating Dose-Response Relationship Drug Cell Cycle Drug Synergism Flow Cytometry Antineoplastic Agents Phytogenic Dacarbazine Kinetics Models Chemical Camptothecin Female Cisplatin Cell Division Neoplasm Transplantation DNA Damage |
| Zdroj: | Molecular cancer therapeutics. 2(4) |
| ISSN: | 1535-7163 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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