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 Rig- shospitalet, 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 LA LA patients (TPMT 549 vs. 364 fmol/µg DNA, p = 0.007, ITPA 465 vs. 387 fmol/µg DNA, p = 0.04). mDNA-TG levels were positively correlated to median Ery-TGN (mEry-TGN)(r = 0.37, p = 0.001), but plateaued at higher mEry-TGN lev- WT LA els. DNA-TG indices (mDNA-TG/mEry-TGN) were 42% higher in TPMT patients as compared to TPMT patients but WT LA no difference in DNA-TG indices was observed between ITPA and ITPA 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 (r = 0.25, p = 0.001). Conclusions
Cancer Chemotherapy and Pharmacology – Springer Journals
Published: Feb 1, 2018
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