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: 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
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 2 Issue 4 Pg. 371-82 (Apr 2003) ISSN: 1535-7163 [Print] United States
• PMID: 12700281 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Antineoplastic Agents, Alkylating
• Antineoplastic Agents, Phytogenic
• CEP-6800
• Enzyme Inhibitors
• Heterocyclic Compounds, 4 or More Rings
• Poly(ADP-ribose) Polymerase Inhibitors
• Irinotecan
• Dacarbazine
• Cisplatin
• Camptothecin
• Temozolomide

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Antineoplastic Agents, Alkylating (pharmacology)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Camptothecin (analogs & derivatives, pharmacology)
• Cell Cycle (drug effects)
• Cell Division
• Cell Line
• Cell Line, Tumor
• Cisplatin (pharmacology)
• DNA Damage
• Dacarbazine (analogs & derivatives, pharmacology)
• Dose-Response Relationship, Drug
• Drug Synergism
• Enzyme Inhibitors (pharmacology)
• Enzyme-Linked Immunosorbent Assay
• Female
• Flow Cytometry
• Heterocyclic Compounds, 4 or More Rings (pharmacology)
• Humans
• Irinotecan
• Kinetics
• Lung Neoplasms (drug therapy)
• Mice
• Mice, Nude
• Models, Chemical
• Neoplasm Transplantation
• Poly(ADP-ribose) Polymerase Inhibitors
• Temozolomide
• Time Factors