Lennard L, Lilleyman J S, Van Loon J, Weinshilboum R M
University of Sheffield, Department of Medicine and Pharmacology, UK.
Lancet. 1990 Jul 28;336(8709):225-9. doi: 10.1016/0140-6736(90)91745-v.
6-mercaptopurine (6-MP) can be inactivated by S-methylation, which is catalysed by thiopurine methyltransferase (TPMT). An alternative metabolic route leads to the formation of cytotoxic 6-thioguanine nucleotides (6-TGN). To investigate whether these two pathways compete with each other to affect the therapeutic response to 6-MP, 6-TGN concentrations and TPMT enzymatic activity were measured in erythrocytes (RBC) from 95 children on long-term 6-MP therapy for lymphoblastic leukaemia (ALL). RBC TPMT activities were also measured in 130 control children and 104 long-term survivors of ALL no longer on treatment. The 95 children on 6-MP showed wide interindividual differences in RBC 6-TGN concentrations at the full protocol dose of 75 mg/m2, and RBC 6-TGN concentrations correlated negatively with RBC TPMT activity. Children with 6-TGN concentrations below the group median had higher TPMT activities and a higher subsequent relapse rate. 50 of the 104 long-term survivors had been treated with "gentle" low-dose protocols, and this subgroup contained an excess of children with lower TPMT activities compared with normal controls. These results indicate that genetically determined TPMT activity may be a substantial regulator of the cytotoxic effect of 6-MP, an effect which in turn could be important in influencing the outcome of therapy for childhood ALL.
6-巯基嘌呤（6-MP）可通过硫嘌呤甲基转移酶（TPMT）催化的S-甲基化作用而失活。另一条代谢途径则导致细胞毒性的6-硫鸟嘌呤核苷酸（6-TGN）的形成。为了研究这两条途径是否相互竞争以影响对6-MP的治疗反应，对95名接受长期6-MP治疗淋巴细胞白血病（ALL）的儿童的红细胞（RBC）中的6-TGN浓度和TPMT酶活性进行了测量。还对130名对照儿童和104名已停止治疗的ALL长期存活者的RBC TPMT活性进行了测量。接受6-MP治疗的95名儿童在75mg/m2的全方案剂量下，RBC 6-TGN浓度存在广泛的个体差异，且RBC 6-TGN浓度与RBC TPMT活性呈负相关。6-TGN浓度低于组中位数的儿童具有较高的TPMT活性和较高的后续复发率。104名长期存活者中有50名接受了“温和”的低剂量方案治疗，与正常对照相比，该亚组中TPMT活性较低的儿童过多。这些结果表明，基因决定的TPMT活性可能是6-MP细胞毒性作用的重要调节因子，而这一作用反过来可能对影响儿童ALL的治疗结果具有重要意义。
