Characterization of in vitro and in vivo hypomethylating effects of decitabine in acute myeloid leukemia by a rapid, specific and sensitive LC-MS/MS method
DNA hypermethylation is a common finding in malignant cells and has been explored as a therapeutic target for hypomethylating agents (e.g., decitabine). Detection of changes in DNA methylation might serve as a pharmacodynamic endpoint to establish the biological activity of these agents and predict...
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| Veröffentlicht in: | Nucleic acids research 2007-03, Vol.35 (5), p.e31-e31 |
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| creator | Liu, Zhongfa Liu, Shujun Xie, Zhiliang Blum, William Perrotti, Danilo Paschka, Peter Klisovic, Rebecca Byrd, John Chan, Kenneth K Marcucci, Guido |
| description | DNA hypermethylation is a common finding in malignant cells and has been explored as a therapeutic target for hypomethylating agents (e.g., decitabine). Detection of changes in DNA methylation might serve as a pharmacodynamic endpoint to establish the biological activity of these agents and predict clinical response. We developed and validated a rapid, sensitive and specific LC-MS/MS method for determination of global DNA methylation (GDM) in vitro and in vivo. Ratios of 5-methyl-2'-deoxycytidine (5mdC) to the internal standard 2-deoxyguanosine (2dG) in mass signal were used to quantify GDM levels. The assay was validated in a linear range from 40 fmol to 200 pmol 5mdC. The intra-day precision values ranged from 2.8 to 9.9% and the inter-day values from 1.1 to 15.0%. The accuracy of the assay varied between 96.7 and 109.5%. This method was initially applied for characterization of decitabine-induced GDM changes in in-vitro-treated leukemia cells. Following exposure to 2.5 μM decitabine, GDM decreased to ~50% of the baseline value. The clinical applicability of this method was then demonstrated in bone marrow samples from patients with acute myeloid leukemia treated with decitabine. Our data support the use of our LC-MS/MS method for clinical pharmacodynamic determination of changes in GDM in vivo. |
| doi_str_mv | 10.1093/nar/gkl1156 |
| format | Article |
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Detection of changes in DNA methylation might serve as a pharmacodynamic endpoint to establish the biological activity of these agents and predict clinical response. We developed and validated a rapid, sensitive and specific LC-MS/MS method for determination of global DNA methylation (GDM) in vitro and in vivo. Ratios of 5-methyl-2'-deoxycytidine (5mdC) to the internal standard 2-deoxyguanosine (2dG) in mass signal were used to quantify GDM levels. The assay was validated in a linear range from 40 fmol to 200 pmol 5mdC. The intra-day precision values ranged from 2.8 to 9.9% and the inter-day values from 1.1 to 15.0%. The accuracy of the assay varied between 96.7 and 109.5%. This method was initially applied for characterization of decitabine-induced GDM changes in in-vitro-treated leukemia cells. Following exposure to 2.5 μM decitabine, GDM decreased to ~50% of the baseline value. The clinical applicability of this method was then demonstrated in bone marrow samples from patients with acute myeloid leukemia treated with decitabine. Our data support the use of our LC-MS/MS method for clinical pharmacodynamic determination of changes in GDM in vivo.</description><identifier>ISSN: 0305-1048</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gkl1156</identifier><identifier>PMID: 17264127</identifier><identifier>CODEN: NARHAD</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Acute Disease ; Antimetabolites, Antineoplastic - pharmacology ; Antimetabolites, Antineoplastic - therapeutic use ; Azacitidine - analogs & derivatives ; Azacitidine - pharmacology ; Azacitidine - therapeutic use ; Cell Line, Tumor ; Chromatography, Liquid - methods ; Clinical Trials, Phase I as Topic ; Decitabine ; Deoxycytidine - analogs & derivatives ; Deoxycytidine - analysis ; Deoxyguanosine - analysis ; DNA (Cytosine-5-)-Methyltransferase 1 ; DNA (Cytosine-5-)-Methyltransferases - metabolism ; DNA Methylation - drug effects ; Humans ; Leukemia, Myeloid - drug therapy ; Leukemia, Myeloid - enzymology ; Leukemia, Myeloid - genetics ; Methods Online ; Tandem Mass Spectrometry - methods</subject><ispartof>Nucleic acids research, 2007-03, Vol.35 (5), p.e31-e31</ispartof><rights>2007 The Author(s). 2007</rights><rights>Copyright Oxford University Press(England) Mar 2007</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c492t-ccd39d0f50101ea4654e0b04ffc904c45d426d7d40c509db3ef67e2453573b1e3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1865075/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1865075/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,1604,27924,27925,53791,53793</link.rule.ids><linktorsrc>$$Uhttps://dx.doi.org/10.1093/nar/gkl1156$$EView_record_in_Oxford_University_Press$$FView_record_in_$$GOxford_University_Press</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17264127$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Zhongfa</creatorcontrib><creatorcontrib>Liu, Shujun</creatorcontrib><creatorcontrib>Xie, Zhiliang</creatorcontrib><creatorcontrib>Blum, William</creatorcontrib><creatorcontrib>Perrotti, Danilo</creatorcontrib><creatorcontrib>Paschka, Peter</creatorcontrib><creatorcontrib>Klisovic, Rebecca</creatorcontrib><creatorcontrib>Byrd, John</creatorcontrib><creatorcontrib>Chan, Kenneth K</creatorcontrib><creatorcontrib>Marcucci, Guido</creatorcontrib><title>Characterization of in vitro and in vivo hypomethylating effects of decitabine in acute myeloid leukemia by a rapid, specific and sensitive LC-MS/MS method</title><title>Nucleic acids research</title><addtitle>Nucleic Acids Res</addtitle><description>DNA hypermethylation is a common finding in malignant cells and has been explored as a therapeutic target for hypomethylating agents (e.g., decitabine). Detection of changes in DNA methylation might serve as a pharmacodynamic endpoint to establish the biological activity of these agents and predict clinical response. We developed and validated a rapid, sensitive and specific LC-MS/MS method for determination of global DNA methylation (GDM) in vitro and in vivo. Ratios of 5-methyl-2'-deoxycytidine (5mdC) to the internal standard 2-deoxyguanosine (2dG) in mass signal were used to quantify GDM levels. The assay was validated in a linear range from 40 fmol to 200 pmol 5mdC. The intra-day precision values ranged from 2.8 to 9.9% and the inter-day values from 1.1 to 15.0%. The accuracy of the assay varied between 96.7 and 109.5%. This method was initially applied for characterization of decitabine-induced GDM changes in in-vitro-treated leukemia cells. Following exposure to 2.5 μM decitabine, GDM decreased to ~50% of the baseline value. The clinical applicability of this method was then demonstrated in bone marrow samples from patients with acute myeloid leukemia treated with decitabine. Our data support the use of our LC-MS/MS method for clinical pharmacodynamic determination of changes in GDM in vivo.</description><subject>Acute Disease</subject><subject>Antimetabolites, Antineoplastic - pharmacology</subject><subject>Antimetabolites, Antineoplastic - therapeutic use</subject><subject>Azacitidine - analogs & derivatives</subject><subject>Azacitidine - pharmacology</subject><subject>Azacitidine - therapeutic use</subject><subject>Cell Line, Tumor</subject><subject>Chromatography, Liquid - methods</subject><subject>Clinical Trials, Phase I as Topic</subject><subject>Decitabine</subject><subject>Deoxycytidine - analogs & derivatives</subject><subject>Deoxycytidine - analysis</subject><subject>Deoxyguanosine - analysis</subject><subject>DNA (Cytosine-5-)-Methyltransferase 1</subject><subject>DNA (Cytosine-5-)-Methyltransferases - metabolism</subject><subject>DNA Methylation - drug effects</subject><subject>Humans</subject><subject>Leukemia, Myeloid - drug therapy</subject><subject>Leukemia, Myeloid - enzymology</subject><subject>Leukemia, Myeloid - genetics</subject><subject>Methods Online</subject><subject>Tandem Mass Spectrometry - methods</subject><issn>0305-1048</issn><issn>1362-4962</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUuP0zAUhSMEYsrAij1YLNhAqB0_0myQUMVL6ohFmbXl2NetZxI72E6l8Ff4s6S0YoANqyvrfj7nXJ2ieErwG4IbuvQqLne3HSFc3CsWhIqqZI2o7hcLTDEvCWari-JRSjcYE0Y4e1hckLoSjFT1ovix3quodIbovqvsgkfBIufRweUYkPLm9DgEtJ-G0EPeT93M-R0Ca0HndOQNaJdV6zwcaaXHDKifoAvOoA7GW-idQu2EFIpqcOY1SsP8wzr9yyCBTy67A6DNurzaLq-26OgTzOPigVVdgifneVlcf3j_df2p3Hz5-Hn9blNq1lS51NrQxmDLMcEEFBOcAW4xs1Y3mGnGDauEqQ3DmuPGtBSsqKFinPKatgToZfH2pDuMbQ9Gg89RdXKIrldxkkE5-ffGu73chYMkK8FxzWeBl2eBGL6NkLLsXdLQdcpDGJMkjeCzF53BF_-AN2GMfj5OVhiLatVQMkOvTpCOIaUI9ncSguWxcTk3Ls-Nz_SzP8PfseeK78KFcfiP0vMTaFWQahddktfbChOKcS1E3dT0J5JbwJs</recordid><startdate>200703</startdate><enddate>200703</enddate><creator>Liu, Zhongfa</creator><creator>Liu, Shujun</creator><creator>Xie, Zhiliang</creator><creator>Blum, William</creator><creator>Perrotti, Danilo</creator><creator>Paschka, Peter</creator><creator>Klisovic, Rebecca</creator><creator>Byrd, John</creator><creator>Chan, Kenneth K</creator><creator>Marcucci, Guido</creator><general>Oxford University Press</general><general>Oxford Publishing Limited (England)</general><scope>FBQ</scope><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>7QL</scope><scope>7QO</scope><scope>7QP</scope><scope>7QR</scope><scope>7SS</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>200703</creationdate><title>Characterization of in vitro and in vivo hypomethylating effects of decitabine in acute myeloid leukemia by a rapid, specific and sensitive LC-MS/MS method</title><author>Liu, Zhongfa ; 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Detection of changes in DNA methylation might serve as a pharmacodynamic endpoint to establish the biological activity of these agents and predict clinical response. We developed and validated a rapid, sensitive and specific LC-MS/MS method for determination of global DNA methylation (GDM) in vitro and in vivo. Ratios of 5-methyl-2'-deoxycytidine (5mdC) to the internal standard 2-deoxyguanosine (2dG) in mass signal were used to quantify GDM levels. The assay was validated in a linear range from 40 fmol to 200 pmol 5mdC. The intra-day precision values ranged from 2.8 to 9.9% and the inter-day values from 1.1 to 15.0%. The accuracy of the assay varied between 96.7 and 109.5%. This method was initially applied for characterization of decitabine-induced GDM changes in in-vitro-treated leukemia cells. Following exposure to 2.5 μM decitabine, GDM decreased to ~50% of the baseline value. The clinical applicability of this method was then demonstrated in bone marrow samples from patients with acute myeloid leukemia treated with decitabine. Our data support the use of our LC-MS/MS method for clinical pharmacodynamic determination of changes in GDM in vivo.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>17264127</pmid><doi>10.1093/nar/gkl1156</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Acute Disease Antimetabolites, Antineoplastic - pharmacology Antimetabolites, Antineoplastic - therapeutic use Azacitidine - analogs & derivatives Azacitidine - pharmacology Azacitidine - therapeutic use Cell Line, Tumor Chromatography, Liquid - methods Clinical Trials, Phase I as Topic Decitabine Deoxycytidine - analogs & derivatives Deoxycytidine - analysis Deoxyguanosine - analysis DNA (Cytosine-5-)-Methyltransferase 1 DNA (Cytosine-5-)-Methyltransferases - metabolism DNA Methylation - drug effects Humans Leukemia, Myeloid - drug therapy Leukemia, Myeloid - enzymology Leukemia, Myeloid - genetics Methods Online Tandem Mass Spectrometry - methods |
| title | Characterization of in vitro and in vivo hypomethylating effects of decitabine in acute myeloid leukemia by a rapid, specific and sensitive LC-MS/MS method |
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