Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus
Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus
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DOI：
10.1093/jnci/91.23.2001
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发表时间：
1999-12-01
影响因子：
10.3
通讯作者：
Evans, WE
中科院分区：
文献类型：
--
作者：
Relling, MV;Hancock, ML;Evans, WE
背景：急性淋巴细胞白血病患者经常接受6-巯基嘌呤治疗，而硫嘌呤S-甲基转移酶（TPMT）酶活性纯合缺陷的患者由于细胞内硫鸟嘌呤核苷酸浓度较高而对该药物极度敏感。我们研究了不同 TPMT 表型患者中 6-巯基嘌呤的代谢、剂量需求和耐受性。方法：我们通过使用统计模型，比较了 180 名在圣犹达儿童研究医院方案 Total XII 中获得缓解的患者的 6-巯基嘌呤药理学和耐受性，该方案由每周甲氨蝶呤 (40 mg/m(2)) 和每日口服 6-巯基嘌呤 (75 mg/m(2)) 给予 2.5 年，第一年每 6 周中断一次，用大剂量甲氨蝶呤或替尼泊苷加阿糖胞苷治疗，统计检验是双边的，结果：硫鸟嘌呤核苷酸的红细胞浓度 (pmol/8 x 10(8) 红细胞) 与 TPMT 酶活性呈负相关 (P < .01)，平均值TPMT 纯合野生型 (n = 161)、杂合子 (n = 17) 和纯合缺陷 (n = 2) 患者分别有 417 (+/-179)、963 (+/-752) 和 3565 (+/-1282) 例（+/- 标准差），在 TPMT 的一个子集中，TPMT 基因型和表型完全一致。确定了 28 名患者的 TPMT 基因型。硫鸟嘌呤核苷酸浓度 (P = .24)、TPMT 酶活性 (P = .22) 或 6-巯基嘌呤每周平均处方剂量 (P = .49) 没有性别差异。由于毒性而导致 6-巯基嘌呤剂量减少的累积发生率在突变 TPMT 纯合子患者中最高 (100%)，在杂合子患者中居中 (35%)，在野生型患者中最低(7%) (P < .001)，最终每周 6-巯基嘌呤平均剂量（+/- 标准差）分别为 72 (+/-60)、449 (+/-160) 和 528 (+/-90) mg/m(2)。降低 TPMT 杂合子和缺陷患者中 6-巯基嘌呤的剂量，允许在维持高硫鸟嘌呤核苷酸浓度的同时给予完整方案剂量的其他化疗。结论：我们得出结论，TPMT 的遗传多态性是巯基嘌呤毒性的重要决定因素，即使在该性状杂合的患者中也是如此。
Background: Patients with acute lymphoblastic leukemia are often treated with 6-mercaptopurine, and those with homozygous deficiency in thiopurine S-methyltransferase (TPMT) enzyme activity have an extreme sensitivity to this drug as a result of the accumulation of higher cellular concentrations of thioguanine nucleotides. We studied the metabolism, dose requirements, and tolerance of 6-mercaptopurine among patients with different TPMT phenotypes,Methods: We compared, by use of statistical modeling, 6-mercaptopurine pharmacology and tolerance in 180 patients who achieved remission on St. Jude Children's Research Hospital Protocol Total XII composed of weekly methotrexate (40 mg/m(2)) and daily oral 6-mercaptopurine (75 mg/m(2)) given for 2.5 years, interrupted every 6 weeks during the first year for treatment with either high-dose methotrexate or teniposide plus cytarabine, Statistical tests were two-sided,Results: Erythrocyte concentrations of thioguanine nucleotides (pmol/8 x 10(8) erythrocytes) were inversely related to TPMT enzyme activity (P < .01), with averages (+/- standard deviations) of 417 (+/-179), 963 (+/-752), and 3565 (+/-1282) in TPMT homozygous wild-type (n = 161), heterozygous (n = 17), and homozygous-deficient (n = 2) patients, respectively, There was complete concordance between TPMT genotype and phenotype in a subset of 28 patients for whom TPMT genotype was determined. There were no sex differences in thioguanine nucleotide concentrations (P = .24), TPMT enzyme activity (P = .22), or average weekly prescribed dose of 6-mercaptopurine (P = .49), The cumulative incidence of 6-mercaptopurine dose reductions due to toxicity was highest among patients homozygous for mutant TPMT (100%), intermediate among heterozygous patients (35%), and lowest among wild-type patients (7%) (P < .001), with average (+/- standard deviation) final weekly 6-mercaptopurine doses of 72 (+/-60), 449 (+/-160), and 528 (+/-90) mg/m(2), respectively. Lowering doses of 6-mercaptopurine in TPMT heterozygotes and in deficient patients allowed administration of full protocol doses of other chemotherapy while maintaining high thioguanine nucleotide concentrations,Conclusion: We conclude that genetic polymorphism in TPMT is an important determinant of mercaptopurine toxicity, even among patients who are heterozygous for this trait.