Purine Analog-Like Properties of Bendamustine Underlie Rapid Activation of DNA Damage Response and Synergistic Effects with Pyrimidine Analogues in Lymphoid Malignancies
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{"title"=>"Purine analog-like properties of bendamustine underlie rapid activation of DNA damage response and synergistic effects with pyrimidine analogues in lymphoid malignancies", "type"=>"journal", "authors"=>[{"first_name"=>"Nobuya", "last_name"=>"Hiraoka", "scopus_author_id"=>"36888801100"}, {"first_name"=>"Jiro", "last_name"=>"Kikuchi", "scopus_author_id"=>"7102953643"}, {"first_name"=>"Takahiro", "last_name"=>"Yamauchi", "scopus_author_id"=>"7401704856"}, {"first_name"=>"Daisuke", "last_name"=>"Koyama", "scopus_author_id"=>"55556672600"}, {"first_name"=>"Taeko", "last_name"=>"Wada", "scopus_author_id"=>"8518056600"}, {"first_name"=>"Mitsuyo", "last_name"=>"Uesawa", "scopus_author_id"=>"22636291200"}, {"first_name"=>"Miyuki", "last_name"=>"Akutsu", "scopus_author_id"=>"7005652635"}, {"first_name"=>"Shigehisa", "last_name"=>"Mori", "scopus_author_id"=>"7403976614"}, {"first_name"=>"Yuichi", "last_name"=>"Nakamura", "scopus_author_id"=>"55487626500"}, {"first_name"=>"Takanori", "last_name"=>"Ueda", "scopus_author_id"=>"35394691300"}, {"first_name"=>"Yasuhiko", "last_name"=>"Kano", "scopus_author_id"=>"7202131720"}, {"first_name"=>"Yusuke", "last_name"=>"Furukawa", "scopus_author_id"=>"57197826878"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "scopus"=>"2-s2.0-84898765095", "sgr"=>"84898765095", "pui"=>"372786248", "pmid"=>"24626203", "doi"=>"10.1371/journal.pone.0090675"}, "id"=>"1feabe45-ac98-3b6e-b343-0313d42d25da", "abstract"=>"Bendamustine has shown considerable clinical activity against indolent lymphoid malignancies as a single agent or in combination with rituximab, but combination with additional anti-cancer drugs may be required for refractory and/or relapsed cases as well as other intractable tumors. In this study, we attempted to determine suitable anti-cancer drugs to be combined with bendamustine for the treatment of mantle cell lymphoma, diffuse large B-cell lymphoma, aggressive lymphomas and multiple myeloma, all of which are relatively resistant to this drug, and investigated the mechanisms underlying synergism. Isobologram analysis revealed that bendamustine had synergistic effects with alkylating agents (4-hydroperoxy-cyclophosphamide, chlorambucil and melphalan) and pyrimidine analogues (cytosine arabinoside, gemcitabine and decitabine) in HBL-2, B104, Namalwa and U266 cell lines, which represent the above entities respectively. In cell cycle analysis, bendamustine induced late S-phase arrest, which was enhanced by 4-hydroperoxy-cyclophosphamide, and potentiated early S-phase arrest by cytosine arabinoside (Ara-C), followed by a robust increase in the size of sub-G1 fractions. Bendamustine was able to elicit DNA damage response and subsequent apoptosis faster and with shorter exposure than other alkylating agents due to rapid intracellular incorporation via equilibrative nucleoside transporters (ENTs). Furthermore, bendamustine increased the expression of ENT1 at both mRNA and protein levels and enhanced the uptake of Ara-C and subsequent increase in Ara-C triphosphate (Ara-CTP) in HBL-2 cells to an extent comparable with the purine analog fludarabine. These purine analog-like properties of bendamustine may underlie favorable combinations with other alkylators and pyrimidine analogues. Our findings may provide a theoretical basis for the development of more effective bendamustine-based combination therapies.", "link"=>"http://www.mendeley.com/research/purine-analoglike-properties-bendamustine-underlie-rapid-activation-dna-damage-response-synergistic", "reader_count"=>15, "reader_count_by_academic_status"=>{"Researcher"=>4, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>5, "Other"=>2, "Student > Bachelor"=>2}, "reader_count_by_user_role"=>{"Researcher"=>4, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>5, "Other"=>2, "Student > Bachelor"=>2}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>3, "Medicine and Dentistry"=>5, "Agricultural and Biological Sciences"=>4, "Business, Management and Accounting"=>1, "Computer Science"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>5}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>4}, "Computer Science"=>{"Computer Science"=>2}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1417927"], "description"=>"<p>(A) HBL-2 cells were cultured with bendamustine alone, cytosine arabinoside alone or their combination for 48 hours. (B) HBL-2 cells were cultured with bendamustine alone, 4-OHCY alone or their combination for 48 hours. Cell cycle profiles were obtained by flow cytometry as described in Materials and Methods. The size of the sub-G1 fraction was calculated by analyzing DNA histograms with the ModFitLT 2.0 program. The data shown are representative of multiple independent experiments with various concentrations of the drugs.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Nucleic acids", "nucleotides", "Cell death", "hematology", "Hematologic cancers and related disorders", "lymphomas", "Myelomas and lymphoproliferative diseases", "oncology", "Cancer treatment", "Chemotherapy and drug treatment", "Cancers and neoplasms", "Non-Hodgkin lymphoma", "Oncology agents", "bendamustine", "4-ohcy", "cytosine"], "article_id"=>960288, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Nobuya Hiraoka", "Jiro Kikuchi", "Takahiro Yamauchi", "Daisuke Koyama", "Taeko Wada", "Mitsuyo Uesawa", "Miyuki Akutsu", "Shigehisa Mori", "Yuichi Nakamura", "Takanori Ueda", "Yasuhiko Kano", "Yusuke Furukawa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0090675.g003", "stats"=>{"downloads"=>0, "page_views"=>27, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cell_cycle_effects_of_the_combination_of_bendamustine_with_4_OHCY_or_cytosine_arabinoside_/960288", "title"=>"Cell cycle effects of the combination of bendamustine with 4-OHCY or cytosine arabinoside.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-03-13 08:21:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/1417925"], "description"=>"<p>Cells were cultured with various concentrations of bendamustine in combination with (A) 4-hydroperoxy-cyclophosphamide (4-HC), (B) cytosine arabinoside (araC), (C) doxorubicin (DOX) and (D) methotrexate (MTX) for 4 days (Namalwa and HBL-2) or 7 days (U266). Isobolograms were generated from dose-response curves of each combination as described previously <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090675#pone.0090675-Furukawa1\" target=\"_blank\">[31]</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090675#pone.0090675-Koyama1\" target=\"_blank\">[32]</a>. The results of data quantification and statistical analysis are shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090675#pone-0090675-t001\" target=\"_blank\">Table 1</a>.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Nucleic acids", "nucleotides", "Cell death", "hematology", "Hematologic cancers and related disorders", "lymphomas", "Myelomas and lymphoproliferative diseases", "oncology", "Cancer treatment", "Chemotherapy and drug treatment", "Cancers and neoplasms", "Non-Hodgkin lymphoma", "Oncology agents", "drugs", "bendamustine"], "article_id"=>960286, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Nobuya Hiraoka", "Jiro Kikuchi", "Takahiro Yamauchi", "Daisuke Koyama", "Taeko Wada", "Mitsuyo Uesawa", "Miyuki Akutsu", "Shigehisa Mori", "Yuichi Nakamura", "Takanori Ueda", "Yasuhiko Kano", "Yusuke Furukawa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0090675.g002", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_selection_of_suitable_drugs_to_be_combined_with_bendamustine_using_isobologram_/960286", "title"=>"The selection of suitable drugs to be combined with bendamustine using isobologram.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-03-13 08:21:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/1417922"], "description"=>"<p>A) We cultured the indicated cell lines with various concentrations of bendamustine and measured cell proliferation with the MTT reduction assay after 72 hours. IC50 and IC80 values are defined as the concentrations of drugs that produce 50 and 80% inhibition of cell growth, respectively. The means ± S.D. (bars) of three independent experiments are shown. B) HBL-2 cells were cultured in the absence (−) or presence (+) of the IC50 value of bendamustine (BDM), harvested at the indicated time points, and stained with propidium iodide in preparation for cell cycle analysis. C) HBL-2 cells were cultured in the absence (None) or presence of IC50 values of 4-OHCY or chlorambucil (CB), harvested at the indicated time points, and stained with propidium iodide in preparation for cell cycle analysis. Columns indicate the quantification of cells in each phase of the cell cycle obtained with the ModFitLT 2.0 program. The means ± S.D. (bars) of three independent experiments are shown. <i>P</i>-values were calculated by one-way ANOVA with the Student-Newman-Keuls multiple comparisons test. Asterisks denote <i>p</i><0.05 against the untreated control.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Nucleic acids", "nucleotides", "Cell death", "hematology", "Hematologic cancers and related disorders", "lymphomas", "Myelomas and lymphoproliferative diseases", "oncology", "Cancer treatment", "Chemotherapy and drug treatment", "Cancers and neoplasms", "Non-Hodgkin lymphoma", "Oncology agents", "apoptosis", "alkylating", "agents", "exert", "cytotoxicity"], "article_id"=>960283, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Nobuya Hiraoka", "Jiro Kikuchi", "Takahiro Yamauchi", "Daisuke Koyama", "Taeko Wada", "Mitsuyo Uesawa", "Miyuki Akutsu", "Shigehisa Mori", "Yuichi Nakamura", "Takanori Ueda", "Yasuhiko Kano", "Yusuke Furukawa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0090675.g001", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Bendamustine_induces_apoptosis_faster_than_other_alkylating_agents_but_does_not_exert_sufficient_cytotoxicity_against_all_tumors_/960283", "title"=>"Bendamustine induces apoptosis faster than other alkylating agents but does not exert sufficient cytotoxicity against all tumors.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-03-13 08:21:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/1417944", "https://ndownloader.figshare.com/files/1417945"], "description"=>"<div><p>Bendamustine has shown considerable clinical activity against indolent lymphoid malignancies as a single agent or in combination with rituximab, but combination with additional anti-cancer drugs may be required for refractory and/or relapsed cases as well as other intractable tumors. In this study, we attempted to determine suitable anti-cancer drugs to be combined with bendamustine for the treatment of mantle cell lymphoma, diffuse large B-cell lymphoma, aggressive lymphomas and multiple myeloma, all of which are relatively resistant to this drug, and investigated the mechanisms underlying synergism. Isobologram analysis revealed that bendamustine had synergistic effects with alkylating agents (4-hydroperoxy-cyclophosphamide, chlorambucil and melphalan) and pyrimidine analogues (cytosine arabinoside, gemcitabine and decitabine) in HBL-2, B104, Namalwa and U266 cell lines, which represent the above entities respectively. In cell cycle analysis, bendamustine induced late S-phase arrest, which was enhanced by 4-hydroperoxy-cyclophosphamide, and potentiated early S-phase arrest by cytosine arabinoside (Ara-C), followed by a robust increase in the size of sub-G1 fractions. Bendamustine was able to elicit DNA damage response and subsequent apoptosis faster and with shorter exposure than other alkylating agents due to rapid intracellular incorporation via equilibrative nucleoside transporters (ENTs). Furthermore, bendamustine increased the expression of ENT1 at both mRNA and protein levels and enhanced the uptake of Ara-C and subsequent increase in Ara-C triphosphate (Ara-CTP) in HBL-2 cells to an extent comparable with the purine analog fludarabine. These purine analog-like properties of bendamustine may underlie favorable combinations with other alkylators and pyrimidine analogues. Our findings may provide a theoretical basis for the development of more effective bendamustine-based combination therapies.</p></div>", "links"=>[], "tags"=>["Molecular cell biology", "Nucleic acids", "nucleotides", "Cell death", "hematology", "Hematologic cancers and related disorders", "lymphomas", "Myelomas and lymphoproliferative diseases", "oncology", "Cancer treatment", "Chemotherapy and drug treatment", "Cancers and neoplasms", "Non-Hodgkin lymphoma", "Oncology agents", "analog-like", "bendamustine", "underlie", "activation", "dna", "synergistic", "pyrimidine", "analogues", "lymphoid"], "article_id"=>960295, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Nobuya Hiraoka", "Jiro Kikuchi", "Takahiro Yamauchi", "Daisuke Koyama", "Taeko Wada", "Mitsuyo Uesawa", "Miyuki Akutsu", "Shigehisa Mori", "Yuichi Nakamura", "Takanori Ueda", "Yasuhiko Kano", "Yusuke Furukawa"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0090675.s001", "https://dx.doi.org/10.1371/journal.pone.0090675.s002"], "stats"=>{"downloads"=>0, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Purine_Analog_Like_Properties_of_Bendamustine_Underlie_Rapid_Activation_of_DNA_Damage_Response_and_Synergistic_Effects_with_Pyrimidine_Analogues_in_Lymphoid_Malignancies_/960295", "title"=>"Purine Analog-Like Properties of Bendamustine Underlie Rapid Activation of DNA Damage Response and Synergistic Effects with Pyrimidine Analogues in Lymphoid Malignancies", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-03-13 08:21:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/1417930"], "description"=>"<p>(A) Effects of dilazep (left panel) and NBTI (right panel) on cytotoxicity of the indicated drugs at IC50 against HBL-2 (upper panel) and Namalwa (lower panel) cells. (B) <i>ENT1</i> mRNA expression in HBL-2 and Namalwa cells treated with the indicated drugs. The y-axes indicate relative gene expression against the expression levels of the untreated control being set at 1.0. The means ± S.D. (bars) of three independent experiments are shown. <i>P</i>-values were calculated by one-way ANOVA with the Student-Newman-Keuls multiple comparisons test. Asterisks denote <i>p</i><0.05 against the untreated control. (C) HBL-2 and Namalwa cells were cultured in the absence (Control) or presence of IC50 values of the indicated drugs. Whole cell lysates were isolated after 48 hours and subjected to immunoblot analysis for the expression of ENT1, ENT2 and GAPDH (internal control). The data shown are representative of multiple independent experiments.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Nucleic acids", "nucleotides", "Cell death", "hematology", "Hematologic cancers and related disorders", "lymphomas", "Myelomas and lymphoproliferative diseases", "oncology", "Cancer treatment", "Chemotherapy and drug treatment", "Cancers and neoplasms", "Non-Hodgkin lymphoma", "Oncology agents", "analog-like"], "article_id"=>960291, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Nobuya Hiraoka", "Jiro Kikuchi", "Takahiro Yamauchi", "Daisuke Koyama", "Taeko Wada", "Mitsuyo Uesawa", "Miyuki Akutsu", "Shigehisa Mori", "Yuichi Nakamura", "Takanori Ueda", "Yasuhiko Kano", "Yusuke Furukawa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0090675.g005", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Purine_analog_like_properties_of_bendamustine_/960291", "title"=>"Purine analog-like properties of bendamustine.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-03-13 08:21:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/1417929"], "description"=>"<p>(A) Time-course analysis of Chk1 and Chk2 phosphorylation in HBL-2 and Namalwa cells treated with IC50 values of bendamustine or 4-OHCY. (B) Dose-response analysis of Chk1 and Chk2 phosphorylation in HBL-2 and Namalwa cells treated with bendamustine or 4-OHCY for 12 hours. (C) Chk1 and Chk2 phosphorylation was detected in HBL-2 and Namalwa cells treated with IC50 values of the indicated drugs for 6 hours. The membranes were reprobed with anti-GAPDH antibody to serve as a loading control in each experiment. The data shown are representative of multiple independent experiments. (D) After treatment for the indicated periods (3–24 hours) with the indicated doses of bendamustine or 4-OHCY, HBL-2 cells were washed twice with fresh medium and cultured in complete medium without drugs. The cells were cultured for 72 hours in total and subjected to MTT assays. Panels show the dose-response curves of bendamustine- and 4-OHCY-treated cells. The means ± S.D. (bars) of three independent experiments are shown. <i>P</i>-values were calculated by one-way ANOVA with the Student-Newman-Keuls multiple comparisons test. Asterisks indicate <i>p</i><0.05 against each value of 24 h exposure.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Nucleic acids", "nucleotides", "Cell death", "hematology", "Hematologic cancers and related disorders", "lymphomas", "Myelomas and lymphoproliferative diseases", "oncology", "Cancer treatment", "Chemotherapy and drug treatment", "Cancers and neoplasms", "Non-Hodgkin lymphoma", "Oncology agents", "elicits", "dna", "apoptosis", "shorter", "alkylating"], "article_id"=>960290, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Nobuya Hiraoka", "Jiro Kikuchi", "Takahiro Yamauchi", "Daisuke Koyama", "Taeko Wada", "Mitsuyo Uesawa", "Miyuki Akutsu", "Shigehisa Mori", "Yuichi Nakamura", "Takanori Ueda", "Yasuhiko Kano", "Yusuke Furukawa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0090675.g004", "stats"=>{"downloads"=>0, "page_views"=>20, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Bendamustine_elicits_DNA_damage_response_and_subsequent_apoptosis_faster_and_with_a_shorter_exposure_time_than_other_alkylating_agents_/960290", "title"=>"Bendamustine elicits DNA damage response and subsequent apoptosis faster and with a shorter exposure time than other alkylating agents.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-03-13 08:21:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/1417932"], "description"=>"<p>*Mean values of observed data (S.D. not shown).</p><p>**Mean values of the predicted minimum values for an additive effect (S.D. not shown).</p><p>***Mean values of the predicted maximum values for an additive effect (S.D. not shown).</p>#<p>Overall effect of drug combination (see Materials and Methods for the method of evaluation).</p>", "links"=>[], "tags"=>["Molecular cell biology", "Nucleic acids", "nucleotides", "Cell death", "hematology", "Hematologic cancers and related disorders", "lymphomas", "Myelomas and lymphoproliferative diseases", "oncology", "Cancer treatment", "Chemotherapy and drug treatment", "Cancers and neoplasms", "Non-Hodgkin lymphoma", "Oncology agents", "bendamustine", "drugs", "lymphoid"], "article_id"=>960293, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Nobuya Hiraoka", "Jiro Kikuchi", "Takahiro Yamauchi", "Daisuke Koyama", "Taeko Wada", "Mitsuyo Uesawa", "Miyuki Akutsu", "Shigehisa Mori", "Yuichi Nakamura", "Takanori Ueda", "Yasuhiko Kano", "Yusuke Furukawa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0090675.t001", "stats"=>{"downloads"=>2, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Quantitative_analysis_of_the_combination_of_bendamustine_and_other_drugs_in_lymphoid_malignancies_/960293", "title"=>"Quantitative analysis of the combination of bendamustine and other drugs in lymphoid malignancies.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-03-13 08:21:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/1417931"], "description"=>"<p>(A) HBL-2 cells were pretreated with the vehicle alone (Control), F-Ara-A or bendamustine (BDM), followed by the incubation with either [5-<sup>3</sup>H]Ara-C (left panel) and [8-<sup>3</sup>H]F-Ara-A (right panel). Drug incorporation was estimated by counting radioactivity of the nucleotide pool. (B) HBL-2 cells were pretreated with the vehicle alone (ara-C), F-Ara-A (F-ara-A+ara-C) or bendamustine (Bendamustine+ara-C), followed by the incubation with Ara-C. Intracellular Ara-CTP levels were determined using HPLC as described in Materials and Methods. (C) HBL-2 cells were treated with Ara-C and bendamustine (BDM) under three different conditions as described in Materials and Methods and subjected to isobologram analysis to compare the combination index. The means ± S.D. (bars) of three independent experiments are shown. <i>P</i>-values were calculated by one-way ANOVA with the Student-Newman-Keuls multiple comparisons test. Asterisks denote <i>p</i><0.05 against the untreated control.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Nucleic acids", "nucleotides", "Cell death", "hematology", "Hematologic cancers and related disorders", "lymphomas", "Myelomas and lymphoproliferative diseases", "oncology", "Cancer treatment", "Chemotherapy and drug treatment", "Cancers and neoplasms", "Non-Hodgkin lymphoma", "Oncology agents", "uptake", "ara-c", "ara-ctp", "hbl-2"], "article_id"=>960292, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Nobuya Hiraoka", "Jiro Kikuchi", "Takahiro Yamauchi", "Daisuke Koyama", "Taeko Wada", "Mitsuyo Uesawa", "Miyuki Akutsu", "Shigehisa Mori", "Yuichi Nakamura", "Takanori Ueda", "Yasuhiko Kano", "Yusuke Furukawa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0090675.g006", "stats"=>{"downloads"=>0, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Bendamustine_enhances_the_uptake_of_Ara_C_and_subsequent_increase_in_Ara_CTP_in_HBL_2_cells_/960292", "title"=>"Bendamustine enhances the uptake of Ara-C and subsequent increase in Ara-CTP in HBL-2 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-03-13 08:21:47"}

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