Dokmanovic Lidija, Urosevic Jelena, Janic Dragana, Jovanovic Nada, Petrucev Branka, Tosic Natasa, Pavlovic Sonja
Department of Hematology and Oncology, University Children's Hospital, Belgrade, Serbia, and Montenegro.
Ther Drug Monit. 2006 Dec;28(6):800-6. doi: 10.1097/01.ftd.0000249947.17676.92.
Thiopurine S-methyltransferase (TPMT) is an enzyme that converts thiopurine drugs into inactive metabolites. It is now well established that interindividual variation in sensitivity to thiopurines can be the result of the presence of genetic polymorphisms in the TPMT gene. The aim of this study was to determine the frequency and type of TPMT polymorphisms in the population of Serbia and Montenegro and to assess its relevance in the management of childhood acute lymphoblastic leukemia (ALL). Blood samples from 100 healthy adults and 100 children with ALL were analyzed for common mutations in the TPMT gene using polymerase chain reaction-based assays. The results revealed that allelic frequencies were 0.2% for TPMT2, 3.2% for TPMT3A, and 0.5% for TPMT3B. A rare TPMT3B allele was detected in 2 families. No TPMT*3C allele was found. The general pattern of TPMT-variant allele distribution as well as their frequencies in the population of Serbia and Montenegro, is similar to those determined for other Slavic and Mediterranean populations. The ability to tolerate 6-mercaptopurine (6-MP) -based maintenance therapy was used as a surrogate marker of hematologic toxicity. In the study of 50 patients with childhood ALL treated according to the BFM-like protocol, it was found that even TPMT-heterozygous patients are at greater risk of thiopurine drug-related leukopenia (mean duration of period when children missed therapy as a result of leukopenia for TPMT-heterozygous patients was 11.3 weeks vs 3.4 weeks for wild-type genotype patients, P < 0.01). In another group of 50 patients, the TPMT genotype was determined prospectively. The therapy protocol was modified considering their TPMT genotype. Administering reduced 6-MP dosages in the initial phase of maintenance allowed TPMT-heterozygous patients to later receive full protocol doses of both 6-MP and nonthiopurine therapy without omitting therapy resulting from myelotoxicity. These results justify performing TPMT genotyping before initiating thiopurine therapy in all children with ALL to minimize consequent toxicity.
硫嘌呤甲基转移酶（TPMT）是一种将硫嘌呤药物转化为无活性代谢产物的酶。现已明确，个体对硫嘌呤敏感性的差异可能是由于TPMT基因存在遗传多态性。本研究的目的是确定塞尔维亚和黑山人群中TPMT多态性的频率和类型，并评估其在儿童急性淋巴细胞白血病（ALL）治疗中的相关性。使用基于聚合酶链反应的检测方法，对100名健康成年人和100名ALL患儿的血样进行TPMT基因常见突变分析。结果显示，TPMT2的等位基因频率为0.2%，TPMT3A为3.2%，TPMT3B为0.5%。在2个家族中检测到罕见的TPMT3B等位基因。未发现TPMT*3C等位基因。塞尔维亚和黑山人群中TPMT变异等位基因的总体分布模式及其频率，与其他斯拉夫和地中海人群中所确定的相似。以耐受基于6-巯基嘌呤（6-MP）的维持治疗的能力作为血液学毒性的替代标志物。在一项对50例按照类似BFM方案治疗的儿童ALL患者的研究中，发现即使是TPMT杂合子患者发生硫嘌呤药物相关白细胞减少的风险也更高（由于白细胞减少，TPMT杂合子患者错过治疗的平均时长为11.3周，而野生型基因型患者为3.4周，P<0.01）。在另一组50例患者中，前瞻性地确定了TPMT基因型。根据其TPMT基因型对治疗方案进行了调整。在维持治疗的初始阶段给予降低剂量的6-MP，使TPMT杂合子患者后来能够接受全方案剂量的6-MP和非硫嘌呤治疗，而不会因骨髓毒性而遗漏治疗。这些结果证明，在所有ALL患儿开始硫嘌呤治疗前进行TPMT基因分型是合理的，以尽量减少随之而来的毒性。
