Common resistance mechanisms to deoxynucleoside analogues in variants of the human erythroleukaemic line K562

Resistant variants of the human leukaemic line K562 were developed using se lection with the deoxynucleoside analogues cyto sine arabinoside, 2-chlorod eoxyadenosine, fludarabine and gemcitabine. The resistant lines displayed a high degree of cross resistance to all deoxynucleoside analogues, with lit tle or no cross resistance to other agents. There was a profound accumulati on defect of all nucleoside analogues in the resistant variants but no sign ificant defect in nucleoside transport in any of the variants, 5' nucleotid ase activity was strongly increased and deoxycytidine kinase activity was m oderately reduced in all of the resistant variants, resulting in reduced ac cumulation of triphosphate analogues. Ln addition a deletion in one of the alleles of the deoxycytidine kinase was detected in the fludarabine-resista nt line. Ribonucleotide reductase activity was found to be strongly increas ed in the gemcitabine-selected line and purine nucleoside phosphorylase was increased in the 2-chlorodeoxyadenosine-selected line. Free nucleotide poo ls were increased in the 2-chorodeoxyadenosine-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(q 16-q22) region which contains the 5'-nucleotidase gene. Early events in the activation and degradation of deoxynucleoside analogues appear to constitu te common mechanisms of resistance to these compounds.