Two distinct molecular mechanisms underlying cytarabine resistance in human leukemic cells.

摘要: To understand the mechanism of cellular resistance to nucleoside analogue cytarabine (1-beta-D-arabinofuranosylcytosine, AraC), two resistant derivatives human leukemic line CCRF-CEM were obtained by stepwise selection in different concentrations AraC. CEM/4xAraC cells showed low AraC resistance, whereas CEM/20xAraC high resistance. Both cell lines similar patterns cross-resistance multiple cytotoxic analogues, with exception that remained sensitive 5-fluorouridine and 2-deoxy-5-fluorouridine. 5-fluorouracil a variety natural product drugs. Although both displayed reduced intracellular accumulation [(3)H]AraC, only uptake [(3)H]uridine, which was used assess transport activities. Genes encoding proteins known be involved transport, efflux, metabolism analyzed for presence mutations lines. In cells, independent identified at each allele equilibrative transporter 1 (hENT1; SLC29A1), one corresponding single-nucleotide change exon 4, other being complex intronic mutation disrupting splicing 13. contrast did not bind hENT1/SLC29A1 ligand nitrobenzylmercaptopurine ribonucleoside lacked detectable protein. impairing exons 2 3 found deoxycytidine kinase gene. These studies point least distinct mechanisms cells.