title: Resistance to 9-beta-D-arabinofuranosyl-2-fluoroadenine due to reduced incorporation into DNA from competition by excess deoxyadenosine triphosphate: implications for different sensitivities to nucleoside analogues.
abstract: The cytotoxic action of the deoxyadenosine analogue 9-beta-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) depends on the incorporation into DNA after being phosphorylated to F-ara-A triphosphate (F-ara-ATP) by deoxycytidine kinase (dCK). The mechanisms of resistance to F-ara-A were investigated in a newly established variant of L1210 mouse leukemia cells (L1210/F). L1210/F was more than 41-fold more resistant to F-ara-A than the parental cell line and had a 55% lower dCK activity. Interestingly, L1210/F showed a modest level of cross-resistance to deoxycytidine analogues phosphorylated by dCK, for instance, 1-beta-D-arabinofuranosylcytosine (ara-C). The comparative study of F-ara-A and ara-C demonstrated that the difference in the accumulation of their respective triphosphates was minor. In contrast, the incorporation of F-ara-A into DNA was strikingly suppressed compared with that of ara-C. In general, the high natural triphosphate levels interfere with corresponding analogue incorporation into DNA. The deoxyadenosine triphosphate (dATP) and deoxycytidine triphosphate pool sizes in L1210/F cells were increased by 4.9-fold and 1.9-fold, respectively, compared with the parental cells. Treatment with hydroxyurea increased the ratio of F-ara-ATP to dATP 2.1-fold and enhanced the action of F-ara-A in L1210/F. This is the first cell line to show that the profoundly defective incorporation of F-ara-A into DNA during competition with excess dATP confers a high degree of resistance to F-ara-A.
authors.affiliation: First Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yoshio
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Kawai
authors.forename: Hiroki
authors.initials: H
authors.lastname: Hori
authors.forename: Takanori
authors.initials: T
authors.lastname: Ueda
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001711:Biotransformation; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003561:Cytarabine / Q000493:pharmacokinetics; D004247:DNA / Q000378:metabolism*; D003838:Deoxyadenine Nucleotides / Q000032:analysis / Q000378:metabolism*; D003845:Deoxycytosine Nucleotides / Q000032:analysis; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D006918:Hydroxyurea / Q000494:pharmacology; D051379:Mice; D009705:Nucleosides / Q000494:pharmacology / Q000627:therapeutic use; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D003838:Deoxyadenine Nucleotides; D003845:Deoxycytosine Nucleotides; D009705:Nucleosides; D003561:Cytarabine; C024107:2'-deoxycytidine 5'-triphosphate; D004247:DNA; D014740:Vidarabine; C026600:2'-deoxyadenosine triphosphate; C024352:fludarabine; D006918:Hydroxyurea