DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma
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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).
We studied these metabolites in 229 blood samples from 18 children with ALL (N = 16) or NHL (N = 2) on 6MP/Methotrexate maintenance therapy.
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.
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.
KeywordsAcute lymphoblastic leukaemia Non-Hodgkin lymphoma Maintenance therapy Pharmacokinetics Paediatric cancer Paediatric pharmacology
This study has received financial support from H:S Research Fund 2000 (Grant no. 120), the Danish Cancer Society (Grant no. 99144069132), the Danish Childhood Cancer Foundation, The University Hospital Rigshospitalet, Novo Nordic Foundation, Home Secretary Research Grant for Individualised Therapy, and Danish Research Council for Health and Disease (Grant no. 271-0615). Kjeld Schmiegelow holds the Childhood Cancer Foundation Research Professorship in Pediatric Oncology. A special thanks to Jens Bo Thomsen, who has performed the DNA-6TGN analysis and data registration.
Conflict of interest statement
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