Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.
Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
Cancer Chemother Pharmacol. 2018 Mar;81(3):579-586. doi: 10.1007/s00280-018-3525-8. Epub 2018 Feb 1.
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.
Blood samples were drawn during 6MP/MTX maintenance therapy from 132 children treated for ALL at Rigshospitalet, Copenhagen. The samples were analysed for thiopurine metabolites and compared to TPMT (rs1800460 and rs1142345) and ITPA (rs1127354) genotypes.
Median DNA-TG (mDNA-TG) levels were higher in TPMT and ITPA low-activity patients as compared to wildtype 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 levels. DNA-TG indices (mDNA-TG/mEry-TGN) were 42% higher in TPMT patients as compared to TPMT patients but 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).
TPMT and ITPA genotypes significantly influence the metabolism of 6MP. DNA-TG may prove to be a more relevant pharmacokinetic parameter for monitoring 6MP treatment intensity than cytosolic metabolites. Prospective trials are needed to evaluate the usefulness of DNA-TGN for individual dose adjustments in childhood ALL maintenance therapy.
探讨儿童急性淋巴细胞白血病（ALL）6-巯基嘌呤（6MP）/甲氨蝶呤（MTX）维持治疗期间，巯嘌呤掺入 DNA 水平（DNA-TG）以及红细胞 6-硫代鸟嘌呤核苷酸（Ery-TGN）和甲基化代谢物（Ery-MeMP）水平，并分析其与肌苷三磷酸酶（ITPA）和硫嘌呤甲基转移酶（TPMT）基因变异的关系。
在哥本哈根 Rigshospitalet 对 132 例 ALL 患儿进行 6MP/MTX 维持治疗时，采集血液样本进行巯嘌呤代谢物分析，并与 TPMT（rs1800460 和 rs1142345）和 ITPA（rs1127354）基因型进行比较。
与野生型患者相比，TPMT 和 ITPA 低活性患者的 mDNA-TG（中位数 DNA-TG，mDNA-TG）水平更高（TPMT 549 与 364 fmol/µg DNA，p=0.007；ITPA 465 与 387 fmol/µg DNA，p=0.04）。mDNA-TG 水平与 mEry-TGN（中位数 Ery-TGN，mEry-TGN）呈正相关（r=0.37，p=0.001），但在更高的 mEry-TGN 水平时趋于平稳。与 TPMT 患者相比，TPMT 患者的 DNA-TG 指数（mDNA-TG/mEry-TGN）高 42%，但 ITPA 患者与 ITPA 患者之间的 DNA-TG 指数无差异（中位数 1.7 与 1.6 fmol/µg DNA/ nmol/mmol Hb，p=0.81）。DNA-TG 指数随 mEry-MeMP（中位数 Ery-MeMP）水平增加而升高（r=0.25，p=0.001）。
TPMT 和 ITPA 基因型显著影响 6MP 的代谢。与细胞溶质代谢物相比，DNA-TG 可能是监测 6MP 治疗强度更相关的药代动力学参数。需要前瞻性试验来评估 DNA-TGN 用于儿童 ALL 维持治疗个体化剂量调整的实用性。
