title: A nelarabine-resistant T-lymphoblastic leukemia CCRF-CEM variant cell line is cross-resistant to the purine nucleoside phosphorylase inhibitor forodesine.
abstract: OBJECTIVE
  Forodesine inhibits purine nucleoside phosphorylase, resulting in an accumulation of intracellular dGTP and consequently cell death. 9-β-D-Arabinofuranosylguanine (ara-G) is an active compound of nelarabine that is intracellularly phosphorylated to a triphosphate form, which inhibits DNA synthesis. Both agents show cytotoxicity toward T-cell malignancies. In the present study, we investigated the cytotoxicity of forodesine in vitro using ara-G-resistant leukemia cells.
  
  
  METHODS
  T-Lymphoblastic leukemia cell line CCRF-CEM and ara-G-resistant CEM variant cell line CEM/ara-G that we had previously established were used.
  
  
  RESULTS
  A growth-inhibition assay demonstrated that CEM cells were insensitive to single-agent forodesine treatment. The cells were also insensitive to deoxyguanosine at a maximal concentration of 10 μM. CEM/ara-G cells were 80-fold more resistant to ara-G than were CEM cells, and the mode of sensitivity to forodesine and deoxyguanosine was similar to that of CEM cells. In the presence of 10 μM deoxyguanosine, forodesine effectively inhibited the growth of CEM cells but not that of CEM/ara-G cells. Flow cytometric analyses showed that combination of forodesine and deoxyguanosine induced apoptosis of CEM cells but not of CEM/ara-G cells. The addition of ara-G did not augment the cytotoxicity of the forodesine/deoxyguanosine combination towards CEM cells or CEM/ara-G cells. The combination index revealed antagonism between forodesine and ara-G. The intracellular production of ara-G triphosphate was reduced in the presence of forodesine.
  
  
  CONCLUSIONS
  Nelarabine-resistant CEM/ara-G cells are insensitive to forodesine.
authors.affiliation: Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Matsuoka, Fukui, Japan tyamauch@u-fukui.ac.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamauchi
authors.affiliation: Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Matsuoka, Fukui, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Uzui
authors.affiliation: Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Matsuoka, Fukui, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Nishi
authors.affiliation: Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Matsuoka, Fukui, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Tasaki
authors.affiliation: Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Matsuoka, Fukui, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Ueda
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity; D001087:Arabinonucleosides / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D018922:HL-60 Cells; D006801:Humans; D016393:Lymphoma, B-Cell / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D011684:Purine Nucleosides / Q000494:pharmacology* / Q000633:toxicity; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D011744:Pyrimidinones / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D011684:Purine Nucleosides; D011744:Pyrimidinones; C113101:forodesine; C104457:nelarabine; D011683:Purine-Nucleoside Phosphorylase
keywords: Forodesine; ara-G; ara-GTP; deoxyguanosine; leukemia; nelarabine