title: Common resistance mechanisms to deoxynucleoside analogues in variants of the human erythroleukaemic line K562.
abstract: Resistant variants of the human leukaemic line K562 were developed using selection with the deoxynucleoside analogues cytosine arabinoside, 2-chlorodeoxyadenosine, fludarabine and gemcitabine. The resistant lines displayed a high degree of cross resistance to all deoxynucleoside analogues, with little or no cross resistance to other agents. There was a profound accumulation defect of all nucleoside analogues in the resistant variants but no significant defect in nucleoside transport in any of the variants. 5' nucleotidase activity was strongly increased and deoxycytidine kinase activity was moderately reduced in all of the resistant variants, resulting in reduced accumulation of triphosphate analogues. In addition a deletion in one of the alleles of the deoxycytidine kinase was detected in the fludarabine-resistant line. Ribonucleotide reductase activity was found to be strongly increased in the gemcitabine-selected line and purine nucleoside phosphorylase was increased in the 2-chlorodeoxyadenosine-selected line. Free nucleotide pools were increased in the 2-chlorodeoxyadenosine-selected line. There was no expression of the mdr1 gene by the resistant lines. Karyotypic analysis and FISH experiments using a 6q21 specific probe showed alterations in the 6(q16-q22) region which contains the 5'-nucleotidase gene. Early events in the activation and degradation of deoxynucleoside analogues appear to constitute common mechanisms of resistance to these compounds.
authors.affiliation: Laboratoire d'Immunochimie, Service et Laboratoire Central d'Hématologie et de Biochimie, Hospices Civils de Lyon Pierre Bénite, France. cd@hematologie.univ-lyon.fr
authors.forename: C
authors.initials: C
authors.lastname: Dumontet
authors.forename: K
authors.initials: K
authors.lastname: Fabianowska-Majewska
authors.forename: D
authors.initials: D
authors.lastname: Mantincic
authors.forename: E
authors.initials: E
authors.lastname: Callet Bauchu
authors.forename: I
authors.initials: I
authors.lastname: Tigaud
authors.forename: V
authors.initials: V
authors.lastname: Gandhi
authors.forename: M
authors.initials: M
authors.lastname: Lepoivre
authors.forename: G J
authors.initials: GJ
authors.lastname: Peters
authors.forename: M O
authors.initials: MO
authors.lastname: Rolland
authors.forename: D
authors.initials: D
authors.lastname: Wyczechowska
authors.forename: X
authors.initials: X
authors.lastname: Fang
authors.forename: S
authors.initials: S
authors.lastname: Gazzo
authors.forename: D A
authors.initials: DA
authors.lastname: Voorn
authors.forename: A
authors.initials: A
authors.lastname: Vanier-Viornery
authors.forename: J
authors.initials: J
authors.lastname: MacKey
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017338:Cladribine / Q000627:therapeutic use*; D003561:Cytarabine / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003842:Deoxycytidine Kinase / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020014:K562 Cells; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy* / Q000201:enzymology; D010641:Phenotype; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D003561:Cytarabine; D003841:Deoxycytidine; D017338:Cladribine; D003842:Deoxycytidine Kinase; D014740:Vidarabine; C024352:fludarabine; D000093542:Gemcitabine