St. Jude Children's Research Hospital, Department of Pharmaceutical Sciences, 262 Danny Thomas Place MS 272, Memphis, TN 38105, USA.
Expert Opin Drug Saf. 2010 Jan;9(1):23-37. doi: 10.1517/14740330903426151.
Although genetic polymorphisms in the gene encoding human thiopurine methyltransferase (TPMT) are known to have a marked effect on mercaptopurine metabolism and toxicity, there are many patients with wild-type TPMT who develop toxicity. Furthermore, when mercaptopurine dosages are adjusted in patients who are heterozygous at the TPMT locus, there are still some patients who develop toxicity for reasons that are not fully understood. Therefore, we recently studied the effects of a common polymorphism in another gene encoding an enzyme involved in mercaptopurine metabolism (SNP rs1127354 in inosine-triphospate-pyrophosphatase, ITPA), showing that genetic polymorphism of ITPA is a significant determinant of mercaptopurine metabolism and of febrile neutropenia following combination chemotherapy of acute lymphoblastic leukemia (ALL) in which mercaptopurine doses are individualized based on TPMT genotype.
In this review, we summarize the knowledge available about the effect and clinical relevance of TPMT and ITPA on mercaptopurine pharmacogenomics, with a particular focus on the use of this medication in pediatric patients with ALL.
Reader will gain insights into: i) the effects of pharmacogenomic traits on mercaptopurine toxicity and efficacy for the treatment of ALL and ii) individualization strategies that can be used to mitigate toxicity without compromising efficacy in pediatric patients with ALL.
Mercaptopurine dose can be adjusted on the basis of TPMT genotype to mitigate toxicity in pediatric patients with ALL. As treatment is individualized in this way for the most relevant genetic determinant of drug response (i.e., for mercaptopurine, TPMT), the importance of other genetic polymorphisms emerges (e.g., ITPA).
虽然已知编码人类硫嘌呤甲基转移酶（TPMT）的基因中的遗传多态性对巯基嘌呤代谢和毒性有显著影响，但仍有许多野生型 TPMT 患者发生毒性。此外，当对 TPMT 基因座杂合的患者调整巯基嘌呤剂量时，仍有一些患者因尚未完全了解的原因发生毒性。因此，我们最近研究了另一个编码参与巯基嘌呤代谢的酶的基因（肌苷三磷酸磷酸酶中的 SNP rs1127354，ITPA）中的常见多态性的影响，结果表明 ITPA 的遗传多态性是巯基嘌呤代谢的重要决定因素，也是急性淋巴细胞白血病（ALL）联合化疗中根据 TPMT 基因型个体化巯基嘌呤剂量时出现发热性中性粒细胞减少的重要决定因素。
这篇综述总结了 TPMT 和 ITPA 对巯基嘌呤药物基因组学的影响和临床相关性的现有知识，特别关注该药物在接受 ALL 治疗的儿科患者中的应用。
可以根据 TPMT 基因型调整巯基嘌呤剂量，以减轻 ALL 儿科患者的毒性。由于以这种方式针对药物反应的最相关遗传决定因素（即巯基嘌呤，TPMT）进行个体化治疗，因此其他遗传多态性的重要性凸显出来（例如 ITPA）。
