BACKGROUND: Cytosine arabinoside (1-beta-D-arabinofuranosylcytosine;Ara-C) is the most important antimetabolite used for acute leukemia. We established Ara-C (0.003-1 micromol/l)-resistant NALM-6 leukemia cells, and attempted the characterization of their resistance. METHODS: The Ara-C-resistant cell lines were developed by stepwise increases in the drug. The mRNA expressions were analyzed by reverse transcription-polymerase chain reaction (RT-PCR). The uptake of Ara-C, deoxycytidine kinase (dCK) activity and cytidine deaminase (CDA) activity were measured using radioisotope methods. Cytotoxicity was evaluated using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay. RESULTS: The mRNA expression of human equilibrative nucleoside transporter-1 (hENT-1), which is an uptake transporter of Ara-C, was initially decreased during the acquisition of resistance to Ara-C. The expression of dCK, an activation enzyme, and of CDA, an inactivation enzyme, was decreased and increased in the late phase, respectively. The cytotoxic effect of Ara-C on parental NALM-6 cells was ameliorated by hENT-1 inhibitors. There were no differences in the cytotoxic effect of other anticancer drugs, but there was similar resistance to nucleoside analogues via hENT-1 between the parental and resistant cells. CONCLUSIONS: Decreased hENT-1 expression and function is causatively responsible for the acquisition of Ara-C resistance and alterations in dCK and CDA contribute to the higher concentration range.
BACKGROUND:Cytosine arabinoside (1-beta-D-arabinofuranosylcytosine;Ara-C) is the most important antimetabolite used for acute leukemia. We established Ara-C (0.003-1 micromol/l)-resistant NALM-6 leukemia cells, and attempted the characterization of their resistance. METHODS: The Ara-C-resistant cell lines were developed by stepwise increases in the drug. The mRNA expressions were analyzed by reverse transcription-polymerase chain reaction (RT-PCR). The uptake of Ara-C, deoxycytidine kinase (dCK) activity and cytidine deaminase (CDA) activity were measured using radioisotope methods. Cytotoxicity was evaluated using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay. RESULTS: The mRNA expression of humanequilibrative nucleoside transporter-1 (hENT-1), which is an uptake transporter of Ara-C, was initially decreased during the acquisition of resistance to Ara-C. The expression of dCK, an activation enzyme, and of CDA, an inactivation enzyme, was decreased and increased in the late phase, respectively. The cytotoxic effect of Ara-C on parental NALM-6 cells was ameliorated by hENT-1 inhibitors. There were no differences in the cytotoxic effect of other anticancer drugs, but there was similar resistance to nucleoside analogues via hENT-1 between the parental and resistant cells. CONCLUSIONS: Decreased hENT-1 expression and function is causatively responsible for the acquisition of Ara-C resistance and alterations in dCK and CDA contribute to the higher concentration range.
Authors: Daniel Nowak; Natalia L M Liem; Maximilian Mossner; Marion Klaumünzer; Rachael A Papa; Verena Nowak; Johann C Jann; Tadayuki Akagi; Norihiko Kawamata; Ryoko Okamoto; Nils H Thoennissen; Motohiro Kato; Masashi Sanada; Wolf-Karsten Hofmann; Seishi Ogawa; Glenn M Marshall; Richard B Lock; H Phillip Koeffler Journal: Exp Hematol Date: 2014-10-29 Impact factor: 3.084
Authors: Patricia Macanas-Pirard; Andrea Leisewitz; Richard Broekhuizen; Kelly Cautivo; Francisco M Barriga; Francisco Leisewitz; Victoria Gidi; Erick Riquelme; Viviana P Montecinos; Pilar Swett; Pelayo Besa; Pablo Ramirez; Mauricio Ocqueteau; Alexis M Kalergis; Matthew Holt; Michael Rettig; John F DiPersio; Bruno Nervi Journal: PLoS One Date: 2012-05-22 Impact factor: 3.240
Authors: Patricia Macanas-Pirard; Richard Broekhuizen; Alfonso González; Claudia Oyanadel; Daniel Ernst; Patricia García; Viviana P Montecinos; Felipe Court; Mauricio Ocqueteau; Pablo Ramirez; Bruno Nervi Journal: Oncotarget Date: 2017-04-04
Authors: Peng Li; Sarah Diab; Mingfeng Yu; Julian Adams; Saiful Islam; Sunita K C Basnet; Hugo Albrecht; Robert Milne; Shudong Wang Journal: Oncotarget Date: 2016-08-30