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Biological Activity and Intracellular Metabolism of ZD1694 in Human Leukemia Cell Lines with Different Resistance Mechanisms to Antifolate Drugs
The biological activity and cellular metabolism of ZD1694, a novel folate‐based thymidylate synthase (TS) inhibitor, were analyzed in a human leukemia cell line, MOLT‐3, and its antifolate‐resistant sublines with different mechanisms of resistance to methotrexate (MTX), trimetrexate (TMQ) and N(10)‐...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Blackwell Publishing Ltd
1996
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5921156/ https://www.ncbi.nlm.nih.gov/pubmed/8698629 http://dx.doi.org/10.1111/j.1349-7006.1996.tb00291.x |
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author | Takemura, Yuzuru Kobayashi, Hiroyuki Miyachi, Hayato Gibson, William Kimbell, Rosemary Jackman, Ann L. |
author_facet | Takemura, Yuzuru Kobayashi, Hiroyuki Miyachi, Hayato Gibson, William Kimbell, Rosemary Jackman, Ann L. |
author_sort | Takemura, Yuzuru |
collection | PubMed |
description | The biological activity and cellular metabolism of ZD1694, a novel folate‐based thymidylate synthase (TS) inhibitor, were analyzed in a human leukemia cell line, MOLT‐3, and its antifolate‐resistant sublines with different mechanisms of resistance to methotrexate (MTX), trimetrexate (TMQ) and N(10)‐propargyl‐5,8‐dideazafolic acid (CB3717). MOLT‐3/CB3717(40), which was selected for CB3717 resistance, demonstrated impaired membrane drug transport via reduced folate carrier (RFC) and lower accumulation of [(3)H]ZD1694‐polyglutamates in the cells with a shift in the polyglutamate distribution profile to shorter chain length polyglutamates, indicating an alteration in polyglutamation capacity in this subline. Impaired RFC and reduced rate of polyglutamation could explain the cross‐resistance (12‐fold) of this subline to ZD1694. On the other hand, there was little or no cross‐resistance to this drug in a subline (MOLT‐3/TMQ(800)) reportedly resistant to TMQ through impaired membrane transport for TMQ and an increase in dihydrofolate reductase (DHFR) activity. Total amount of ZD1694 polyglutamated to a level higher than diglutamate was approximately 1.7‐fold higher in the TMQ‐resistant cells than that in the parent cells, but a low degree of increase in TS activity in the cells counteracted the supposed increase in sensitivity to ZD1694. MOLT‐3/TMQ(800)‐MTX(10000) cells, which were established by sequential exposure of the TMQ‐resistant cells to MTX and were previously shown to amplify mutated DHFR with low affinity for MTX, showed a decreased accumulation of polyglutamated ZD1694 as compared with the parent line and this was consistent with cross‐resistance to ZD1694 in this subline. Overproduction of variant DHFR scarcely influenced the sensitivity to this drug. These results indicate that ZD1694 could overcome antifolate resistance through a mechanism such as amplified DHFR activity, and the biological activity of this drug against the cells paralleled the amount of polyglutamated drug inside the cells. Determination of polyglutamation capacity in tumor cells may allow prediction of sensitivity to this drug. |
format | Online Article Text |
id | pubmed-5921156 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 1996 |
publisher | Blackwell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-59211562018-05-11 Biological Activity and Intracellular Metabolism of ZD1694 in Human Leukemia Cell Lines with Different Resistance Mechanisms to Antifolate Drugs Takemura, Yuzuru Kobayashi, Hiroyuki Miyachi, Hayato Gibson, William Kimbell, Rosemary Jackman, Ann L. Jpn J Cancer Res Article The biological activity and cellular metabolism of ZD1694, a novel folate‐based thymidylate synthase (TS) inhibitor, were analyzed in a human leukemia cell line, MOLT‐3, and its antifolate‐resistant sublines with different mechanisms of resistance to methotrexate (MTX), trimetrexate (TMQ) and N(10)‐propargyl‐5,8‐dideazafolic acid (CB3717). MOLT‐3/CB3717(40), which was selected for CB3717 resistance, demonstrated impaired membrane drug transport via reduced folate carrier (RFC) and lower accumulation of [(3)H]ZD1694‐polyglutamates in the cells with a shift in the polyglutamate distribution profile to shorter chain length polyglutamates, indicating an alteration in polyglutamation capacity in this subline. Impaired RFC and reduced rate of polyglutamation could explain the cross‐resistance (12‐fold) of this subline to ZD1694. On the other hand, there was little or no cross‐resistance to this drug in a subline (MOLT‐3/TMQ(800)) reportedly resistant to TMQ through impaired membrane transport for TMQ and an increase in dihydrofolate reductase (DHFR) activity. Total amount of ZD1694 polyglutamated to a level higher than diglutamate was approximately 1.7‐fold higher in the TMQ‐resistant cells than that in the parent cells, but a low degree of increase in TS activity in the cells counteracted the supposed increase in sensitivity to ZD1694. MOLT‐3/TMQ(800)‐MTX(10000) cells, which were established by sequential exposure of the TMQ‐resistant cells to MTX and were previously shown to amplify mutated DHFR with low affinity for MTX, showed a decreased accumulation of polyglutamated ZD1694 as compared with the parent line and this was consistent with cross‐resistance to ZD1694 in this subline. Overproduction of variant DHFR scarcely influenced the sensitivity to this drug. These results indicate that ZD1694 could overcome antifolate resistance through a mechanism such as amplified DHFR activity, and the biological activity of this drug against the cells paralleled the amount of polyglutamated drug inside the cells. Determination of polyglutamation capacity in tumor cells may allow prediction of sensitivity to this drug. Blackwell Publishing Ltd 1996-07 /pmc/articles/PMC5921156/ /pubmed/8698629 http://dx.doi.org/10.1111/j.1349-7006.1996.tb00291.x Text en |
spellingShingle | Article Takemura, Yuzuru Kobayashi, Hiroyuki Miyachi, Hayato Gibson, William Kimbell, Rosemary Jackman, Ann L. Biological Activity and Intracellular Metabolism of ZD1694 in Human Leukemia Cell Lines with Different Resistance Mechanisms to Antifolate Drugs |
title | Biological Activity and Intracellular Metabolism of ZD1694 in Human Leukemia Cell Lines with Different Resistance Mechanisms to Antifolate Drugs |
title_full | Biological Activity and Intracellular Metabolism of ZD1694 in Human Leukemia Cell Lines with Different Resistance Mechanisms to Antifolate Drugs |
title_fullStr | Biological Activity and Intracellular Metabolism of ZD1694 in Human Leukemia Cell Lines with Different Resistance Mechanisms to Antifolate Drugs |
title_full_unstemmed | Biological Activity and Intracellular Metabolism of ZD1694 in Human Leukemia Cell Lines with Different Resistance Mechanisms to Antifolate Drugs |
title_short | Biological Activity and Intracellular Metabolism of ZD1694 in Human Leukemia Cell Lines with Different Resistance Mechanisms to Antifolate Drugs |
title_sort | biological activity and intracellular metabolism of zd1694 in human leukemia cell lines with different resistance mechanisms to antifolate drugs |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5921156/ https://www.ncbi.nlm.nih.gov/pubmed/8698629 http://dx.doi.org/10.1111/j.1349-7006.1996.tb00291.x |
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