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目的 探讨巯基嘌呤甲基转移酶 (TPMT)活性、基因型和硫鸟嘌呤核苷酸 (TGNs)浓度检测对 6 巯基嘌呤 (6 MP)化疗个体化的意义。方法 用放射性核素标记方法测定红细胞TPMT活性 ,用特异引物序列 PCR和限制性片段长度多态性 PCR方法检测低活性者的基因型 ,通过高效液相色谱法(HPLC)检测急性淋巴细胞白血病 (ALL)患儿在服用 6 MP后红细胞内的TGNs浓度。结果 371名受检者的平均TPMT活性为 (16 .6± 4.5 )U mlpRBCs ,其中≤ 10U mlpRBCs的低活性比例为 8.1%,男性和女性的平均TPMT活性分别为 (16 .8± 5 .0 )U mlpRBCs和 (16 .5± 4.4)U mlpRBCs ,汉族人TPMT活性不存在性别、年龄差异 ,健康志愿者与白血病患儿之间差异亦无显著性 ;30名TPMT活性低下者的DNA中包括TPMT 2型 5例 ,TPMT 3A型 4例 ,TPMT 3B型 6例 ,TPMT 3C型 10例 ,另有 5例未出现上述基因型 ;ALL患儿治疗前红细胞TPMT活性与服用 6 MP 7～ 14d的红细胞内TGNs稳态浓度呈负相关。TGNs浓度与测定后第 14天的白细胞计数呈负相关。结论 服用 6 MP前测定TPMT活性和服药时监测TGNs浓度能够有助于预防抗嘌呤代谢药物的不良反应 ,指导其化疗个体化 ,改善疗效。
Objective To investigate the significance of the detection of thiopurine methyltransferase (TPMT) activity, genotype and thioguanine nucleotide (TGNs) concentration on the individualization of 6-mercaptopurine (6 MP) chemotherapy. Methods The TPMT activity of erythrocytes was determined by radionuclide labeling method. The genotypes of low activity were detected by PCR and restriction fragment length polymorphism (PCR). The acute lymphoblastic leukemia (AML) was detected by high performance liquid chromatography (HPLC) ALL) in children after taking 6 MP erythrocyte TGNs concentration. RESULTS: The average TPMT activity of 371 subjects was (16.6 ± 4.5) U mlpRBCs, with a low activity ratio of ≤10 U mlpRBCs of 8.1%. The average TPMT activity of males and females was (16.8 ± 5.0) ) U mlpRBCs and (16.5 ± 4.4) U mlpRBCs, Han did not exist sex and age difference of TPMT activity, there was no significant difference between healthy volunteers and children with leukemia; 30 TPMT low activity of DNA include TPMT 2 type 5 cases, TPMT 3A type 4 cases, TPMT 3B type 6 cases, TPMT 3C type 10 cases, the other 5 cases did not appear the above genotype; ALL children with pretreatment erythrocyte TPMT activity and taking 6 MP 7 ~ 14d The steady-state concentrations of TGNs in erythrocytes were negatively correlated. The concentration of TGNs was negatively correlated with the white blood cell count on the 14th day after the test. Conclusions The determination of TPMT activity before 6 MP administration and the monitoring of TGNs concentration during medication may be helpful to prevent the side effects of antipurin metabolism drugs and guide the individualization of chemotherapy and improve the curative effect.