Should TPMT genotype and activity be used to monitor 6-mercaptopurine treatment in children with acute lymphoblastic leukaemia?
Summary Background and objective: The activity of thiopurine S‐methyltransferase (TPMT), a key enzyme in the metabolism of purine analogues, displays wide inter‐subject variability partly due to a genetic polymorphism. Previous studies have suggested adjusting purine analogues dosing according to T...
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| Veröffentlicht in: | Journal of clinical pharmacy and therapeutics 2007-12, Vol.32 (6), p.633-639 |
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| creator | Fakhoury, M. Andreu-Gallien, J. Mahr, A. Medard, Y. Azougagh, S. Vilmer, E. Jacqz-Aigrain, E. |
| description | Summary
Background and objective: The activity of thiopurine S‐methyltransferase (TPMT), a key enzyme in the metabolism of purine analogues, displays wide inter‐subject variability partly due to a genetic polymorphism. Previous studies have suggested adjusting purine analogues dosing according to TPMT activity but measurements are costly and time‐consuming. It is still unclear, especially under treatment, whether the simpler TPMT genotyping reliably predicts enzyme activity. Our aim was to study the possible correlation of TPMT genotype with phenotype.
Methods: We determined the genotypic status and TMPT activity, at diagnosis and after 6 months of maintenance therapy, of 118 children with acute lymphoblastic leukaemia (ALL).
Results and Discussion: Eighty‐nine per cent of the children had a homozygous wild‐type genotype (group 1), 11% had one or two mutant allele(s) (group 2). At both time points, TPMT activity (U/mL peripheral red blood cell) was significantly higher in group 1 than in group 2 (P |
| doi_str_mv | 10.1111/j.1365-2710.2007.00858.x |
| format | Article |
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Background and objective: The activity of thiopurine S‐methyltransferase (TPMT), a key enzyme in the metabolism of purine analogues, displays wide inter‐subject variability partly due to a genetic polymorphism. Previous studies have suggested adjusting purine analogues dosing according to TPMT activity but measurements are costly and time‐consuming. It is still unclear, especially under treatment, whether the simpler TPMT genotyping reliably predicts enzyme activity. Our aim was to study the possible correlation of TPMT genotype with phenotype.
Methods: We determined the genotypic status and TMPT activity, at diagnosis and after 6 months of maintenance therapy, of 118 children with acute lymphoblastic leukaemia (ALL).
Results and Discussion: Eighty‐nine per cent of the children had a homozygous wild‐type genotype (group 1), 11% had one or two mutant allele(s) (group 2). At both time points, TPMT activity (U/mL peripheral red blood cell) was significantly higher in group 1 than in group 2 (P < 0·001) but inter‐group levels overlapped considerably. There was considerable heterogeneity in the percentage increase in TPMT activity after therapy, and little correlation between metabolites ratio [6‐methylmercaptopurine derivative/6‐thioguanine nucleotides (6‐TGN)] and TPMT activity at the end of 6 months’ maintenance treatment. These results show that TPMT activity cannot be used as an accurate tool for 6‐mercaptopurine monitoring.
Conclusion: Genotyping at diagnosis identifies patients with a homozygous mutant TPMT and may prevent severe and life‐threatening toxicity. ALL treatment monitoring should preferentially be based on repeated determinations of intracellular active metabolites (6‐TGN) and methylated metabolites.</description><identifier>ISSN: 0269-4727</identifier><identifier>EISSN: 1365-2710</identifier><identifier>DOI: 10.1111/j.1365-2710.2007.00858.x</identifier><identifier>PMID: 18021342</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>6-mercaptopurine ; acute lymphoblastic leukaemia ; Adolescent ; Antimetabolites, Antineoplastic - therapeutic use ; Biological and medical sciences ; Child ; Child, Preschool ; Erythrocytes - enzymology ; Female ; Genotype ; Hematologic and hematopoietic diseases ; Humans ; Infant ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Male ; Medical sciences ; Mercaptopurine - metabolism ; Mercaptopurine - therapeutic use ; Methyltransferases - genetics ; Methyltransferases - metabolism ; pharmacogenetics ; Pharmacology. Drug treatments ; phenotype ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics ; thiopurine S-methyltransferase</subject><ispartof>Journal of clinical pharmacy and therapeutics, 2007-12, Vol.32 (6), p.633-639</ispartof><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5168-c048e4bdfb5dadfe7ac5839791be701f04837c33587a1fb239ffaf595ce103733</citedby><cites>FETCH-LOGICAL-c5168-c048e4bdfb5dadfe7ac5839791be701f04837c33587a1fb239ffaf595ce103733</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fj.1365-2710.2007.00858.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1365-2710.2007.00858.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1416,27922,27923,45572,45573</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=19866020$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18021342$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fakhoury, M.</creatorcontrib><creatorcontrib>Andreu-Gallien, J.</creatorcontrib><creatorcontrib>Mahr, A.</creatorcontrib><creatorcontrib>Medard, Y.</creatorcontrib><creatorcontrib>Azougagh, S.</creatorcontrib><creatorcontrib>Vilmer, E.</creatorcontrib><creatorcontrib>Jacqz-Aigrain, E.</creatorcontrib><title>Should TPMT genotype and activity be used to monitor 6-mercaptopurine treatment in children with acute lymphoblastic leukaemia?</title><title>Journal of clinical pharmacy and therapeutics</title><addtitle>J Clin Pharm Ther</addtitle><description>Summary
Background and objective: The activity of thiopurine S‐methyltransferase (TPMT), a key enzyme in the metabolism of purine analogues, displays wide inter‐subject variability partly due to a genetic polymorphism. Previous studies have suggested adjusting purine analogues dosing according to TPMT activity but measurements are costly and time‐consuming. It is still unclear, especially under treatment, whether the simpler TPMT genotyping reliably predicts enzyme activity. Our aim was to study the possible correlation of TPMT genotype with phenotype.
Methods: We determined the genotypic status and TMPT activity, at diagnosis and after 6 months of maintenance therapy, of 118 children with acute lymphoblastic leukaemia (ALL).
Results and Discussion: Eighty‐nine per cent of the children had a homozygous wild‐type genotype (group 1), 11% had one or two mutant allele(s) (group 2). At both time points, TPMT activity (U/mL peripheral red blood cell) was significantly higher in group 1 than in group 2 (P < 0·001) but inter‐group levels overlapped considerably. There was considerable heterogeneity in the percentage increase in TPMT activity after therapy, and little correlation between metabolites ratio [6‐methylmercaptopurine derivative/6‐thioguanine nucleotides (6‐TGN)] and TPMT activity at the end of 6 months’ maintenance treatment. These results show that TPMT activity cannot be used as an accurate tool for 6‐mercaptopurine monitoring.
Conclusion: Genotyping at diagnosis identifies patients with a homozygous mutant TPMT and may prevent severe and life‐threatening toxicity. ALL treatment monitoring should preferentially be based on repeated determinations of intracellular active metabolites (6‐TGN) and methylated metabolites.</description><subject>6-mercaptopurine</subject><subject>acute lymphoblastic leukaemia</subject><subject>Adolescent</subject><subject>Antimetabolites, Antineoplastic - therapeutic use</subject><subject>Biological and medical sciences</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Erythrocytes - enzymology</subject><subject>Female</subject><subject>Genotype</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Humans</subject><subject>Infant</subject><subject>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mercaptopurine - metabolism</subject><subject>Mercaptopurine - therapeutic use</subject><subject>Methyltransferases - genetics</subject><subject>Methyltransferases - metabolism</subject><subject>pharmacogenetics</subject><subject>Pharmacology. Drug treatments</subject><subject>phenotype</subject><subject>Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy</subject><subject>Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics</subject><subject>thiopurine S-methyltransferase</subject><issn>0269-4727</issn><issn>1365-2710</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkE1v1DAQhi0EotvCX0C-wC2LHSd2ckAIraAFtbBSF3G0HGfMeut8YDt0c-Kv42VX7RVfbM0874z1IIQpWdJ03u6WlPEyy0Uq5ISIJSFVWS33T9DiofEULUjO66wQuThD5yHsCCFc5Ow5OqMVySkr8gX6c7sdJtfizfpmg39CP8R5BKz6Fisd7W8bZ9wAngK0OA64G3obB4951oHXaozDOHnbA44eVOygj9j2WG-taz30-N7GbZozRcBu7sbt0DgVotXYwXSnoLPq_Qv0zCgX4OXpvkDfP33crK6y62-Xn1cfrjNdUl5lmhQVFE1rmrJVrQGhdFmxWtS0AUGoSW0mNGNlJRQ1Tc5qY5Qp61IDJUwwdoHeHOeOfvg1QYiys0GDc6qHYQoyWUxiGU9gdQS1H0LwYOTobaf8LCmRB_lyJw-O5cHxISbkP_lyn6KvTjumpoP2MXiynYDXJ0AFrZzxqtc2PHJ1xTnJSeLeHbl762D-7w_IL6v1Jr1SPjvmbYiwf8grfye5YKKUP75eSs74uiDVjbxlfwETyLDt</recordid><startdate>200712</startdate><enddate>200712</enddate><creator>Fakhoury, M.</creator><creator>Andreu-Gallien, J.</creator><creator>Mahr, A.</creator><creator>Medard, Y.</creator><creator>Azougagh, S.</creator><creator>Vilmer, E.</creator><creator>Jacqz-Aigrain, E.</creator><general>Blackwell Publishing Ltd</general><general>Blackwell</general><scope>BSCLL</scope><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>7T5</scope><scope>H94</scope></search><sort><creationdate>200712</creationdate><title>Should TPMT genotype and activity be used to monitor 6-mercaptopurine treatment in children with acute lymphoblastic leukaemia?</title><author>Fakhoury, M. ; Andreu-Gallien, J. ; Mahr, A. ; Medard, Y. ; Azougagh, S. ; Vilmer, E. ; Jacqz-Aigrain, E.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5168-c048e4bdfb5dadfe7ac5839791be701f04837c33587a1fb239ffaf595ce103733</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>6-mercaptopurine</topic><topic>acute lymphoblastic leukaemia</topic><topic>Adolescent</topic><topic>Antimetabolites, Antineoplastic - therapeutic use</topic><topic>Biological and medical sciences</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Erythrocytes - enzymology</topic><topic>Female</topic><topic>Genotype</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Humans</topic><topic>Infant</topic><topic>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mercaptopurine - metabolism</topic><topic>Mercaptopurine - therapeutic use</topic><topic>Methyltransferases - genetics</topic><topic>Methyltransferases - metabolism</topic><topic>pharmacogenetics</topic><topic>Pharmacology. Drug treatments</topic><topic>phenotype</topic><topic>Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy</topic><topic>Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics</topic><topic>thiopurine S-methyltransferase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fakhoury, M.</creatorcontrib><creatorcontrib>Andreu-Gallien, J.</creatorcontrib><creatorcontrib>Mahr, A.</creatorcontrib><creatorcontrib>Medard, Y.</creatorcontrib><creatorcontrib>Azougagh, S.</creatorcontrib><creatorcontrib>Vilmer, E.</creatorcontrib><creatorcontrib>Jacqz-Aigrain, E.</creatorcontrib><collection>Istex</collection><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>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>Journal of clinical pharmacy and therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fakhoury, M.</au><au>Andreu-Gallien, J.</au><au>Mahr, A.</au><au>Medard, Y.</au><au>Azougagh, S.</au><au>Vilmer, E.</au><au>Jacqz-Aigrain, E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Should TPMT genotype and activity be used to monitor 6-mercaptopurine treatment in children with acute lymphoblastic leukaemia?</atitle><jtitle>Journal of clinical pharmacy and therapeutics</jtitle><addtitle>J Clin Pharm Ther</addtitle><date>2007-12</date><risdate>2007</risdate><volume>32</volume><issue>6</issue><spage>633</spage><epage>639</epage><pages>633-639</pages><issn>0269-4727</issn><eissn>1365-2710</eissn><abstract>Summary
Background and objective: The activity of thiopurine S‐methyltransferase (TPMT), a key enzyme in the metabolism of purine analogues, displays wide inter‐subject variability partly due to a genetic polymorphism. Previous studies have suggested adjusting purine analogues dosing according to TPMT activity but measurements are costly and time‐consuming. It is still unclear, especially under treatment, whether the simpler TPMT genotyping reliably predicts enzyme activity. Our aim was to study the possible correlation of TPMT genotype with phenotype.
Methods: We determined the genotypic status and TMPT activity, at diagnosis and after 6 months of maintenance therapy, of 118 children with acute lymphoblastic leukaemia (ALL).
Results and Discussion: Eighty‐nine per cent of the children had a homozygous wild‐type genotype (group 1), 11% had one or two mutant allele(s) (group 2). At both time points, TPMT activity (U/mL peripheral red blood cell) was significantly higher in group 1 than in group 2 (P < 0·001) but inter‐group levels overlapped considerably. There was considerable heterogeneity in the percentage increase in TPMT activity after therapy, and little correlation between metabolites ratio [6‐methylmercaptopurine derivative/6‐thioguanine nucleotides (6‐TGN)] and TPMT activity at the end of 6 months’ maintenance treatment. These results show that TPMT activity cannot be used as an accurate tool for 6‐mercaptopurine monitoring.
Conclusion: Genotyping at diagnosis identifies patients with a homozygous mutant TPMT and may prevent severe and life‐threatening toxicity. ALL treatment monitoring should preferentially be based on repeated determinations of intracellular active metabolites (6‐TGN) and methylated metabolites.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>18021342</pmid><doi>10.1111/j.1365-2710.2007.00858.x</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 6-mercaptopurine acute lymphoblastic leukaemia Adolescent Antimetabolites, Antineoplastic - therapeutic use Biological and medical sciences Child Child, Preschool Erythrocytes - enzymology Female Genotype Hematologic and hematopoietic diseases Humans Infant Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Male Medical sciences Mercaptopurine - metabolism Mercaptopurine - therapeutic use Methyltransferases - genetics Methyltransferases - metabolism pharmacogenetics Pharmacology. Drug treatments phenotype Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics thiopurine S-methyltransferase |
| title | Should TPMT genotype and activity be used to monitor 6-mercaptopurine treatment in children with acute lymphoblastic leukaemia? |
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