摘要
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 association of methylenetetrahydrofolate reductase（MTHFR） gene C677T polymorphism of childhood acute lymphoblastic leukemia（ALL） and excretion and toxicity caused by high-dose methotrexate（HDMTX）.Methods A total of 40 children with ALL at complete remission stage hospitalized in pediatric and hematologic departments of our hospital from Mar.2008 to Feb.2010 were selected.MTHFR C677T polymorphisms of subjects were determined by using restriction fragment length polymorphism polymerase chain reaction（PCR-RFLP）.The plasma MTX concentration of 24 h and 48 h after the start of HDMTX（MTX-48 h） was detected with fluorescence polarization immunoassay（FPIA）.Adverse reactions of patients receiving HDMTX chemotherapy were recorded and graded.Results Of all the cases who had HDMTX-related toxity,the incidence rates of hepatotoxity and myelosuppression were the highest.The probabilities of hepatotoxicity in carriers with MTHFR 677CC,677 TT and 677CT genotype were 40.0%,60.0% and 80.0%,respectively.The probability of hepatotoxicity was 6-fold higher in carriers of MTHFR 677 CT genotype as compared with patients with 677 CC genotype（OR=6.00,95%CI：1.05-34.32,P=0.044）,and the incidence rate of hepatotoxicity was 4.13-fold higher in carriers of MTHFR 677 CT＋TT genotype as compared with patients with 677 CC genotype（OR=4.13,95%CI：1.02-16.67,P=0.047）.There was no evident relation between MTHFR-677 CT and the incidence rate of myelosuppression caused by HDMTX.The MTX-48 h was significantly higher in patients with MTHFR 677 CT＋TT genotype than that with 677 CC genotype（P=0.006）.Conclusions The incidence rate of HDMTX-induced hepatotoxicity and delayed elimination of MTX have significant correlation.This study suggests that MTHFR gene 677 polymorphism may serve as predictors of HDMTX-related toxicity in children with ALL.
出处
《实用儿科临床杂志》
CAS
CSCD
北大核心
2012年第6期440-442,共3页
Journal of Applied Clinical Pediatrics
基金
广东省自然科学基金(8451051501000516)
