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- Title
Dynamics of leucocyte DNA thioguanine nucleotide levels during maintenance therapy of childhood acute lymphoblastic leukemia.
- Authors
Larsen, Rikke Hebo; Hjalgrim, Lisa Lyngsie; Degn, Matilda; Nersting, Jacob; Als-Nielsen, Bodil; Grell, Kathrine; Schmiegelow, Kjeld
- Abstract
<bold>Purpose: </bold>Methotrexate (MTX)/6-Mercaptopurine (6MP)-based maintenance therapy is crucial to cure childhood acute lymphoblastic leukemia (ALL). Cytotoxicity is mediated by incorporation of thioguanine nucleotides (TGN) into DNA (DNA-TG) with higher levels in leucocytes being associated with reduced relapse risk. To further understand the dynamics of DNA-TG formation, we measured DNA-TG levels in leucocyte subsets during maintenance therapy and in the months following its discontinuation.<bold>Methods: </bold>DNA-TG levels were measured in leucocytes (DNA-TGTotal), polymorph nucleated granulocytes (neutrophils, eosinophils, basophils [DNA-TGPMN]) and mononucleated cells (lymphocytes, monocytes [DNA-TGMNC]) in 1013 samples from 52 patients on ALL maintenance therapy (951 samples during therapy and 62 samples after therapy discontinuation, respectively).<bold>Results: </bold>Median DNA-TGTotal, DNA-TGPMN and DNA-TGMNC during maintenance therapy were 539, 563 and 384 fmol/µg DNA, respectively. DNA-TGPMN displayed more pronounced fluctuation than DNA-TGMNC (range 0-3084 [interquartile range IQR 271-881] versus 30-1411 [IQR 270-509] fmol/µg DNA). DNA-TGTotal was more strongly correlated with DNA-TGPMN (rS = 0.95, p < 0.0001) than DNA-TGMNC (rS = 0.73, p < 0.0001). DNA-TGPMN correlated less with DNA-TGMNC (rS = 0.64, p < 0.0001) and to a much lesser extent with absolute neutrophil count (rS = 0.35, p < 0.0001). Following discontinuation of therapy, DNA-TGPMN was rapidly eliminated, and not measurable beyond day 22 after discontinuation, whereas DNA-TGMNC was slowly eliminated, and five patients demonstrated a measurable DNA-TGMNC more than 365 days after therapy discontinuation.<bold>Conclusion: </bold>Fluctuations in DNA-TGTotal are predominantly caused by corresponding fluctuations in DNA-TGPMN, thus DNA-TGTotal measures recent TGN incorporation in these short-lived cells. Measurement of DNA-TGTotal at 2-4 weeks intervals provides a reliable profile of DNA-TG levels.
- Subjects
LYMPHOBLASTIC leukemia; ACUTE leukemia; LEUCOCYTES; EOSINOPHILS; DNA; GRANULOCYTES; THERAPEUTIC use of antimetabolites; DNA metabolism; NUCLEOTIDE metabolism; THERAPEUTIC use of antineoplastic agents; PURINE metabolism; RESEARCH; RESEARCH methodology; MEDICAL cooperation; EVALUATION research; NEUTROPHILS; METHOTREXATE; COMPARATIVE studies; LEUKOCYTE count
- Publication
Cancer Chemotherapy & Pharmacology, 2021, Vol 88, Issue 1, p53
- ISSN
0344-5704
- Publication type
journal article
- DOI
10.1007/s00280-020-04219-5