Chemopotentiation of temozolomide, irinotecan, and cisplatin activity by CEP-6800, a poly(ADP-ribose) polymerase inhibitor (original) (raw)
Related papers
Molecular Cancer Therapeutics, 2007
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 G 2-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 G 2-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.
Clinical Cancer Research, 2008
Purpose-One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA. PARP-1 is a nuclear enzyme involved in base excision repair, one of the 5 major repair pathways. PARP inhibitors are emerging as a new class of agents which can potentiate chemo and radiotherapy. The paper reports safety, efficacy, pharmacokinetic and pharmacodynamic results of Corresponding author details, Dr Ruth Plummer, Northern Institute for Cancer research, Paul O'Gorman Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK, ruth.plummer@ncl.ac.uk, tel +44 191 2464414, fax +44 191 2454301. * These authors contributed equally to the reported research Previous presentation of work This work has been previously published in abstract form only and presented at the following major scientific meetings ASCO 2005 (poster presentation) NCI/EORTC/AACR Molecular Therapeutics Philadelphia meeting 2005 (oral presentation) Plummer, R., M. Middleton, et al. (2005). "First in human phase I trial of the PARP inhibitor AG-014699 with temozolomide (TMZ) in patients (pts) with advanced solid tumors." Journal of Clinical Oncology 23(16): 208S-208S. Plummer, R., M. Middleton, et al. (2005). "Final clinical, pharmacokinetic and pharmacodynamic results of the phase I study of the novel poly(ADP-ribose)polymerase (PARP) inhibitor, AG014699, in combination with temozolomide." Clinical Cancer Research 11(24): 9099S-9099S.
Molecular Cancer Therapeutics, 2005
Temozolomide is a DNA-methylating agent used in the treatment of malignant gliomas. In this study, we have examined if inhibition of poly(ADP-ribose) polymerase (PARP) could increase the cytotoxicity of temozolomide, particularly in cells deficient in DNA mismatch repair. Athymic mice, transplanted with mismatch repair–proficient [D-245 MG] or deficient [D-245 MG (PR)] xenografts, were treated with a combination of temozolomide and the PARP inhibitor, INO-1001. For the tumors deficient in mismatch repair, the most effective dose of INO-1001 was found to be 150 mg/kg, given i.p. thrice at 4-hour intervals with the first injection in combination with 262.5 mg/kg temozolomide (0.75 LD10). This dose of temozolomide by itself induced no partial regressions and a 4-day growth delay. In two separate experiments, the combination therapy increased the growth delay by 21.6 and 9.7 days with partial regressions observed in four of eight and three of nine mice, respectively. The addition of INO...
Glia, 2002
Temozolomide (TZM) is a novel methylating agent currently under investigation for treatment of recurrent high-grade gliomas. Although TZM generates a wide spectrum of methyl adducts, its cytotoxicity has been attributed to mismatch repair (MR)-mediated processing of O6-methylguanine:T mispairs. N3-methyladenine and N7-methylguanine adducts are promptly repaired by the base excision repair system, unless a poly(ADP-ribose) polymerase (PARP) inhibitor is combined to TZM. In this case, the repair process of N-methylpurines cannot be completed and the deriving DNA strand breaks contribute to cytotoxicity. In this study, we investigated the influence on cell growth and cell cycle of treatment with TZM + PARP inhibitor in glioma cells characterized by different susceptibility to TZM. The results indicated that PARP inhibitor increases growth inhibition induced by TZM in either p53–wild-type or p53-mutant glioblastoma cells, as early as 24 h after drug exposure. The enhancing effect exerted by PARP inhibitor was particularly evident in glioma cells characterized by a defective expression of MR, since these cells are tolerant to O6-methylguanine damage and show low sensitivity to TZM. In O6-alkylguanine-DNA alkyltransferase (OGAT)-deficient and MR-proficient tumor cells bearing wild-type p53, the drug combination markedly reduced cell accumulation in the G2/M phase of cell cycle and induction of the G2 checkpoint regulator Chk1 kinase. In short-term cultures of glioma cells derived from surgical specimens, PARP inhibitor enhanced chemosensitivity to TZM and this effect was especially evident in OGAT-proficient tumors. Thus, a pharmacological strategy based on the interruption of N-methylpurine repair might represent a novel strategy to restore or increase glioma sensitivity to TZM. GLIA 40:44–54, 2002. © 2002 Wiley-Liss, Inc.
Medicinal Chemistry, 2006
pharmacological inhibition of DnA repair pathways has been emerging as an effective tool for cancer treatment. poly(ADp-ribose) polymerase (pArp) is involved in DnA repair and transcriptional regulation and is now recognized as a key regulator of cell survival and cell death. In vitro and in vivo data suggest that pArp inhibitors could be used not only as chemo/radiotherapy sensitizers but also as single agents to selectively kill cancer cells in certain types of tumors. In the present study, we investigate the effects of 3-aminobenzamide (3-AB), a potent inhibitor of pArp, on human osteosarcoma cells and whether or not it can sensitize the tumor cells to chemotherapeutic agents. the results indicated that 3-AB suppressed U2os cell growth in a time-and dose-dependent manner, and the suppressive effects of 3-AB were associated with increased cell apoptosis. In addition, 3-AB suppressed cell invasion in vitro and enhanced the suppressive effects of cisplatin in U2os cells. our work suggests that this pArp-1 inhibitor may be developed into an effective agent for the treatment of human osteosarcoma.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2003
The nuclear enzyme poly(ADP-ribose) polymerase (PARP-1) facilitates DNA repair, and is, therefore, an attractive target for anticancer chemo- and radio-potentiation. Novel benzimidazole-4-carboxamides (BZ1-6) and tricyclic lactam indoles (TI1-5) with PARP-1 K(i) values of <10 nM have been identified. Whole cell PARP-1 inhibition, intrinsic cell growth inhibition, and chemopotentiation of the cytotoxic agents temozolomide (TM) and topotecan (TP) were evaluated in LoVo human colon carcinoma cells. The acute toxicity of the inhibitors was investigated in PARP-1 null and wild-type mice. Tissue distribution and in vivo chemopotentiation activity was determined in nude mice bearing LoVo xenografts. At a nontoxic concentration (0.4 micro M) the PARP-1 inhibitors potentiated TM-induced growth inhibition 1.0-5.3-fold and TP-induced inhibition from 1.0-2.1-fold. Concentrations of the PARP-1 inhibitors that alone inhibited cell growth by 50% ranged from 8 to 94 micro M. Maximum potentiation...
Cancer Chemotherapy and Pharmacology, 2001
Purpose: To evaluate the antitumor activity of single versus split exposure of neoplastic cells to temozolomide (TZM) and poly(ADP-ribose) polymerase (PARP) inhibitor. Methods: A leukemic Jurkat cell line and freshly isolated leukemic blasts were used. Jurkat cells are resistant to O 6-methylguanine damage induced by TZM due to high levels of O 6-alkylguanine-DNA alkyltransferase and to a functional defect in the mismatch repair system. Cells were treated with 3-aminobenzamide or with NU1025 to inhibit PARP activity. TZM was added to cell cultures immediately after PARP inhibitors. The concentrations of TZM used were 62.5 µM (corresponding to the peak plasma concentration in patients) or 125 µM. Treatment design: Cells were treated with 125 µM TZM plus PARP inhibitors (single exposure), or twice with 62.5 µM TZM plus PARP inhibitors with an interval of 24 h between treatments (split exposure). Tumor cell growth, clastogenicity and base excision repair gene transcripts or enzymatic activity were evaluated. Results: The split exposure of Jurkat cells to TZM induced more pronounced and persistent growth inhibition and comparable chromosome damage in comparison with the single exposure. In addition, PARP inhibitors potentiated the cytotoxic effects induced by repeated treatment with TZM in fresh leukemic blasts. A marked decrease in X-ray repair cross-complementing 1 transcript and methylpurine glycosylase (MPG) transcript was detected in Jurkat cells subjected to the split exposure. In this case, a significant reduction in the corresponding enzymatic activity was also observed. Conclusions: Cytotoxicity induced by TZM and PARP inhibitors can be improved by a fractionated modality of drug treatment. The reduction in MPG transcript and function would presumably contribute to an increase in cell susceptibility to DNA damage induced by the methylating agent and PARP inhibitors.
2004
Background: Poly(ADP-ribose) polymerase-1 (PARP-1) facilitates the repair of DNA strand breaks. Inhibiting PARP-1 increases the cytotoxicity of DNA-damaging chemotherapy and radiation therapy in vitro. Because classical PARP-1 inhibitors have limited clinical utility, we investigated whether AG14361, a novel potent PARP-1 inhibitor (inhibition constant <5 nM), enhances the effects of chemotherapy and radiation therapy in human cancer cell cultures and xenografts. Methods: The effect of AG14361 on the antitumor activity of the DNA alkylating agent temozolomide, topoisomerase I poisons topotecan or irinotecan, or x-irradiation or ␥-radiation was investigated in human cancer cell lines A549, LoVo, and SW620 by proliferation and survival assays and in xenografts in mice by tumor volume determination. The specificity of AG14361 for PARP-1 was investigated by microarray analysis and by antiproliferation and acute toxicity assays in PARP-1 ؊/؊ and PARP-1 ؉/؉ cells and mice. After intraperitoneal administration, the concentration of AG14361 was determined in mouse plasma and tissues, and its effect on PARP-1 activity was determined in tumor homogenates. All statistical tests were two-sided. Results: AG14361 at 0.4 M did not affect cancer cell gene expression or growth, but it did increase the antiproliferative activity of temozolomide (e.g., in LoVo cells by 5.5-fold, 95% confidence interval [CI] ؍ 4.9-fold to 5.9-fold; P ؍ .004) and topotecan (e.g., in LoVo cells by 1.6-fold, 95% CI ؍ 1.3-fold to 1.9-fold; P ؍ .002) and inhibited recovery from potentially lethal ␥-radiation damage in LoVo cells by 73% (95% CI ؍ 48% to 98%). In vivo, nontoxic doses of AG14361 increased the delay of LoVo xenograft growth induced by irinotecan, x-irradiation, or temozolomide by two-to threefold. The combination of AG14361 and temozolomide caused complete regression of SW620 xenograft tumors. AG14361 was retained in xenografts in which PARP-1 activity was inhibited by more than 75% for at least 4 hours. Conclusion: AG14361 is, to our knowledge, the first high-potency PARP-1 inhibitor with the specificity and in vivo activity to enhance chemotherapy and radiation therapy of human cancer. [J Natl Cancer Inst 2004;96:56 -67]
Clinical Cancer Research, 2007
To evaluate the preclinical pharmacokinetics and antitumor efficacy of a novel orally bioavailable poly(ADP-ribose) polymerase (PARP) inhibitor, ABT-888. Experimental Design: In vitro potency was determined in a PARP-1 and PARP-2 enzyme assay. In vivo efficacy was evaluated in syngeneic and xenograft models in combination with temozolomide, platinums, cyclophosphamide, and ionizing radiation. Results: ABT-888 is a potent inhibitor of both PARP-1 and PARP-2 with K i s of 5.2 and 2.9 nmol/L, respectively.The compound has good oral bioavailability and crosses the blood-brain barrier. ABT-888 strongly potentiated temozolomide in the B16F10 s.c. murine melanoma model. PARP inhibition dramatically increased the efficacy of temozolomide at ABT-888 doses as low as 3.1 mg/kg/d and a maximal efficacy achieved at 25 mg/kg/d. In the 9L orthotopic rat glioma model, temozolomide alone exhibited minimal efficacy, whereas ABT-888, when combined with temozolomide, significantly slowed tumor progression. In the MX-1breast xenograft model (BRCA1 deletion and BRCA2 mutation), ABT-888 potentiated cisplatin, carboplatin, and cyclophosphamide, causing regression of established tumors, whereas with comparable doses of cytotoxic agents alone, only modest tumor inhibition was exhibited. Finally, ABT-888 potentiated radiation (2 Gy/d  10) in an HCT-116 colon carcinoma model. In each model, ABT-888 did not display single-agent activity. Conclusions: ABT-888 is a potent inhibitor of PARP, has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. This broad spectrum of chemopotentiation and radiopotentiation makes this compound an attractive candidate for clinical evaluation.
Clinical Cancer Research an Official Journal of the American Association For Cancer Research, 2000
have been developed that potentiate the cytotoxicity of ionizing radiation and anticancer drugs. The biological effects of two novel PARP inhibitors, NU1025 (8-hydroxy-2-methylquinazolin-4-[3H]one, K i ؍ 48 nM) and NU1085 [2-(4hydroxyphenyl)benzamidazole-4-carboxamide, K i ؍ 6 nM], in combination with temozolomide (TM) or topotecan (TP) have been studied in 12 human tumor cell lines (lung, colon, ovary, and breast cancer). Cells were treated with increasing concentrations of TM or TP ؎ NU1025 (50, 200 M) or NU1085 (10 M) for 72 h. The potentiation of growth inhibition by NU1025 and NU1085 varied between the cell lines from 1.5-to 4-fold for TM and 1-to 5-fold for TP and was unaffected by p53 status. Clonogenic assays undertaken in two of the cell lines confirmed that the potentiation of growth inhibition reflected the potentiation of cytotoxicity. NU1025 (50 M) was about as effective as 10 M NU1085 at potentiating growth inhibition and cytotoxicity, consistent with the relative potencies of the two molecules as PARP inhibitors. Potentiation of cytotoxicity was obtained at concentrations of NU1025 and NU1085 that were not toxic per se; however, NU1085 alone was 3-fold more cytotoxic (LC 50 values ranged from 83 to 94 M) than NU1025 alone (LC 50 > 900 M). These data demonstrate that PARP inhibitors are effective resistance-modifying agents in human tumor cell lines and have provided a comprehensive assess-ment protocol for the selection of optimum combinations of anticancer drugs, PARP inhibitors, and cell lines for in vivo studies. The abbreviations used are: PARP, poly(ADP-ribose) polymerase; LC 50 , concentration of drug causing 50% cytotoxicity; PF 50 , potentiation factor at 50% growth inhibition; TM, temozolomide; TP, topotecan; NU1025, 8-hydroxy-2-methylquinazolin-4-[3H]one; NU1085, 2-(4hydroxyphenyl)benzamidazole-4-carboxamide; BER, base excision repair.