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The role of folates in the development of methotrexate resistance in human leukemia cell line K562

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  • Experimental Oncology
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Summary

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-acidfree 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 acqured MTX resistance in vivo.

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Abbreviations

MTX:

methotrexate

PGA:

pteroylglutamic acid

PDDF:

N 10-propargyl-5,8-dideazafolate

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

IC50 :

50% inhibitory concentration for cell growth by MTT assay

FCS:

fetal calf serum

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Authors and Affiliations

  1. Department of Clinical Pathology, Tokai University School of Medicine, Bohseidai, 259-11, Isehara, Kanagawa, Japan

    Hayato Miyachi & Yasuhiko Ando

  2. Department of Laboratory Medicine, National Defense Medical College, 3-2 Namiki, 359, Tokorozawa, Saitama, Japan

    Yuzuru Takemura

  3. Section of Biochemical Pharmacology, Department of Medical Oncology, City of Hope National Medical Center, 1500 E. Duarte Rd., 91010, Duarte, CA, USA

    Kevin J. Scanlon

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  1. Hayato Miyachi
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  2. Yuzuru Takemura
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  3. Yasuhiko Ando
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  4. Kevin J. Scanlon
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Miyachi, H., Takemura, Y., Ando, Y. et al. The role of folates in the development of methotrexate resistance in human leukemia cell line K562. J Cancer Res Clin Oncol 119, 101–105 (1992). https://doi.org/10.1007/BF01209664

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  • DOI: https://doi.org/10.1007/BF01209664

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