DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma

TY - JOUR

T1 - DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma

AU - Hedeland, Rikke L

AU - Hvidt, Kristian

AU - Nersting, Jacob

AU - Rosthøj, Susanne

AU - Dalhoff, Kim

AU - Lausen, Birgitte

AU - Schmiegelow, Kjeld

PY - 2010/8/1

Y1 - 2010/8/1

N2 - Purpose: To explore the DNA incorporation of 6-thioguanine nucleotide levels (DNA-6TGN) during 6-mercaptopurine (6MP) therapy of childhood acute lymphoblastic leukaemia (ALL) and non-Hodgkin lymphoma (NHL) and its relation to erythrocyte levels of their metabolites: 6-thioguanine-nucleotides (E-6TGN), methylated metabolites (E-MeMP), Methotrexate polyglutamates (E-MTX), and to thiopurine methyltransferase activity (TPMT). Methods:We studied these metabolites in 229 blood samples from 18 children with ALL (N = 16) or NHL (N = 2) on 6MP/Methotrexate maintenance therapy. Results: DNA-6TGN levels were significantly correlated to E-6TGN (rp = 0.66, p = 0.003) with a trend to reach a plateau at high E-6TGN levels. To explore the relative DNA incorporation of 6TGN in relation to cytosol 6TGN levels, a DNA-6TGN index was calculated as DNA-6TGN/E-6TGN. The DNA-6TGN index was inversely correlated to E-6TGN (rp =-0.58, p = 0.012), which implies that with increasing levels of E-6TGN relatively less 6TGN are incorporated into DNA. E-MeMP levels were correlated to the DNA-TGN index (rp = 0.60, p = 0.008), indicating that high levels of MeMP result in enhanced DNA-6TGN incorporation, possibly due to inhibition of purine de novo synthesis, mediated by some of the methylated 6MP metabolites. Conclusions: DNA-6TGN may prove to be a more relevant pharmacokinetic parameter for monitoring 6MP treatment intensity than the previously used erythrocyte 6MP metabolites levels. Prospective clinical trials are needed to evaluate the usefulness of DNA-6TGN for individual dose adjustments.

AB - Purpose: To explore the DNA incorporation of 6-thioguanine nucleotide levels (DNA-6TGN) during 6-mercaptopurine (6MP) therapy of childhood acute lymphoblastic leukaemia (ALL) and non-Hodgkin lymphoma (NHL) and its relation to erythrocyte levels of their metabolites: 6-thioguanine-nucleotides (E-6TGN), methylated metabolites (E-MeMP), Methotrexate polyglutamates (E-MTX), and to thiopurine methyltransferase activity (TPMT). Methods:We studied these metabolites in 229 blood samples from 18 children with ALL (N = 16) or NHL (N = 2) on 6MP/Methotrexate maintenance therapy. Results: DNA-6TGN levels were significantly correlated to E-6TGN (rp = 0.66, p = 0.003) with a trend to reach a plateau at high E-6TGN levels. To explore the relative DNA incorporation of 6TGN in relation to cytosol 6TGN levels, a DNA-6TGN index was calculated as DNA-6TGN/E-6TGN. The DNA-6TGN index was inversely correlated to E-6TGN (rp =-0.58, p = 0.012), which implies that with increasing levels of E-6TGN relatively less 6TGN are incorporated into DNA. E-MeMP levels were correlated to the DNA-TGN index (rp = 0.60, p = 0.008), indicating that high levels of MeMP result in enhanced DNA-6TGN incorporation, possibly due to inhibition of purine de novo synthesis, mediated by some of the methylated 6MP metabolites. Conclusions: DNA-6TGN may prove to be a more relevant pharmacokinetic parameter for monitoring 6MP treatment intensity than the previously used erythrocyte 6MP metabolites levels. Prospective clinical trials are needed to evaluate the usefulness of DNA-6TGN for individual dose adjustments.

KW - 6-Mercaptopurine

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Child

KW - Child, Preschool

KW - Cytosol

KW - DNA

KW - Drug Monitoring

KW - Erythrocytes

KW - Female

KW - Guanine Nucleotides

KW - Humans

KW - Infant

KW - Lymphoma, Non-Hodgkin

KW - Male

KW - Methotrexate

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma

KW - Purines

KW - Thionucleotides

U2 - 10.1007/s00280-009-1184-5

DO - 10.1007/s00280-009-1184-5

M3 - Journal article

C2 - 19956952

SN - 0943-9404

VL - 66

SP - 485

EP - 491

JO - Cancer Chemotherapy and Pharmacology, Supplement

JF - Cancer Chemotherapy and Pharmacology, Supplement

IS - 3

ER -