摘要
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。
Objective For the purpose of clarifying the influence of thiopurine methyltransferase (TPMT) gene single nucleotide polymorphisms (SNPs) on the efficacy of thiopurines and risk for its toxicity and therefore improving the safety and efficacy of thiopurines, the authors investigated TPMT genotype in acute leukemia in children who were intolerant to the treatment with 6-mercap topurine (6-MP). Methods TPMT genotype was determined in an unrelated population of 250 Chinese healthy blood donors and 280 children with acute leukemia. TPMT genotyping assay was based on polymerase chain reaction (PCR), restriction digestion of PCR products, denaturing high-performance liquid chromatography (DHPLC) and direct DNA sequencing in the TPMT*2(G238C), TPMT*3A(G460A, A719G) and TPMT*3C (A719G).Results There were 10 TPMT*1/TPMT*3C heterozygotes in 280 children. The frequency of the polymorphism was 3.6%. All the involved alleles were TPMT*3C. Of the 160 children acute leukemia evaluated, 45 (26%) were intolerant to 6-MP. Presentations included hepatotoxicity and hematological toxicity. Six out of 45 children were heterozygous, while the other 39 were wild type homozygous. Before dosage adjustments for thiopurine, the hematologic toxicity and hepatotoxicity in TPMT heterozygous individuals occurred more frequently than in homozygous. Therefore, cases of TPMT heterozygotes experienced more missed doses of 6-MP. Conclusions TPMT genotype is associated with tolerance in acute leukemia in children. The heterozygote individuals have low TPMT activity. Therefore the frequencies of hemtopoietic toxicity and hepatoxicity are high after using 6-MP. Detection of SNPs in the TPMT genes is useful in identifying children before administration of 6-MP.
出处
《中华儿科杂志》
CAS
CSCD
北大核心
2003年第12期929-933,共5页
Chinese Journal of Pediatrics
关键词
巯嘌呤甲基转移酶
基因多态性位点
白血病
巯嘌呤耐受性
Methyltransferases
Polymorphism,single nucleotide
6-Mercaptopurine
Leukemia
Drug resistance, neoplasm
