Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine
Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine
复制标题
DOI：
10.1200/jco.2001.19.8.2293
复制
发表时间：
2001-04-15
影响因子：
45.3
通讯作者：
Relling, MV
中科院分区：
文献类型：
--
作者：
Evans, WE;Hon, YY;Relling, MV
目的：评估巯基嘌呤（MP）或硫唑嘌呤（AZA）治疗不耐受患者的硫嘌呤5-甲基转移酶（TPMT）表型和基因型，并评估其临床管理。采用放射化学分析法测定TPMT活性，采用突变特异性聚合酶链反应限制性片段长度多态性分析法测定TPMT*2、*3A、*38和 *3C等位基因的TPMT基因型，采用高效液相色谱法测定硫嘌呤代谢产物（浓缩RBC [pRBC]的活性< 5 U/mL：纯合突变体），9个具有中等TPMT活性（pRBC的5至13 U/mL;杂合子），8个具有高TPMT活性（pRBC的> 13.5 U/mL;纯合野生型）。这些中毒患者中TPMT缺陷和杂合子个体的频率为65.2%，显著高于一般人群中预期的10%频率（P 6倍），在因含硫嘌呤治疗而发生剂量限制性造血毒性的患者中，TPMT缺陷或杂合子的比例过高。然而，通过适当的剂量调整，TPMT缺陷和杂合子患者可以用硫嘌呤治疗，而没有急性剂量限制性毒性。(C)2001年，美国临床肿瘤学会。
Purpose: to assess thiopurine 5-methyltransferase (TPMT) phenotype and genotype in patients who were intolerant to treatment with mercaptopurine (MP) or azathioprine (AZA), and to evaluate their clinical management.Patients and Methods: TPMT phenotype and thiopurine metabolism were assessed in all patients referred between 1994 and 1999 for evaluation of excessive toxicity while receiving MP or AZA. TPMT activity was measured by radiochemical analysis, TPMT genotype was determined by mutation-specific polymerase chain reaction restriction fragment length polymorphism analyses for the TPMT*2, *3A, *38, and *3C alleles, and thiopurine metabolites were measured by high performance liquid chromatography.Results: Of 23 patients evaluated, six had TPMT deficiency (activity < 5 U/mL of packed RBCs [pRBCs]: homozygous mutant), nine had intermediate TPMT activity (5 to 13 U/mL of pRBCs; heterozygotes), and eight had high TPMT activity(> 13.5 U/mL of pRBCs; homozygous wildtype). The 65.2% frequency of TPMT-deficient and heterozygous individuals among these toxic patients is significantly greater than the expected 10% frequency in the general population (P six-fold) overrepresentation of TPMT deficiency or heterozygosity among patients developing dose-limiting hematopoietic toxicity from therapy containing thiopurines. However, with appropriate dosage adjustments, TPMT-deficient and heterozygous patients can be treated with thiopurines, without acute dose-limiting toxicity. (C) 2001 by American Society of Clinical Oncology.