Eldem İrem, Yavuz Duygu, Cumaoğullari Özge, İleri Talia, Ünal İnce Elif, Ertem Mehmet, Doğanay Erdoğan Beyza, Bindak Recep, Özdağ Hilal, Şatiroğlu-Tufan N Lale, Uysal L Zümrüt
Departments of Pediatrics.
Forensic Medicine and Sciences.
J Pediatr Hematol Oncol. 2018 Jul;40(5):e289-e294. doi: 10.1097/MPH.0000000000001153.
Therapy discontinuations and toxicities occur because of significant interindividual variations in 6-mercaptopurine (6-MP) and methotrexate (MTX) response during maintenance therapy of childhood acute lymphoblastic leukemia (ALL). 6-MP/MTX intolerance in some of the patients cannot be explained by thiopurine S-methyl transferase (TPMT) gene variants. In this study, we aimed to investigate candidate pharmacogenetic determinants of 6-MP and MTX intolerance in Turkish ALL children.
In total, 48 children with ALL who had completed or were receiving maintenance therapy according to Children's Oncology Group (COG) protocols were enrolled. Fifteen single-nucleotide polymorphisms in 8 candidate genes that were related to drug toxicity or had a role in the 6-MP/MTX metabolism (TPMT, ITPA, MTHFR, IMPDH2, PACSIN2, SLCO1B1, ABCC4, and PYGL) were genotyped by competitive allele-specific PCR (KASP). Drug doses during maintenance therapy were modified according to the protocol.
The median drug dose intensity was 50% (28% to 92%) for 6-MP and 58% (27% to 99%) for MTX in the first year of maintenance therapy, which were lower than that scheduled in all patients. Among the analyzed polymorphisms, variant alleles in SLCO1B1 rs4149056 and rs11045879 were found to be associated with lower 6-MP/MTX tolerance.
SLCO1B1 rs4149056 and rs11045879 polymorphisms may be important genetic markers to individualize 6-MP/MTX doses.
在儿童急性淋巴细胞白血病（ALL）维持治疗期间，由于6-巯基嘌呤（6-MP）和甲氨蝶呤（MTX）反应存在显著个体差异，导致治疗中断和出现毒性反应。部分患者的6-MP/MTX不耐受无法用硫嘌呤甲基转移酶（TPMT）基因变异来解释。在本研究中，我们旨在调查土耳其ALL儿童中6-MP和MTX不耐受的候选药物遗传学决定因素。
总共纳入了48例根据儿童肿瘤学组（COG）方案完成或正在接受维持治疗的ALL儿童。通过竞争性等位基因特异性PCR（KASP）对8个与药物毒性相关或在6-MP/MTX代谢中起作用的候选基因（TPMT、ITPA、MTHFR、IMPDH2、PACSIN2、SLCO1B1、ABCC4和PYGL）中的15个单核苷酸多态性进行基因分型。维持治疗期间的药物剂量根据方案进行调整。
维持治疗第一年中，6-MP的中位药物剂量强度为50%（28%至92%），MTX为58%（27%至99%），均低于所有患者的计划剂量。在分析的多态性中，发现SLCO1B1基因的rs4149056和rs11045879变异等位基因与较低 的6-MP/MTX耐受性相关。
SLCO1B1基因的rs4149056和rs11045879多态性可能是个体化6-MP/MTX剂量的重要遗传标志物。
