巯嘌呤甲基转移酶基因多态性对成人急性淋巴细胞白血病6-MP治疗个体化的意义

Significance of TPMT gene polymorphism for individualizing 6-MP chemotherapy in adults with acute lymphoblastic leukemia

目的检测使用6-巯基嘌呤(6-MP)维持治疗的成人急性淋巴细胞白血病(ALL)患者巯嘌呤甲基转移酶(TPMT)基因型和酶活性,并应用至临床以指导6-MP维持治疗。方法提取白细胞基因组DNA,以PCR结合限制性片断长度多态性(PCR-RFLP)等技术检测TPMT基因型;以高效液相色谱法(HPLC)检测TPMT酶活性,对使用6-MP和甲氨蝶呤(MTX)维持化疗的69例成人ALL患者,监测化疗药物的临床和血液学毒性。结果 69例成人ALL患者中有4例酶活性较低的TPMT*1/*3C杂合子,未发现TPMT*2、TPMT*3A、TPMT*3B。成人ALL患者使用6-MP治疗后,TPMT酶活性较治疗前上升。TPMT突变型组与野生型组观察到的临床药物毒性反应相近,但前者维持治疗期间6-MP的使用量明显低于后者[42.17 mg/(m2·d)和69.36 mg/(m2·d),P<0.01]。结论 TPMT基因多态性对6-MP治疗的药物毒性有实质性影响。成人ALL患者使用6-MP治疗前监测TPMT基因型和活性,有助于减少6-MP药物不良反应,实现临床治疗个体化。

Objective To observe thiopurine S-methyhransferase（TPMT） genotype and phenotype in adult patients with acute lymphoblastic leukemia （ALL） who had been given maintenance treatment with 6-mercaptopurine （6- MP） and to assess their clinical management for individualizing 6-MP chemotherapy. Methods Genomic DNA was extracted from peripheral blood leukocytes. PCR-restriction fragment length polymorphism（RFLP） technique was used to determine the TPMT genotype. TPMT activity was quantitated by reversed-phase high-performance liquid chromatography （HPLC） assay. Clinical and hematological toxicities were detected during the first 6 months of maintenance therapy with oral 6-MP and methotrexate（MTX） in the 69 adults with ALL. Results The heterozygous TPMT ＊ 1/＊ 3C genotype with low activity was found in 4 of the 69 adults with ALL; TPMT ＊ 2, TPMT ＊ 3A and TPMT ＊ 3B were not. We found a higher TPMT activity during maintenance treatment with 6-MP than at diagnosis. The median 6-mercaptopurine dose administered during the maintenance therapy was lower among patients with heterozygous TPMT alleles versus the rest [2.17 mg/（ m2 . d） and 69.36 mg/（ m2 . d）, P 〈0. 01 ], though the clinical toxicities were similar in both groups. Conclusion TPMT gene polymorphism has a substantial impact on mercaptopurine toxicity. Identification of TPMT genotype and activity appears to be important in making the ALL treatment less toxic and individualizing 6-MP chemotherapy