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Reversal of Methotrexate Cytotoxicity to Human Bone Marrow Cells and Leukemic K562 Cells by Leucovorin: Methotrexate Polyglutamates Formation as a Possible Important Factor

Methotrexate (MIX) is metabolized intracellularly to MTX‐polyglutamates (MTX‐PGs), which markedly inhibit several folate‐dependent enzymes. Polyglutamation defect, therefore, is one of the important factors in drug resistance. In this study, reversal of MTX cytotoxicity by l‐leucovorin (l‐LV) was in...

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Autores principales: Koizumi, Shoichi, Ueno, Yoshiki, Ohno, Ichiro, Ichihara, Tsuyoshi, Tamaru, Yoichi, Matsukawa, Harumi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 1990
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5917995/
https://www.ncbi.nlm.nih.gov/pubmed/1702414
http://dx.doi.org/10.1111/j.1349-7006.1990.tb02529.x
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author Koizumi, Shoichi
Ueno, Yoshiki
Ohno, Ichiro
Ichihara, Tsuyoshi
Tamaru, Yoichi
Matsukawa, Harumi
author_facet Koizumi, Shoichi
Ueno, Yoshiki
Ohno, Ichiro
Ichihara, Tsuyoshi
Tamaru, Yoichi
Matsukawa, Harumi
author_sort Koizumi, Shoichi
collection PubMed
description Methotrexate (MIX) is metabolized intracellularly to MTX‐polyglutamates (MTX‐PGs), which markedly inhibit several folate‐dependent enzymes. Polyglutamation defect, therefore, is one of the important factors in drug resistance. In this study, reversal of MTX cytotoxicity by l‐leucovorin (l‐LV) was investigated using normal human bone marrow granulocyte progenitor cells (G‐CFCs), and MTX‐sensitive and ‐resistant leukemic K562 cell lines; the latter showed diminished polyglutamation. Cytotoxicity of 10(‐7)M MTX to G‐CFCs was completely reversed by an equimolar concentration of l‐LV, but with higher MTX concentrations, relatively more l‐LV was required. The reversal of MTX cytotoxicity by l‐LV was more effective against bone marrow cells than MTX‐sensitive K562 cells; this reversal seemed to be correlated to the total intracellular MTX levels as well as MTX‐PG formation (low in bone marrow cells and high in K562 cells). When MTX‐sensitive and ‐resistant K562 cells were incubated with MTX under conditions in which the total intracellular MTX levels of both cells were similar, successful reversal of MTX toxicity by l‐LV was demonstrated in MTX‐resistant cells, but not in MTX‐sensitive cells, suggesting that an increase of MTX‐PG formation in MTX‐sensitive cells may explain the failure of l‐LV to overcome MTX cytotoxicity. In addition to competitive reversal of MTX cytotoxicity by LV, noncompetitive reversal relating to variable formation of MTX‐PGs is suggested to be another important factor in the mechanism of the reversal of MTX cytotoxicity by LV.
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spelling pubmed-59179952018-05-11 Reversal of Methotrexate Cytotoxicity to Human Bone Marrow Cells and Leukemic K562 Cells by Leucovorin: Methotrexate Polyglutamates Formation as a Possible Important Factor Koizumi, Shoichi Ueno, Yoshiki Ohno, Ichiro Ichihara, Tsuyoshi Tamaru, Yoichi Matsukawa, Harumi Jpn J Cancer Res Article Methotrexate (MIX) is metabolized intracellularly to MTX‐polyglutamates (MTX‐PGs), which markedly inhibit several folate‐dependent enzymes. Polyglutamation defect, therefore, is one of the important factors in drug resistance. In this study, reversal of MTX cytotoxicity by l‐leucovorin (l‐LV) was investigated using normal human bone marrow granulocyte progenitor cells (G‐CFCs), and MTX‐sensitive and ‐resistant leukemic K562 cell lines; the latter showed diminished polyglutamation. Cytotoxicity of 10(‐7)M MTX to G‐CFCs was completely reversed by an equimolar concentration of l‐LV, but with higher MTX concentrations, relatively more l‐LV was required. The reversal of MTX cytotoxicity by l‐LV was more effective against bone marrow cells than MTX‐sensitive K562 cells; this reversal seemed to be correlated to the total intracellular MTX levels as well as MTX‐PG formation (low in bone marrow cells and high in K562 cells). When MTX‐sensitive and ‐resistant K562 cells were incubated with MTX under conditions in which the total intracellular MTX levels of both cells were similar, successful reversal of MTX toxicity by l‐LV was demonstrated in MTX‐resistant cells, but not in MTX‐sensitive cells, suggesting that an increase of MTX‐PG formation in MTX‐sensitive cells may explain the failure of l‐LV to overcome MTX cytotoxicity. In addition to competitive reversal of MTX cytotoxicity by LV, noncompetitive reversal relating to variable formation of MTX‐PGs is suggested to be another important factor in the mechanism of the reversal of MTX cytotoxicity by LV. Blackwell Publishing Ltd 1990-11 /pmc/articles/PMC5917995/ /pubmed/1702414 http://dx.doi.org/10.1111/j.1349-7006.1990.tb02529.x Text en
spellingShingle Article
Koizumi, Shoichi
Ueno, Yoshiki
Ohno, Ichiro
Ichihara, Tsuyoshi
Tamaru, Yoichi
Matsukawa, Harumi
Reversal of Methotrexate Cytotoxicity to Human Bone Marrow Cells and Leukemic K562 Cells by Leucovorin: Methotrexate Polyglutamates Formation as a Possible Important Factor
title Reversal of Methotrexate Cytotoxicity to Human Bone Marrow Cells and Leukemic K562 Cells by Leucovorin: Methotrexate Polyglutamates Formation as a Possible Important Factor
title_full Reversal of Methotrexate Cytotoxicity to Human Bone Marrow Cells and Leukemic K562 Cells by Leucovorin: Methotrexate Polyglutamates Formation as a Possible Important Factor
title_fullStr Reversal of Methotrexate Cytotoxicity to Human Bone Marrow Cells and Leukemic K562 Cells by Leucovorin: Methotrexate Polyglutamates Formation as a Possible Important Factor
title_full_unstemmed Reversal of Methotrexate Cytotoxicity to Human Bone Marrow Cells and Leukemic K562 Cells by Leucovorin: Methotrexate Polyglutamates Formation as a Possible Important Factor
title_short Reversal of Methotrexate Cytotoxicity to Human Bone Marrow Cells and Leukemic K562 Cells by Leucovorin: Methotrexate Polyglutamates Formation as a Possible Important Factor
title_sort reversal of methotrexate cytotoxicity to human bone marrow cells and leukemic k562 cells by leucovorin: methotrexate polyglutamates formation as a possible important factor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5917995/
https://www.ncbi.nlm.nih.gov/pubmed/1702414
http://dx.doi.org/10.1111/j.1349-7006.1990.tb02529.x
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