Keuzenkamp-Jansen C W, Leegwater P A, De Abreu R A, Lambooy M A, Bokkerink J P, Trijbels J M
Center for Pediatric Oncology SE Netherlands, St Radboud University Hospital, Nijmegen, Netherlands.
J Chromatogr B Biomed Appl. 1996 Mar 29;678(1):15-22. doi: 10.1016/0378-4347(95)00432-7.
Thiopurine methyltransferase (TPMT) is an important enzyme in the metabolism of 6-mercaptopurine (6MP), which is used in the treatment of acute lymphoblastic leukemia (ALL). TPMT catalyzes the formation of methylthioinosine monophosphate (MetIMP), which is cytotoxic for cultured cell lines, and it plays a role in detoxification of 6MP. Population studies show a genetic polymorphism for TPMT with both high and low activity alleles. About 1 of 300 subjects is homozygous for the low activity. The function TPMT plays in detoxification or therapeutic efficacy of 6MP in vivo is not clear. In this article the genetic polymorphism of TPMT is reviewed and the contribution of TPMT to the cytotoxic action, or detoxification, of 6MP in children with ALL is discussed. Induction of TPMT activity has been described during the treatment for ALL. We performed a pilot study on the influence of high-dose 6MP infusions (1300 mg/m2 in 24 h) on TPMT activity of peripheral blood mononuclear cells (pMNC) of eleven patients with ALL. The TPMT activities were in, or, above the normal range. There was no statistically significant difference between the TPMT activities before and after the 6MP infusions. MetIMP levels in pMNC increased during successive courses. This might be explained by TPMT induction, but other explanations are plausible as well. Twenty five percent of the TPMT assays failed, because less than the necessary 5.10(6) pMNC could be isolated from the blood of leukopenic patients. Red blood cells can not be used for TPMT measurements, since transfusions are frequently required during the treatment with 6MP infusions. Therefore, the influence of high-dose 6MP infusions on TPMT activity can only be investigated further when a TPMT assay which requires less pMNC has been developed.
硫嘌呤甲基转移酶（TPMT）是6-巯基嘌呤（6MP）代谢中的一种重要酶，6MP用于治疗急性淋巴细胞白血病（ALL）。TPMT催化形成对培养细胞系具有细胞毒性的甲基硫代肌苷单磷酸（MetIMP），它在6MP的解毒过程中发挥作用。群体研究显示TPMT存在基因多态性，具有高活性和低活性等位基因。约300名受试者中有1人是低活性纯合子。TPMT在体内6MP解毒或治疗效果中所起的作用尚不清楚。本文综述了TPMT的基因多态性，并讨论了TPMT对ALL患儿6MP细胞毒性作用或解毒作用的贡献。在ALL治疗期间已描述了TPMT活性的诱导。我们对11例ALL患者进行了一项关于高剂量6MP输注（24小时内1300mg/m²）对外周血单个核细胞（pMNC）TPMT活性影响的初步研究。TPMT活性处于或高于正常范围。6MP输注前后的TPMT活性之间无统计学显著差异。连续疗程中pMNC中的MetIMP水平升高。这可能是由TPMT诱导解释的，但其他解释也合理。25%的TPMT检测失败，因为从白细胞减少患者的血液中无法分离出所需的5×10⁶个pMNC。由于在6MP输注治疗期间经常需要输血，红细胞不能用于TPMT测量。因此，只有在开发出需要较少pMNC的TPMT检测方法后，才能进一步研究高剂量6MP输注对TPMT活性的影响。
