Cellular pharmacokinetic of methotrexate and its modulation by folylpolyglutamate synthetase and γ-glutamyl hydrolase in tumor cells
Clinical studies showed that prolonged infusion of methotrexate (MTX) leads to more severe adverse reactions than short infusion of MTX at the same dose. We hypothesized that it is the saturation of folate polyglutamate synthetase (FPGS) at high MTX concentration that limits the intracellular synthe...
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| description | Clinical studies showed that prolonged infusion of methotrexate (MTX) leads to more severe adverse reactions than short infusion of MTX at the same dose. We hypothesized that it is the saturation of folate polyglutamate synthetase (FPGS) at high MTX concentration that limits the intracellular synthesis rate of methotrexate polyglutamate (MTX-PG). Due to a similar accumulation rate, a longer infusion duration may increase the concentration of MTX-PG and, result in more serious adverse reactions. In this study, we validated this hypothesis.
A549, BEL-7402 and MHCC97H cell lines were treated with MTX at gradient concentrations. Liquid chromatograph-mass spectrometer (UPLC-MS/MS) was used to quantify the intracellular concentration of MTX-PG and the abundance of FPGS and γ-glutamyl hydrolase (GGH). High quality data were used to fit the cell pharmacokinetic model.
Both cell growth inhibition rate and intracellular MTX-PG concentration showed a nonlinear relationship with MTX concentration. The parameter Vmax in the model, which represents the synthesis rate of MTX-PG, showed a strong correlation with the abundance of intracellular FPGS.
According to the model fitting results, it was confirmed that the abundance of FPGS is a decisive factor limiting the synthesis rate of MTX-PG. The proposed hypothesis was verified in this study. In addition, based on the intracellular metabolism, a reasonable explanation was provided for the correlation between the severity of adverse reactions of MTX and infusion time. This study provides a new strategy for the individualized treatment and prediction of efficacy/side effects of MTX. |
| doi_str_mv | 10.1371/journal.pone.0302663 |
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A549, BEL-7402 and MHCC97H cell lines were treated with MTX at gradient concentrations. Liquid chromatograph-mass spectrometer (UPLC-MS/MS) was used to quantify the intracellular concentration of MTX-PG and the abundance of FPGS and γ-glutamyl hydrolase (GGH). High quality data were used to fit the cell pharmacokinetic model.
Both cell growth inhibition rate and intracellular MTX-PG concentration showed a nonlinear relationship with MTX concentration. The parameter Vmax in the model, which represents the synthesis rate of MTX-PG, showed a strong correlation with the abundance of intracellular FPGS.
According to the model fitting results, it was confirmed that the abundance of FPGS is a decisive factor limiting the synthesis rate of MTX-PG. The proposed hypothesis was verified in this study. In addition, based on the intracellular metabolism, a reasonable explanation was provided for the correlation between the severity of adverse reactions of MTX and infusion time. This study provides a new strategy for the individualized treatment and prediction of efficacy/side effects of MTX.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0302663</identifier><identifier>PMID: 38833640</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Abundance ; Acids ; Antimetabolites, Antineoplastic - pharmacokinetics ; Antimetabolites, Antineoplastic - pharmacology ; Biology and Life Sciences ; Cell growth ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cytotoxicity ; Dihydrofolate reductase ; Drug dosages ; Enzymes ; Folic acid ; gamma-Glutamyl Hydrolase - metabolism ; Humans ; Hypotheses ; Immunomodulators ; Intracellular ; Liver cancer ; Mass spectrometry ; Medicine and Health Sciences ; Metabolism ; Metabolites ; Methotrexate ; Methotrexate - analogs & derivatives ; Methotrexate - pharmacokinetics ; Peptide Synthases - metabolism ; Peptides ; Pharmacokinetics ; Physical Sciences ; Polyglutamic Acid - analogs & derivatives ; Proteins ; Scientific imaging ; Side effects ; Synthesis ; Tandem Mass Spectrometry ; Toxicity ; Tumor cells ; Vitamin B</subject><ispartof>PloS one, 2024-06, Vol.19 (6), p.e0302663-e0302663</ispartof><rights>Copyright: © 2024 Tang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</rights><rights>2024 Tang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2024 Tang et al 2024 Tang et al</rights><rights>2024 Tang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c406t-4fc0c03569ad49a502cd74c95e301e8c839998a5d287634334ac1f164c49fc623</cites><orcidid>0000-0001-6417-522X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11149982/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11149982/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38833640$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tang, Fang</creatorcontrib><creatorcontrib>Zou, Le</creatorcontrib><creatorcontrib>Chen, Jingyao</creatorcontrib><creatorcontrib>Meng, Fanqi</creatorcontrib><title>Cellular pharmacokinetic of methotrexate and its modulation by folylpolyglutamate synthetase and γ-glutamyl hydrolase in tumor cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Clinical studies showed that prolonged infusion of methotrexate (MTX) leads to more severe adverse reactions than short infusion of MTX at the same dose. We hypothesized that it is the saturation of folate polyglutamate synthetase (FPGS) at high MTX concentration that limits the intracellular synthesis rate of methotrexate polyglutamate (MTX-PG). Due to a similar accumulation rate, a longer infusion duration may increase the concentration of MTX-PG and, result in more serious adverse reactions. In this study, we validated this hypothesis.
A549, BEL-7402 and MHCC97H cell lines were treated with MTX at gradient concentrations. Liquid chromatograph-mass spectrometer (UPLC-MS/MS) was used to quantify the intracellular concentration of MTX-PG and the abundance of FPGS and γ-glutamyl hydrolase (GGH). High quality data were used to fit the cell pharmacokinetic model.
Both cell growth inhibition rate and intracellular MTX-PG concentration showed a nonlinear relationship with MTX concentration. The parameter Vmax in the model, which represents the synthesis rate of MTX-PG, showed a strong correlation with the abundance of intracellular FPGS.
According to the model fitting results, it was confirmed that the abundance of FPGS is a decisive factor limiting the synthesis rate of MTX-PG. The proposed hypothesis was verified in this study. In addition, based on the intracellular metabolism, a reasonable explanation was provided for the correlation between the severity of adverse reactions of MTX and infusion time. This study provides a new strategy for the individualized treatment and prediction of efficacy/side effects of MTX.</description><subject>Abundance</subject><subject>Acids</subject><subject>Antimetabolites, Antineoplastic - pharmacokinetics</subject><subject>Antimetabolites, Antineoplastic - pharmacology</subject><subject>Biology and Life Sciences</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Cytotoxicity</subject><subject>Dihydrofolate reductase</subject><subject>Drug dosages</subject><subject>Enzymes</subject><subject>Folic acid</subject><subject>gamma-Glutamyl Hydrolase - metabolism</subject><subject>Humans</subject><subject>Hypotheses</subject><subject>Immunomodulators</subject><subject>Intracellular</subject><subject>Liver cancer</subject><subject>Mass spectrometry</subject><subject>Medicine and Health Sciences</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Methotrexate</subject><subject>Methotrexate - analogs & derivatives</subject><subject>Methotrexate - pharmacokinetics</subject><subject>Peptide Synthases - metabolism</subject><subject>Peptides</subject><subject>Pharmacokinetics</subject><subject>Physical Sciences</subject><subject>Polyglutamic Acid - analogs & derivatives</subject><subject>Proteins</subject><subject>Scientific imaging</subject><subject>Side effects</subject><subject>Synthesis</subject><subject>Tandem Mass Spectrometry</subject><subject>Toxicity</subject><subject>Tumor cells</subject><subject>Vitamin B</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNptUsFu1DAQjRCIlsIfILDEhUsWO-M49gmhVYFKlbjA2Zo6zm4WJ15sB5EP4Iv4j34TTndbtYiLbXneezNv9IriJaMrBg17t_NTGNGt9n60Kwq0EgIeFadMQVWKisLje--T4lmMO0prkEI8LU5ASgDB6Wnxe22dmxwGst9iGND47_1oU2-I78hg09anYH9hsgTHlvQpksG3GZ96P5KrmXTezW6fj42bEg4LMM5j2tqE8cC5_lMearMj27kN3i2VfiRpGnwgJvePz4snHbpoXxzvs-Lbx_Ov68_l5ZdPF-sPl6XhVKSSd4YaCrVQ2HKFNa1M23CjaguUWWkkKKUk1m0lGwEcgKNhHRPccNUZUcFZ8fqgu3c-6uMGowYqVNVQaGRGXBwQrced3od-wDBrj72--fBhozHk9TirQZoqqzOTudxWKBvKWomdao0AkCprvT92m64G2xo7poDugejDythv9cb_1Iwxno0s8749KgT_Y7Ix6aGPy8ZwtH66GZyritaqztA3_0D_b48fUCb4GIPt7qZhVC-xumXpJVb6GKtMe3XfyR3pNkfwFx37zs8</recordid><startdate>20240604</startdate><enddate>20240604</enddate><creator>Tang, Fang</creator><creator>Zou, Le</creator><creator>Chen, Jingyao</creator><creator>Meng, Fanqi</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0001-6417-522X</orcidid></search><sort><creationdate>20240604</creationdate><title>Cellular pharmacokinetic of methotrexate and its modulation by folylpolyglutamate synthetase and γ-glutamyl hydrolase in tumor cells</title><author>Tang, Fang ; Zou, Le ; Chen, Jingyao ; Meng, Fanqi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c406t-4fc0c03569ad49a502cd74c95e301e8c839998a5d287634334ac1f164c49fc623</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Abundance</topic><topic>Acids</topic><topic>Antimetabolites, Antineoplastic - pharmacokinetics</topic><topic>Antimetabolites, Antineoplastic - pharmacology</topic><topic>Biology and Life Sciences</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Cytotoxicity</topic><topic>Dihydrofolate reductase</topic><topic>Drug dosages</topic><topic>Enzymes</topic><topic>Folic acid</topic><topic>gamma-Glutamyl Hydrolase - metabolism</topic><topic>Humans</topic><topic>Hypotheses</topic><topic>Immunomodulators</topic><topic>Intracellular</topic><topic>Liver cancer</topic><topic>Mass spectrometry</topic><topic>Medicine and Health Sciences</topic><topic>Metabolism</topic><topic>Metabolites</topic><topic>Methotrexate</topic><topic>Methotrexate - analogs & derivatives</topic><topic>Methotrexate - pharmacokinetics</topic><topic>Peptide Synthases - metabolism</topic><topic>Peptides</topic><topic>Pharmacokinetics</topic><topic>Physical Sciences</topic><topic>Polyglutamic Acid - analogs & derivatives</topic><topic>Proteins</topic><topic>Scientific imaging</topic><topic>Side effects</topic><topic>Synthesis</topic><topic>Tandem Mass Spectrometry</topic><topic>Toxicity</topic><topic>Tumor cells</topic><topic>Vitamin B</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tang, Fang</creatorcontrib><creatorcontrib>Zou, Le</creatorcontrib><creatorcontrib>Chen, Jingyao</creatorcontrib><creatorcontrib>Meng, Fanqi</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tang, Fang</au><au>Zou, Le</au><au>Chen, Jingyao</au><au>Meng, Fanqi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cellular pharmacokinetic of methotrexate and its modulation by folylpolyglutamate synthetase and γ-glutamyl hydrolase in tumor cells</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2024-06-04</date><risdate>2024</risdate><volume>19</volume><issue>6</issue><spage>e0302663</spage><epage>e0302663</epage><pages>e0302663-e0302663</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Clinical studies showed that prolonged infusion of methotrexate (MTX) leads to more severe adverse reactions than short infusion of MTX at the same dose. We hypothesized that it is the saturation of folate polyglutamate synthetase (FPGS) at high MTX concentration that limits the intracellular synthesis rate of methotrexate polyglutamate (MTX-PG). Due to a similar accumulation rate, a longer infusion duration may increase the concentration of MTX-PG and, result in more serious adverse reactions. In this study, we validated this hypothesis.
A549, BEL-7402 and MHCC97H cell lines were treated with MTX at gradient concentrations. Liquid chromatograph-mass spectrometer (UPLC-MS/MS) was used to quantify the intracellular concentration of MTX-PG and the abundance of FPGS and γ-glutamyl hydrolase (GGH). High quality data were used to fit the cell pharmacokinetic model.
Both cell growth inhibition rate and intracellular MTX-PG concentration showed a nonlinear relationship with MTX concentration. The parameter Vmax in the model, which represents the synthesis rate of MTX-PG, showed a strong correlation with the abundance of intracellular FPGS.
According to the model fitting results, it was confirmed that the abundance of FPGS is a decisive factor limiting the synthesis rate of MTX-PG. The proposed hypothesis was verified in this study. In addition, based on the intracellular metabolism, a reasonable explanation was provided for the correlation between the severity of adverse reactions of MTX and infusion time. This study provides a new strategy for the individualized treatment and prediction of efficacy/side effects of MTX.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>38833640</pmid><doi>10.1371/journal.pone.0302663</doi><orcidid>https://orcid.org/0000-0001-6417-522X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Abundance Acids Antimetabolites, Antineoplastic - pharmacokinetics Antimetabolites, Antineoplastic - pharmacology Biology and Life Sciences Cell growth Cell Line, Tumor Cell Proliferation - drug effects Cytotoxicity Dihydrofolate reductase Drug dosages Enzymes Folic acid gamma-Glutamyl Hydrolase - metabolism Humans Hypotheses Immunomodulators Intracellular Liver cancer Mass spectrometry Medicine and Health Sciences Metabolism Metabolites Methotrexate Methotrexate - analogs & derivatives Methotrexate - pharmacokinetics Peptide Synthases - metabolism Peptides Pharmacokinetics Physical Sciences Polyglutamic Acid - analogs & derivatives Proteins Scientific imaging Side effects Synthesis Tandem Mass Spectrometry Toxicity Tumor cells Vitamin B |
| title | Cellular pharmacokinetic of methotrexate and its modulation by folylpolyglutamate synthetase and γ-glutamyl hydrolase in tumor cells |
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