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目的 分析巯嘌呤甲基转移酶 (thiopurinemethyltransferase,TPMT)基因型对急性白血病 (AL)患儿巯嘌呤 (6 mercaptopurine,6 MP)耐受性的影响 ,提高患儿对巯嘌呤类药物治疗的有效性和安全性。方法 应用以聚合酶链反应 (PCR)为基础的 2种方法并结合DNA直接测序 ,检测 2 5 0例健康成人和 2 80例AL患儿TPMT基因第 5外显子G2 38C、第 7外显子G4 6 0A和第 10外显子A719G的 3个多态性位点。详细记录 16 0例患儿 6 MP全量治疗时间、减少剂量时间和未治疗时间。结果 2 80例AL患儿中 ,10例为TPMT第 10外显子A719G杂合变异 ,变异率为 3 6 %,未发现纯合变异 ,变异的等位基因均为TPMT 3C。AL患儿TPMT基因变异的频率和类型与健康成人差异无显著性。在观察的 16 0例患儿中 ,有 2 8%的患儿未接受 6 MP标准剂量、全疗程治疗。其中TPMT野生型者 39例 ,占野生型患儿的 2 6 %,杂合型者 6例 ,占杂合型患儿的 6 0 %(P =0 0 3)。而且 ,6 / 10例TPMT杂合型者和 30 / 15 0例野生型者减少 6 MP的剂量 (P =0 0 0 9)。结论 TPMT基因的多态性位点与AL患儿 6 MP的耐受性有关。TPMT杂合型患儿中不耐受 6 MP的比例明显高于TPMT野生型者 ,必须中断治疗或减少剂量以避免较大毒性反应的发生。提示检测TPMT基因型有利于提高巯
Objective To analyze the effect of thiopurine methyltransferase (TPMT) genotype on the tolerance of 6 mercaptopurine (6 MP) in children with acute leukemia (AL) and to improve the efficacy of thiopurine methyltransferase And safety. Methods Two methods based on polymerase chain reaction (PCR) were used in combination with DNA direct sequencing to detect G2 38C, exon 5 of TPMT gene in 250 healthy children and 280 children with AL. G4 60A and exon 10 A719G three polymorphic loci. A detailed record of 60 patients with 6 MP full treatment time, reduce the dose of time and untreated time. Results Among the 80 AL children, 10 were heterozygous mutation of A719G of exon 10 of TPMT, the mutation rate was 36%. No homozygous mutation was found. The alleles of variation were all TPMT 3C. The frequency and type of TPMT gene mutation in children with AL were not significantly different from healthy adults. Of the 160 patients observed, 28% of children did not receive a 6-MP standard dose and were treated with a full course of treatment. Among them, 39 cases were TPMT wild type, accounting for 26% of wild-type children and 6 cases of heterozygous type, accounting for 60% (P = 0 0 3) of heterozygous children. Moreover, 6/10 reduced the dose of 6 MP in 6/10 of the TPMT heterozygotes and 30/15 of the wild type. Conclusion The polymorphism of TPMT gene is associated with 6 MP tolerance in children with AL. TPMT heterozygous children intolerant of 6 MP was significantly higher than the proportion of TPMT wild-type, treatment must be discontinued or reduce the dose to avoid the occurrence of a larger toxicity. Tip detection of TPMT genotype is conducive to raising the mercaptan