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首页> 外文期刊>Clinical Pharmacology and Therapeutics >The thiopurine methyltransferase genetic polymorphism is associated with thioguanine-related veno-occlusive disease of the liver in children with acute lymphoblastic leukemia.
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The thiopurine methyltransferase genetic polymorphism is associated with thioguanine-related veno-occlusive disease of the liver in children with acute lymphoblastic leukemia.

机译：硫代嘌呤甲基转移酶基因多态性与急性淋巴细胞白血病儿童的硫鸟嘌呤相关性肝静脉闭塞性疾病有关。

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OBJECTIVE: Thiopurine metabolism was investigated in children with acute lymphoblastic leukemia treated in the United Kingdom Medical Research Council trial ALL97. This trial compared the efficacy and toxicity of thioguanine (INN, thioguanine) versus mercaptopurine. METHODS: Consecutive children were randomized to receive thioguanine or mercaptopurine during maintenance chemotherapy. Toxicity data were collected by an adverse event-reporting system with follow-up questionnaires. Red blood cell thiopurine methyltransferase (TPMT) activity and thioguanine nucleotide concentrations were measured by standard techniques. RESULTS: Of the children, 748 were randomized to thioguanine and 744 were randomized to mercaptopurine. There was no difference in the event-free survival rate between the 2 groups (80% and 81%, respectively, at 5 years). Thioguanine was associated with veno-occlusive disease (VOD) of the liver in 95 children, and persistent splenomegaly as a result of portal hypertension developed in 43 children. TPMT activity was significantly lower in the children in whom VOD developed, with a median of 13.4 U (range, 5.8-23 U) compared with 15.2 U (range, 5.3-27) in a control group of 161 leukemia patients in whom VOD did not develop (median difference, 1.8 U; 95% confidence interval, 0.9-2.7 U; P = .0001). TPMT activity in children with persistent splenomegaly was also lower than that in control subjects (median difference, 1.6 U; 95% confidence interval, 0.3-2.8 U; P = .012). There was no difference in red blood cell thioguanine nucleotide concentrations. CONCLUSIONS: Thioguanine was associated with liver damage in 11% of children randomized to thioguanine without an improvement in event-free survival rate. The association of lower TPMT activity with thioguanine-related liver damage could provide a means of identifying at-risk patients.
机译：目的：在英国医学研究理事会的ALL97试验中对急性淋巴细胞白血病患儿的硫嘌呤代谢进行了研究。该试验比较了硫鸟嘌呤（INN，硫鸟嘌呤）与巯基嘌呤的疗效和毒性。方法：连续性儿童在维持性化疗期间随机接受硫鸟嘌呤或巯基嘌呤治疗。不良反应事件报告系统通过随访问卷收集了毒性数据。通过标准技术测量红细胞硫嘌呤甲基转移酶（TPMT）活性和硫鸟嘌呤核苷酸浓度。结果：在这些孩子中，有748名被随机分配到硫鸟嘌呤，而744名被随机分配到巯基嘌呤。两组之间的无事件生存率没有差异（5年时分别为80％和81％）。硫鸟嘌呤与95名儿童的肝静脉闭塞性疾病（VOD）相关，并因43名儿童发展为门脉高压而导致持续性脾肿大。发生VOD的儿童中TPMT活性显着降低，中位值为13.4 U（范围5.8-23 U），而对照组的161名VOD患儿则为15.2 U（范围5.3-27）。不发展（中位数差异为1.8 U; 95％置信区间为0.9-2.7 U; P = .0001）。持续性脾肿大患儿的TPMT活性也低于对照组（中位数差异1.6 U; 95％置信区间0.3-2.8 U; P = 0.012）。红细胞硫鸟嘌呤核苷酸浓度没有差异。结论：硫鸟嘌呤与11％随机分配给硫鸟嘌呤的儿童的肝损害相关，而无事件生存率没有改善。较低的TPMT活性与硫代鸟嘌呤相关的肝损伤的关联可能为识别高危患者提供了一种手段。

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