1. The selective poly(ADP-ribose) polymerase-1(2) inhibitor, CEP-8983, increases the sensitivity of chemoresistant tumor cells to temozolomide and irinotecan but does not potentiate myelotoxicity
- Author
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Bruce Ruggeri, Jean Husten, Robert L. Hudkins, Allison L. Zulli, Candace S. Worrell, Mark A. Ator, Ralph E. Parchment, Natalie McGann, Hong Chang, Jennifer Grobelny, Sonya Pritchard, Sheila J. Miknyoczki, and James Deibold
- Subjects
G2 Phase ,Cancer Research ,Poly Adenosine Diphosphate Ribose ,DNA Repair ,medicine.medical_treatment ,Carbazoles ,Antineoplastic Agents ,Phthalimides ,Pharmacology ,Poly(ADP-ribose) Polymerase Inhibitors ,Irinotecan ,Mice ,In vivo ,Glioma ,Neuroblastoma ,Cell Line, Tumor ,medicine ,Temozolomide ,Animals ,Humans ,Enzyme Inhibitors ,Cell Proliferation ,Chemotherapy ,Cell Death ,Chemistry ,Drug Synergism ,Prodrug ,medicine.disease ,Xenograft Model Antitumor Assays ,Rats ,Dacarbazine ,Oncology ,Drug Resistance, Neoplasm ,Topotecan ,Camptothecin ,Comet Assay ,medicine.drug ,DNA Damage - Abstract
The effect of the potent and selective poly(ADP-ribose) (PAR) polymerase-1 [and PAR polymerase-2] inhibitor CEP-8983 on the ability to sensitize chemoresistant glioblastoma (RG2), rhabdomyosarcoma (RH18), neuroblastoma (NB1691), and colon carcinoma (HT29) tumor cells to temozolomide- and camptothecin-induced cytotoxicity, DNA damage, and G2-M arrest and on the potentiation of chemotherapy-induced myelotoxicity was evaluated using in vitro assays. In addition, the effect of the prodrug CEP-9722 in combination with temozolomide and/or irinotecan on PAR accumulation and tumor growth was also determined using glioblastoma and/or colon carcinoma xenografts relative to chemotherapy alone. CEP-8983 sensitized carcinoma cells to the growth-inhibitory effects of temozolomide and/or SN38 increased the fraction of and/or lengthened duration of time tumor cells accumulated in chemotherapy-induced G2-M arrest and sensitized tumor cells to chemotherapy-induced DNA damage and apoptosis. A granulocyte-macrophage colony-forming unit colony formation assay showed that coincubation of CEP-8983 with temozolomide or topotecan did not potentiate chemotherapy-associated myelotoxicity. CEP-9722 (136 mg/kg) administered with temozolomide (68 mg/kg for 5 days) or irinotecan (10 mg/kg for 5 days) inhibited significantly the growth of RG2 tumors (60%) or HT29 tumors (80%) compared with temozolomide or irinotecan monotherapy, respectively. In addition, CEP-9722 showed “stand alone” antitumor efficacy in these preclinical xenografts. In vivo biochemical efficacy studies showed that CEP-9722 attenuated PAR accumulation in glioma xenografts in a dose- and time-related manner. These data indicate that CEP-8983 and its prodrug are effective chemosensitizing agents when administered in combination with select chemotherapeutic agents against chemoresistant tumors. [Mol Cancer Ther 2007;6(8):2290–302]
- Published
- 2007