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Pharmacogenetic determinants of mercaptopurine disposition in children with acute lymphoblastic leukemia
Background The backbone of drug therapy used in acute lymphoblastic leukemia (ALL) in children includes 6-mercaptopurine (6-MP). Intracellular metabolism of this prodrug is a key component of the therapeutic response. Many metabolizing enzymes are involved in 6-MP disposition and active 6-MP metabol...
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| Published in: | European journal of clinical pharmacology 2012-09, Vol.68 (9), p.1233-1242 |
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| container_issue | 9 |
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| container_title | European journal of clinical pharmacology |
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| creator | Adam de Beaumais, Tiphaine Jacqz-Aigrain, Evelyne |
| description | Background
The backbone of drug therapy used in acute lymphoblastic leukemia (ALL) in children includes 6-mercaptopurine (6-MP). Intracellular metabolism of this prodrug is a key component of the therapeutic response. Many metabolizing enzymes are involved in 6-MP disposition and active 6-MP metabolites are represented by 6-thioguanine nucleotides (6-TGN) and methylated metabolites primarily methylated by the thiopurine S-methyltransferase enzyme (TPMT). The genetic polymorphism affecting TPMT activity displays an important inter-subject variability in metabolites pharmacokinetics and influences the balance between 6-MP efficacy and toxicity: patients with high 6-TGN levels are at risk of myelosuppression while patients with high levels of methylated derivates are at hepatotoxic risk. However, the genetic TPMT polymorphism does not explain all 6-MP adverse events and some severe toxicities leading to life-threatening conditions remain unexplained. Additional single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in 6-MP metabolism and 6-MP transporters may also be responsible for this inter-individual 6-MP response variability.
Aim
This review presents the pharmacogenetic aspects of 6-MP metabolism in great detail. We have focused on published data on ALL treatment supporting the great potential of 6-MP pharmacogenetics to improve efficacy, tolerance, and event-free survival rates in children with ALL. |
| doi_str_mv | 10.1007/s00228-012-1251-4 |
| format | article |
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The backbone of drug therapy used in acute lymphoblastic leukemia (ALL) in children includes 6-mercaptopurine (6-MP). Intracellular metabolism of this prodrug is a key component of the therapeutic response. Many metabolizing enzymes are involved in 6-MP disposition and active 6-MP metabolites are represented by 6-thioguanine nucleotides (6-TGN) and methylated metabolites primarily methylated by the thiopurine S-methyltransferase enzyme (TPMT). The genetic polymorphism affecting TPMT activity displays an important inter-subject variability in metabolites pharmacokinetics and influences the balance between 6-MP efficacy and toxicity: patients with high 6-TGN levels are at risk of myelosuppression while patients with high levels of methylated derivates are at hepatotoxic risk. However, the genetic TPMT polymorphism does not explain all 6-MP adverse events and some severe toxicities leading to life-threatening conditions remain unexplained. Additional single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in 6-MP metabolism and 6-MP transporters may also be responsible for this inter-individual 6-MP response variability.
Aim
This review presents the pharmacogenetic aspects of 6-MP metabolism in great detail. We have focused on published data on ALL treatment supporting the great potential of 6-MP pharmacogenetics to improve efficacy, tolerance, and event-free survival rates in children with ALL.</description><identifier>ISSN: 0031-6970</identifier><identifier>EISSN: 1432-1041</identifier><identifier>DOI: 10.1007/s00228-012-1251-4</identifier><identifier>PMID: 22421815</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer-Verlag</publisher><subject>Age Factors ; Antimetabolites, Antineoplastic - adverse effects ; Antimetabolites, Antineoplastic - pharmacokinetics ; Biological and medical sciences ; Biomedical and Life Sciences ; Biomedicine ; Biotransformation - genetics ; Child ; Drug therapy ; Genetics ; Genotype ; Hematologic and hematopoietic diseases ; Humans ; Leukemia ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Medical sciences ; Mercaptopurine - adverse effects ; Mercaptopurine - pharmacokinetics ; Pediatrics ; Pharmacogenetics ; Pharmacology ; Pharmacology. Drug treatments ; Pharmacology/Toxicology ; Phenotype ; Polymorphism, Single Nucleotide ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism ; Review Article</subject><ispartof>European journal of clinical pharmacology, 2012-09, Vol.68 (9), p.1233-1242</ispartof><rights>Springer-Verlag 2012</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c435t-1a265dde82e4a06031a7387b8f4f2c9edece35dce8e48f87392552c1c64177533</citedby><cites>FETCH-LOGICAL-c435t-1a265dde82e4a06031a7387b8f4f2c9edece35dce8e48f87392552c1c64177533</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26238512$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22421815$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Adam de Beaumais, Tiphaine</creatorcontrib><creatorcontrib>Jacqz-Aigrain, Evelyne</creatorcontrib><title>Pharmacogenetic determinants of mercaptopurine disposition in children with acute lymphoblastic leukemia</title><title>European journal of clinical pharmacology</title><addtitle>Eur J Clin Pharmacol</addtitle><addtitle>Eur J Clin Pharmacol</addtitle><description>Background
The backbone of drug therapy used in acute lymphoblastic leukemia (ALL) in children includes 6-mercaptopurine (6-MP). Intracellular metabolism of this prodrug is a key component of the therapeutic response. Many metabolizing enzymes are involved in 6-MP disposition and active 6-MP metabolites are represented by 6-thioguanine nucleotides (6-TGN) and methylated metabolites primarily methylated by the thiopurine S-methyltransferase enzyme (TPMT). The genetic polymorphism affecting TPMT activity displays an important inter-subject variability in metabolites pharmacokinetics and influences the balance between 6-MP efficacy and toxicity: patients with high 6-TGN levels are at risk of myelosuppression while patients with high levels of methylated derivates are at hepatotoxic risk. However, the genetic TPMT polymorphism does not explain all 6-MP adverse events and some severe toxicities leading to life-threatening conditions remain unexplained. Additional single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in 6-MP metabolism and 6-MP transporters may also be responsible for this inter-individual 6-MP response variability.
Aim
This review presents the pharmacogenetic aspects of 6-MP metabolism in great detail. We have focused on published data on ALL treatment supporting the great potential of 6-MP pharmacogenetics to improve efficacy, tolerance, and event-free survival rates in children with ALL.</description><subject>Age Factors</subject><subject>Antimetabolites, Antineoplastic - adverse effects</subject><subject>Antimetabolites, Antineoplastic - pharmacokinetics</subject><subject>Biological and medical sciences</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Biotransformation - genetics</subject><subject>Child</subject><subject>Drug therapy</subject><subject>Genetics</subject><subject>Genotype</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Humans</subject><subject>Leukemia</subject><subject>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</subject><subject>Medical sciences</subject><subject>Mercaptopurine - adverse effects</subject><subject>Mercaptopurine - pharmacokinetics</subject><subject>Pediatrics</subject><subject>Pharmacogenetics</subject><subject>Pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Pharmacology/Toxicology</subject><subject>Phenotype</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy</subject><subject>Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism</subject><subject>Review Article</subject><issn>0031-6970</issn><issn>1432-1041</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><recordid>eNp10UuLFDEQB_AgijuufgAvEhDBS2sqj07mKIsvWNCDnkMmXb2dtTtpkzSy394MMz4QPIWQX1Uq-RPyFNgrYEy_LoxxbjoGvAOuoJP3yA6kaDsm4T7ZMSag6_eaXZBHpdwyBmrPxENywbnkYEDtyPR5cnlxPt1gxBo8HbBiXkJ0sRaaRrpg9m6tad1yiEiHUNZUQg0p0hCpn8I8ZIz0R6gTdX6rSOe7ZZ3SYXbl2G_G7RsuwT0mD0Y3F3xyXi_J13dvv1x96K4_vf949ea681Ko2oHjvRoGNBylY317gNPC6IMZ5cj9Hgf0KNTg0aA0o9Fiz5XiHnwvQWslxCV5eeq75vR9w1LtEorHeXYR01YsNCT7HnTf6PN_6G3acmzTWWBC89aPm6bgpHxOpWQc7ZrD4vJdQ_YYgz3FYFsM9hiDla3m2bnzdlhw-F3x698beHEGrng3j9lFH8of13NhFPDm-MmVdhRvMP894v9u_wnK2aB3</recordid><startdate>20120901</startdate><enddate>20120901</enddate><creator>Adam de Beaumais, Tiphaine</creator><creator>Jacqz-Aigrain, Evelyne</creator><general>Springer-Verlag</general><general>Springer</general><general>Springer Nature B.V</general><scope>IQODW</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>3V.</scope><scope>7RV</scope><scope>7TK</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20120901</creationdate><title>Pharmacogenetic determinants of mercaptopurine disposition in children with acute lymphoblastic leukemia</title><author>Adam de Beaumais, Tiphaine ; Jacqz-Aigrain, Evelyne</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c435t-1a265dde82e4a06031a7387b8f4f2c9edece35dce8e48f87392552c1c64177533</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Age Factors</topic><topic>Antimetabolites, Antineoplastic - adverse effects</topic><topic>Antimetabolites, Antineoplastic - pharmacokinetics</topic><topic>Biological and medical sciences</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Biotransformation - genetics</topic><topic>Child</topic><topic>Drug therapy</topic><topic>Genetics</topic><topic>Genotype</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Humans</topic><topic>Leukemia</topic><topic>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</topic><topic>Medical sciences</topic><topic>Mercaptopurine - adverse effects</topic><topic>Mercaptopurine - pharmacokinetics</topic><topic>Pediatrics</topic><topic>Pharmacogenetics</topic><topic>Pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Pharmacology/Toxicology</topic><topic>Phenotype</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy</topic><topic>Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism</topic><topic>Review Article</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Adam de Beaumais, Tiphaine</creatorcontrib><creatorcontrib>Jacqz-Aigrain, Evelyne</creatorcontrib><collection>Pascal-Francis</collection><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>ProQuest Nursing and Allied Health Journals</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</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>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>European journal of clinical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Adam de Beaumais, Tiphaine</au><au>Jacqz-Aigrain, Evelyne</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacogenetic determinants of mercaptopurine disposition in children with acute lymphoblastic leukemia</atitle><jtitle>European journal of clinical pharmacology</jtitle><stitle>Eur J Clin Pharmacol</stitle><addtitle>Eur J Clin Pharmacol</addtitle><date>2012-09-01</date><risdate>2012</risdate><volume>68</volume><issue>9</issue><spage>1233</spage><epage>1242</epage><pages>1233-1242</pages><issn>0031-6970</issn><eissn>1432-1041</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Background
The backbone of drug therapy used in acute lymphoblastic leukemia (ALL) in children includes 6-mercaptopurine (6-MP). Intracellular metabolism of this prodrug is a key component of the therapeutic response. Many metabolizing enzymes are involved in 6-MP disposition and active 6-MP metabolites are represented by 6-thioguanine nucleotides (6-TGN) and methylated metabolites primarily methylated by the thiopurine S-methyltransferase enzyme (TPMT). The genetic polymorphism affecting TPMT activity displays an important inter-subject variability in metabolites pharmacokinetics and influences the balance between 6-MP efficacy and toxicity: patients with high 6-TGN levels are at risk of myelosuppression while patients with high levels of methylated derivates are at hepatotoxic risk. However, the genetic TPMT polymorphism does not explain all 6-MP adverse events and some severe toxicities leading to life-threatening conditions remain unexplained. Additional single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in 6-MP metabolism and 6-MP transporters may also be responsible for this inter-individual 6-MP response variability.
Aim
This review presents the pharmacogenetic aspects of 6-MP metabolism in great detail. We have focused on published data on ALL treatment supporting the great potential of 6-MP pharmacogenetics to improve efficacy, tolerance, and event-free survival rates in children with ALL.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer-Verlag</pub><pmid>22421815</pmid><doi>10.1007/s00228-012-1251-4</doi><tpages>10</tpages></addata></record> |
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| subjects | Age Factors Antimetabolites, Antineoplastic - adverse effects Antimetabolites, Antineoplastic - pharmacokinetics Biological and medical sciences Biomedical and Life Sciences Biomedicine Biotransformation - genetics Child Drug therapy Genetics Genotype Hematologic and hematopoietic diseases Humans Leukemia Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Medical sciences Mercaptopurine - adverse effects Mercaptopurine - pharmacokinetics Pediatrics Pharmacogenetics Pharmacology Pharmacology. Drug treatments Pharmacology/Toxicology Phenotype Polymorphism, Single Nucleotide Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism Review Article |
| title | Pharmacogenetic determinants of mercaptopurine disposition in children with acute lymphoblastic leukemia |
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