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目的探讨急性淋巴细胞白血病(ALL)患儿亚甲基四氢叶酸还原酶(MTHFR)基因677位点多态性与大剂量甲氨蝶呤(HDMTX)体内排泄及不良反应的相关性。方法 2008年3月-2010年2月在本院儿科中心和血液内科住院的完全缓解并接受HDMTX治疗的40例ALL患儿,在接受HDMTX治疗前应用PCR-限制性酶切片段长度多态性(RFLP)技术检测MTHFR基因C677T多态性,在HDMTX静脉输注开始后24 h、48 h应用荧光偏振免疫法(FPIA)测定其血浆MTX水平,密切观察ALL患儿HDMTX化疗后的不良反应,对化疗不良反应进行分级。对MTHFR677的基因多态性与MTX不良反应及HDMTX 48 h的MTX水平(MTX-48 h)的相关性进行分析。结果在有HDMTX相关不良反应的ALL患儿中,肝损害和骨髓抑制发生率最高。MTHFR C677T有肝脏损害的基因型分布频率由低到高为CC型40.0%,TT型60.0%,CT型80.0%,CT基因型者肝脏损害发生的风险是CC基因型者的6倍(OR=6.00,95%CI:1.05～34.32,P=0.044);677CT+TT基因型者肝脏损害发生的风险是CC基因型者的4.13倍(OR=4.13,95%CI:1.02～16.67,P=0.047)。MTHFR C677T基因型与骨髓抑制无明显相关性。携有MTHFR突变基因型(CT+TT)患者的48 hMTX血药质量浓度明显高于携带MTHFR野生型基因CC者(P=0.006)。结论 MTHFR 677位基因型可作为ALL患儿HDMTX化疗不良反应和药物体内排泄的有效预测指标。
Objective To investigate the relationship between polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene 677 in children with acute lymphoblastic leukemia (ALL) and in vivo excretion and side effects of high dose methotrexate (HDMTX). METHODS: From March 2008 to February 2010, 40 children with ALL who were hospitalized in Department of Pediatrics and Department of Hematology and were treated with HDMTX were enrolled in this study. Before treatment with HDMTX, PCR-restriction fragment length polymorphism (RFLP) was used to detect the C677T polymorphism of MTHFR gene. Plasma MTX level was measured by fluorescence polarization immunoassay (FPIA) 24 h and 48 h after the start of HDMTX intravenous infusion. The adverse reactions after HDMTX chemotherapy in ALL children were observed closely. Adverse reactions to chemotherapy were graded. The association between MTHFR677 gene polymorphism and MTX adverse reaction and MTX level at 48 h (MTX-48 h) was analyzed. Results The incidence of liver damage and myelosuppression was the highest in ALL children with HDMTX-related adverse reactions. The frequency of liver damage in MTHFR C677T was 40.0% for CC genotype, 60.0% for TT genotype and 80.0% for CT genotype. The risk of liver damage in CT genotype was 6 times that in CC genotype (OR = (OR = 4.13, 95% CI: 1.02 ~ 16.67, P = 0.047), the risk of liver damage in 677CT + TT genotype was 4.13 times of that in CC genotype ). There was no significant correlation between MTHFR C677T genotype and myelosuppression. The 48-h MTX plasma concentrations in patients with MTHFR mutation genotype (CT + TT) were significantly higher than those with MTHFR wild-type gene CC (P = 0.006). Conclusion MTHFR 677 genotype can be used as an effective predictor of HDMTX chemotherapy adverse reactions and excretion of drugs in children with ALL.