title: The role of folates in the development of methotrexate resistance in human leukemia cell line K562.
abstract: The effect of reduced and oxidized folates on the development of methotrexate (MTX) resistance has been examined in human leukemia cell line K562 (K562/S). K562/S cells were made resistant to MTX by soft-agar cloning either in RPMI-1640 medium (K562/MTX-PGA) or in folic-acid-free RPMI-1640 medium containing 10 nM leucovorin (K562/MTX-LV). The optimal concentrations of leucovorin for the growth of K562/S, K562/MTX-PGA and K562/MTX-LV cells were 1 nM, 5 nM and 10 nM respectively. K562/MTX-PGA cells were 24-fold resistant to MTX as noted by impaired MTX transport. In contrast, K562/MTX-LV cells were 26-fold resistant to MTX as noted by gene amplification of dihydrofolate reductase. Furthermore cross-resistance to cytosine arabinoside was only demonstrated in K562/MTX-PGA, while the K562/MTX-LV cells showed no significant cross-resistance to cytosine arabinoside. These results suggest that the type and level of folates used during the development of MTX resistance may play a role in the mechanism for MTX resistance. Leukemia cells that are grown in leucovorin might serve as a model for acquired MTX resistance in vivo.
authors.affiliation: Department of Clinical Pathology, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Miyachi
authors.forename: Y
authors.initials: Y
authors.lastname: Takemura
authors.forename: Y
authors.initials: Y
authors.lastname: Ando
authors.forename: K J
authors.initials: KJ
authors.lastname: Scanlon
mesh_terms: D002453:Cell Cycle; D004351:Drug Resistance; D005492:Folic Acid / Q000502:physiology*; D006801:Humans; D002955:Leucovorin / Q000494:pharmacology; D007938:Leukemia / Q000473:pathology*; D008727:Methotrexate / Q000493:pharmacokinetics / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase; D002955:Leucovorin; D008727:Methotrexate