Nelarabine resistance of childhood T-cell lymphoblastic leukemia/lymphoma cells
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概要
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Background: Nelarabine (NEL) is a new purine nucleoside analogue that has recently become available for both adults and children with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL)and T-lymphoblastic lymphoma (T-LBL). We studied the drug resistance profile of eight children with T-ALL/LBL using an in vitro cytotoxic assay including NEL. Furthermore, we tried to establish a NEL resistant T-ALL cell line model to investigate the mechanism of NEL resistance.Results : Four of 8 patients showed a higher 50% lethal concentration (LC,o) than the maximum clinical concentration of NEL. There were no correlations in LC,o values between NEL and other drugs. To study the mechanism of NEL resistance, we originally established a nucleoside an alogue resistant T-ALL Jurkat cell line model (Jurkat+C) induced by incubation in medium containing cytarabine (AraC) at LC,o ofthe control. Jurkat+C showed resistance to NEL and Fludarabine as well as AraC but not Daunorubicin. Next, we studied the role of Equivalent Nucleoside Transporter-1 (ENT-1), a major cellular nucleoside transporter, in the acquired drug resistance in Jurkat+ C. Nitrobenzylmercaptopurine riboside, an ENT-1-specific inhibitor, showed an inhibitory efTect of nucleoside analogues on in vitro toxicity in both Jurkat and Jurkat+C, while no difTerences in ENT-1 mRNA expression levels between Jurk at and Jurkat + C were found.Conclusions: in vitro NEL resistance was seen in half of the tested childhood T-ALL cells. We couldestablish the NEL resistant T-ALL cell line model by AraC exposure. ENT-1 may partly act as atransporter of NEL, but not play a key role in AraC induced NEL resistance. This cell line model maybe usefu1 to provide a mechanism to explain NEL resistance.
著者
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Arakawa Hirokazu
Department of Pediatrics, Gunma University School of Medicine
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Aizawa Akira
Department Of Cardiology Tokyo Medical University Hachioji Medical Center
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Tamura Kazushi
Department Of Pediatrics And Developmental Medicine Gunma University Graduate School
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KUMAMOTO Tadashi
Department of Dermatology, University of Texas, Southwestern Medical Center
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Kobayashi Yasuko
Department Of Pediatrics Tohoku University School Of Medicine
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KANAZAWA TAKASHI
Department of Pediatrics and Developmental Medicine, Gunma University, Graduate School of Medicine
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Tsukada Shota
Department Of Neurophysiology Gunma University Graduate School Of Medicine
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Yamada Shiro
Department Of Basic Pathology National Defense Medical College
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Shiba Norio
Department of Pediatrics, Gunma University Graduate School of Medicine
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Okuno Haruna
Department of Pediatrics, Gunma University Graduate School of Medicine
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Arakawa Hirokazu
Department Of Pediatrics Gunma University Graduate School Of Medicine
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Kobayashi Yasuko
Department Of Agricultural And Biological Chemistry College Of Bioresource Sciences Nihon University
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Kanazawa Takashi
Department Of Computer Science And Intelligent Systems Oita University
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Kumamoto Tadashi
Department Of Dermatology University Of Texas Southwestern Medical Center
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ARAKAWA Hirokazu
Department of Pediatrics and Developmental Medicine, Gunma University Graduate School
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Yamada Shiro
Department of Pediatrics, Gunma University Graduate School of Medicine
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Kobayashi Ysuko
Department of Pediatrics, Gunma University Graduate School of Medicine
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KUMAMOTO TADASHI
Department of Pediatrics, Mie University Graduate School of Medicine
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Tamura Kazushi
Department of Pediatrics, Gunma University Graduate School of Medicine
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Tamura Kazushi
Department of Biological Sciences, Graduate School of Science, Hokkaido University, North 10 West 8, Kita-ku, Sapporo 060-0810, Japan
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Kanazawa Takashi
Department of Pediatrics, Gunma University Graduate School of Medicine
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Aizawa Akira
Department of Pediatrics, Gunma University Graduate School of Medicine
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Tsukada Shota
Department of Pediatrics, Gunma University Graduate School of Medicine
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Kobayashi Yasuko
Department of Pediatrics, Gunma University Graduate School of Medicine
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