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PARP is a single-strand break sensing protein that catalyses the addition of ADP-ribose to surrounding histones and other nuclear proteins. 7 In the present study, we explored the possibility of exploiting defects in DNA repair in leukemic cells using inhibitors of poly ADP-ribose polymerase (PARP).
5, 6 We have shown previously that myeloid leukemia cells exhibit pronounced error-prone DNA repair. 4Īberrant or impaired repair of double-strand DNA breaks is a common feature of congenital genomic instability syndromes, as well as de novo AML and MDS. 4 Given the different modes of action of these agents, it is not surprising that a number of clinical trials have reported encouraging results with combinations of both DNA methyltransferase and HDAC inhibitors. 3 Similarly, HDAC inhibitors have shown promise in phase I/II studies in both myeloid as well as lymphoid malignancies. Clinical trials of the DNA methyltransferase inhibitors, 5’ aza-cytidine and decitabine, using different dose-schedules have confirmed their anti-leukemic activity in both AML and MDS. Furthermore, relapse is common and only 20–30% of mainly young patients enjoy long-term disease-free survival 1, 2 underscoring the need for novel therapeutic strategies.ĭrugs that interfere with epigenetic control of gene transcription, such as DNA methyltransferase inhibitors and histone deacetylase (HDAC) inhibitors, represent new classes of anti-leukemic agents. Standard chemotherapeutic interventions still fail to induce remission in up to 40% of AML patients over the age of 60 years. Conclusions On the basis of the data presented here, we suggest that PARP inhibitors can potentially exploit defects in double-strand DNA break repair in leukemic cells, paving the way for testing the therapeutic potential of these agents in myelodysplastic syndromes and acute myeloid leukemia.ĭespite major advances in the understanding of the biology and pathogenesis of myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML) identification of the most effective and safe form of treatment continues to present a formidable challenge. Immunofluorescence analysis supported the idea that histone deacetylase inhibitors potentiate cytotoxicity by inhibiting DNA repair processes. In contrast, MS275 potentiated the cytotoxic effect of KU-0058948 and PJ34 in all PARP inhibitor-sensitive leukemic cells. Addition of 5’ aza-2’-deoxycytidine failed to increase the cytotoxicity of PARP inhibitors. Immunofluorescence analysis also revealed that PARP inhibitor sensitivity in these leukemic cells was due to a defect in homologous recombination DNA repair. Results PARP inhibitors, KU-0058948 and PJ34, induced cell cycle arrest and apoptosis of primary myeloid leukemic cells and myeloid leukemic cell lines in vitro.
Design and Methods Leukemic cell lines were exposed to various PARP inhibitors alone and in combination with non-cytotoxic concentrations of DNA methyltransferase inhibitor, 5’ aza-2’-deoxycytidine and/or the histone deacetylase inhibitor, MS275, to test for potentiation of apoptosis with these agents.
Since poly (ADP-ribose) polymerase (PARP) inhibitors have been recently shown to selectively target cells with defects in double-strand DNA repair, the aim of this study was to explore the possibility of exploiting defects in DNA repair in leukemic cells using PARP inhibitors. We focus this review on application of the Combination Index method (as developed by Chou and colleagues) in the evaluation of drug interactions in cell culture assays.Abstract Background Aberrant or impaired repair of double-strand DNA breaks is a common feature of de novo acute myeloid leukemia and myelodysplastic syndromes. Here, we briefly review some of the principles for testing cytotoxic drug interactions. Different mathematical models have been proposed for evaluating drug interactions, which can be classified as synergistic (combinations demonstrating greater than the additive activity expected from each agent alone), additive, or antagonistic (drugs showing less activity in combination than expected from the sum of each agent alone). Because of the desire to speed research and decrease costs, there is increasing interest in moving new drugs into clinical trials in potentially active combinations based on preclinical testing data. The mainstay of clinical antineoplastic chemotherapy is multiagent combinations, most of which were developed empirically.
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