DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma.
OBJECTIVE
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 (r (p) = 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 (r (p) = -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 (r (p) = 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.
Hedeland
Rikke L
RL
The Section for Pediatric Hematology and Oncology, Pediatric Clinic II, The Juliane Marie Center, The University Hospital, Rigshospitalet, 2100, Copenhagen, Denmark.
Hvidt
Kristian
K
Nersting
Jacob
J
Rosthøj
Susanne
S
Dalhoff
Kim
K
Lausen
Birgitte
B
Schmiegelow
Kjeld
K
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D016903:Drug Monitoring; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D006150:Guanine Nucleotides / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008727:Methotrexate / Q000008:administration & dosage; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D011687:Purines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013873:Thionucleotides / Q000378:metabolism*
D006150:Guanine Nucleotides; D011687:Purines; D013873:Thionucleotides; C003964:6-thioguanylic acid; D004247:DNA; D015122:Mercaptopurine; C030985:purine; D008727:Methotrexate