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Rigshospitalet - en del af Københavns Universitetshospital
Udgivet

Role of TPMT and ITPA variants in mercaptopurine disposition

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

DOI

  1. Methotrexate polyglutamate levels and co-distributions in childhood acute lymphoblastic leukemia maintenance therapy

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Measures of 6-mercaptopurine and methotrexate maintenance therapy intensity in childhood acute lymphoblastic leukemia

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. A phase I trial of intravenous catumaxomab: a bispecific monoclonal antibody targeting EpCAM and the T cell coreceptor CD3

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  1. Dyslipidemia at diagnosis of childhood acute lymphoblastic leukemia

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. T-cell acute lymphoblastic leukemia in patients 1-45 years treated with the pediatric NOPHO ALL2008 protocol

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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PURPOSE: To explore the levels of thioguanine incorporated into DNA (DNA-TG), and erythrocyte levels of 6-thioguanine nucleotides (Ery-TGN) and methylated metabolites (Ery-MeMP) during 6-mercaptopurine (6MP)/Methotrexate (MTX) therapy of childhood acute lymphoblastic leukemia (ALL) and the relation to inosine triphosphatase (ITPA) and thiopurine methyltransferase (TPMT) gene variants.

METHODS: Blood samples were drawn during 6MP/MTX maintenance therapy from 132 children treated for ALL at Rigshospitalet, Copenhagen. The samples were analysed for thiopurine metabolites and compared to TPMT (rs1800460 and rs1142345) and ITPA (rs1127354) genotypes.

RESULTS: Median DNA-TG (mDNA-TG) levels were higher in TPMT and ITPA low-activity patients as compared to wildtype patients (TPMTLA 549 vs. 364 fmol/µg DNA, p = 0.007, ITPALA 465 vs. 387 fmol/µg DNA, p = 0.04). mDNA-TG levels were positively correlated to median Ery-TGN (mEry-TGN)(rs = 0.37, p = 0.001), but plateaued at higher mEry-TGN levels. DNA-TG indices (mDNA-TG/mEry-TGN) were 42% higher in TPMTWT patients as compared to TPMTLA patients but no difference in DNA-TG indices was observed between ITPAWT and ITPALA patients (median 1.7 vs. 1.6 fmol/µg DNA/ nmol/mmol Hb, p = 0.81). DNA-TG indices increased with median Ery-MeMP (mEry-MeMP) levels (rs = 0.25, p = 0.001).

CONCLUSIONS: TPMT and ITPA genotypes significantly influence the metabolism of 6MP. DNA-TG may prove to be a more relevant pharmacokinetic parameter for monitoring 6MP treatment intensity than cytosolic metabolites. Prospective trials are needed to evaluate the usefulness of DNA-TGN for individual dose adjustments in childhood ALL maintenance therapy.

OriginalsprogEngelsk
TidsskriftCancer Chemotherapy and Pharmacology
Vol/bind81
Udgave nummer3
Sider (fra-til)579-586
Antal sider8
ISSN0344-5704
DOI
StatusUdgivet - mar. 2018

ID: 56423087