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• W2034965770 abstract "Lymphomas are heterogeneous diseases that require combination therapy for an effective control. A sizable fraction of patients still fail to respond, or suffer progressive disease, after initially responding to treatment. In this setting, hematopoietic stem cell transplantation (HSCT) has been effective particularly in patients who respond to salvage chemotherapy. In an attempt to design more efficacious and safe pre-HSCT conditioning treatment, we expanded our previous observation on the synergistic cytotoxicity of nucleoside-analog-(NA) and DNA alkylating agent (AA) and investigated the interactions between AAs busulfan (Bu) and melphalan (Mel) and NA gemcitabine (Gem) in human lymphoma cell line J45.01. We used ∼IC10 drug concentrations (57 μM Bu, 1 μM Mel and 0.02 μM Gem) which individually did not have significant effects on cell proliferation. However, their combination resulted in 50% inhibition of proliferation. Reduction to almost half (20 μM Bu, 0.7 μM Mel and 0.01 μM Gem) did not result in inhibition of cell proliferation. Addition of 0.6 μM suberoylanilide hydroxamic acid (SAHA) to the latter combination resulted in 65% inhibition of proliferation. The synergistic cytotoxicity of [Bu+Mel+Gem+SAHA] combinations correlates with the activation of the ATM-CHK2 pathway, phosphorylaton of KAP1, epigenetic changes such as methylation and acetylation of histone 3, and activation of apoptosis. We deduce that chromatin alterations mediated by Gem and SAHA may make genomic DNA more accessible to DNA alkylation by Bu and Mel resulting in increased DNA lesions and commitment of cells to apoptosis. The relevance of epigenetic changes in this drug exposure is further shown by the induction of expression of DNA methyltransferases in lymphoma (and leukemia) cells, which have low constitutive levels of DNMT3A and DNMT3B proteins. The addition of 5-aza-2'-deoxycytidine (DAC) to [Bu+Mel+Gem+SAHA] further enhances cell killing. Our results suggest that epigenetic changes mediated by Gem, SAHA and DAC alter chromatin structure and enhance DNA alkylation with Bu and Mel. Such effects are further aggravated by the ability of Gem to inhibit ribonucleotide reductase and DNA repair. In summary, this study expands our previous observation of NA-mediated synergistic toxicity mediated by AAs, and provides a basis to justify future mechanism-based clinical trials using [Bu+Mel+Gem+SAHA] as pre-HSCT conditioning for patients with chemotherapy-refractory lymphoma." @default.
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• W2034965770 date "2012-02-01" @default.
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• W2034965770 title "Epigenetic Changes Enhance the Cytotoxicity of Combined Nucleoside Analog-Dna Alkylating Agents in Lymphoma Cells" @default.
• W2034965770 doi "https://doi.org/10.1016/j.bbmt.2011.12.237" @default.
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