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

Miknyoczki, Sheila; Chang, Hong; Grobelny, Jennifer V.; Pritchard, Sonya; Worrell, Candace S.; McGann, Natalie; Ator, Mark A.; Husten, Jean; Deibold, James; Hudkins, Robert L.; Zulli, Allison L.; Parchment, Ralph E.; Ruggeri, Bruce

doi:10.1158/1535-7163.mct-07-0062

Cited by 82 publications

(60 citation statements)

References 36 publications

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“…It is at this reduced level that we see protective effects. This study has great therapeutic importance and human relevance as recent findings indicate BER inhibitors in combination with the DNA methylating agent temozolomide function as an effective chemopreventive agent in colon cancer (23). In addition, these findings have relevant translational implications, because variants/ polymorphisms in BER have been associated with increased cancer risk, and an alteration in micronutrients could potentially provide protection under the right conditions.…”

Section: Discussionmentioning

confidence: 85%

Folate Deficiency Provides Protection against Colon Carcinogenesis in DNA Polymerase β Haploinsufficient Mice

Ventrella-Lucente¹,

Unnikrishnan²,

Pilling³

et al. 2010

Journal of Biological Chemistry

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Aging and DNA polymerase ␤ deficiency (␤-pol ؉/؊ ) interact to accelerate the development of malignant lymphomas and adenocarcinoma and increase tumor bearing load in mice. Folate deficiency (FD) has been shown to induce DNA damage repaired via the base excision repair (BER) pathway. We anticipated that FD and BER deficiency would interact to accelerate aberrant crypt foci (ACF) formation and tumor development in ␤-pol haploinsufficient animals. FD resulted in a significant increase in ACF formation in wild type (WT) animals exposed to 1,2-dimethylhydrazine, a known colon and liver carcinogen; however, FD reduced development of ACF in ␤-pol haploinsufficient mice. Prolonged feeding of the FD diet resulted in advanced ACF formation and liver tumors in wild type mice. However, FD attenuated onset and progression of ACF and prevented liver tumorigenesis in ␤-pol haploinsufficient mice, i.e. FD provided protection against tumorigenesis in a BER-deficient environment in all tissues where 1,2-dimethylhydrazine exerts its damage. Here we show a distinct down-regulation in DNA repair pathways, e.g. BER, nucleotide excision repair, and mismatch repair, and decline in cell proliferation, as well as an up-regulation in poly(ADP-ribose) polymerase, proapoptotic genes, and apoptosis in colons of FD ␤-pol haploinsufficient mice.Folate deficiency is an important public health concern because of the role folate plays in the development of many different health problems, including neural tube defects, cardiovascular disease, Alzheimer disease, and cancer, specifically colon cancer. It has been proposed that the carcinogenic properties of folate deficiency may be related to a decrease in DNA methylation, perhaps as a function of reduced S-adenosylmethionine levels, an increase in the uracil content of DNA, or an increase in oxidative stress by alterations in thiol switches. Folate deficiency has also been shown to increase (in cells, animal models, and humans) levels of single strand breaks (1-5), micronucleus formation (6, 7), chromosomal aberration (8, 9), and mutation frequency (10, 11), all potentially downstream effects of high levels of uracil in DNA and oxidative damage to DNA.The DNA repair pathway for removal of uracil and oxidized bases is the base excision repair (BER) 2 pathway. The BER pathway is believed to repair small, non-helix-distorting lesions in the DNA. It has been estimated to be responsible for the repair of as many as one million nucleotides per cell per day (12), stressing its importance in the maintenance of genomic stability. It has been suggested that BER has evolved in response to in vivo exposure of DNA to reactive oxygen species and endogenous alkylation, and that this pathway suppresses spontaneous mutagenesis (13). In the initial elucidation of the BER pathway the following steps were involved: (i) removal of the damaged base by a DNA glycosylase; (ii) incision of the phosphate backbone by an endonuclease; (iii) synthesis of new DNA by a polymerase; (iv) excision of the deoxyribose phosphate moie...

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Section: Discussionmentioning

confidence: 85%

Folate Deficiency Provides Protection against Colon Carcinogenesis in DNA Polymerase β Haploinsufficient Mice

Ventrella-Lucente¹,

Unnikrishnan²,

Pilling³

et al. 2010

Journal of Biological Chemistry

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“…The only reported phase II study of these second generation PARP inhibitors using the Pfizer PARP inhibitor (AG-014699), however, showed doselimiting myelosuppression when combined with temozolomide (46). Some more recently developed PARP 1/2 inhibitors are reported to have reduced bone marrow toxicity while maintaining enhanced cytotoxicity to temozolomide and irinotecan in several different in vitro and in vivo human cancer cell models (47).…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Coordination of DNA Mismatch Repair and Base Excision Repair Processing of Chemotherapy and Radiation Damage for Targeting Resistant Cancers

Kinsella

2009

Clinical Cancer Research

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DNA damage processing by mismatch repair (MMR) and/or base excision repair (BER) can determine the therapeutic index following treatment of human cancers using radiation therapy and several classes of chemotherapy drugs. Over the last decade, basic and translational cancer research in DNA repair has led to an increased understanding of how these two DNA repair pathways can modify cytotoxicity to chemotherapy and/or ionizing radiation treatments in both normal and malignant tissues. This Molecular Pathways article provides an overview of the current understanding of mechanisms involved in MMR and BER damage processing, including insights into possible coordination of these two DNA repair pathways after chemotherapy and/or ionizing radiation damage. It also introduces principles of systems biology that have been applied to better understand the complexities and coordination of MMR and BER in processing these DNA damages. Finally, it highlights novel therapeutic approaches to target resistant (or DNA damage tolerant) human cancers using chemical and molecular modifiers of chemotherapy and/or ionizing radiation including poly (ADP-ribose) polymerase inhibitors, methoxyamine and iododeoxyuridine (and the prodrug, 5-iodo-2-pyrimidinone-2'-deoxyribose).

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“…Several preclinical studies suggest that PARP inhibitors enhance the efficacy of TMZ in both sensitive and resistant tumors (4,5). Moreover, their capacity to sensitize glioblastoma cells to TMZ treatment and reverse TMZ resistance has been reported (6)(7)(8). ABT-888 (veliparib) is a potent PARP-1/2 inhibitor and the clinically most advanced candidate for glioblastoma, with several ongoing clinical trials.…”

Section: Introductionmentioning

confidence: 99%

ABCB1, ABCG2, and PTEN Determine the Response of Glioblastoma to Temozolomide and ABT-888 Therapy

Lin

Gooijer

Roig

et al. 2014

Clinical Cancer Research

113

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Purpose: Little is known about the optimal clinical use of for treatment of glioblastoma. ABT-888 is a PARP inhibitor undergoing extensive clinical evaluation in glioblastoma, because it may synergize with the standard-of-care temozolomide (TMZ). We have elucidated important factors controlling ABT-888 efficacy in glioblastoma.Experimental Design: We used genetically engineered spontaneous glioblastoma mouse models and allograft models that were orthotopically transplanted into wild-type (WT) and Abcb1/Abcg2-deficient (KO) recipients.Results: ABT-888/TMZ is not efficacious against p53;p16;LucR allografts in wild-type recipients, indicating inherent resistance. Abcb1/Abcg2 mediated efflux of ABT-888 at the blood-brain barrier (BBB) causes a 5-fold reduction of ABT-888 brain penetration (P < 0.0001) that was fully reversible by elacridar. Efficacy studies in WT and KO recipients and/or concomitant elacridar demonstrate that Abcb1/ Abcg2 at the BBB and in tumor cells impair TMZ/ABT-888 combination treatment efficacy. Elacridar also markedly improved TMZ/ABT-888 combination treatment in the spontaneous p53;p16 Ink4a /p19 Arf ;K-Ras v12 ; LucR glioblastoma model. Importantly, ABT-888 does enhance TMZ efficacy in Pten deficient glioblastoma allografts and spontaneous tumors, even in Abcb1/Abcg2 proficient wild-type mice. Loss of PTEN occurs frequently in glioblastoma (36%) and in silico analysis on patient with glioblastoma samples revealed that it is associated with a worse overall survival (310 days vs. 620 days, n ¼ 117).Conclusions: The potential of ABT-888 in glioblastoma can best be demonstrated in patients with PTEN null tumors. Therefore, clinical trials with ABT-888 should evaluate these patients as a separate group. Importantly, inhibition of ABCB1 and ABCG2 (by elacridar) may improve the efficacy of TMZ/ABT-888 therapy in all glioblastoma patients. Clin Cancer Res; 20(10); 2703-13. Ó2014 AACR.

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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

Cited by 82 publications

References 36 publications

Folate Deficiency Provides Protection against Colon Carcinogenesis in DNA Polymerase β Haploinsufficient Mice

Folate Deficiency Provides Protection against Colon Carcinogenesis in DNA Polymerase β Haploinsufficient Mice

Coordination of DNA Mismatch Repair and Base Excision Repair Processing of Chemotherapy and Radiation Damage for Targeting Resistant Cancers

ABCB1, ABCG2, and PTEN Determine the Response of Glioblastoma to Temozolomide and ABT-888 Therapy

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