IS 6-THIOGUANINE MORE APPROPRIATE THAN 6-MERCAPTOPURINE FOR CHILDREN WITH ACUTE LYMPHOBLASTIC-LEUKEMIA
IS 6-THIOGUANINE MORE APPROPRIATE THAN 6-MERCAPTOPURINE FOR CHILDREN WITH ACUTE LYMPHOBLASTIC-LEUKEMIA
复制标题
DOI：
10.1038/bjc.1993.311
复制
发表时间：
1993-07-01
影响因子：
8.8
通讯作者：
LILLEYMAN, JS
中科院分区：
文献类型：
--
作者：
LENNARD, L;DAVIES, HA;LILLEYMAN, JS
6-巯基嘌呤 (6-MP) 的细胞毒活性受到硫嘌呤甲基转移酶 (TPMT) 的影响，TPMT 是一种基因调控的可变细胞内酶。 6-硫鸟嘌呤 (6-TG) 是一种密切相关的硫嘌呤，受该酶的影响较小，因此它可能是一种更可靠的药物 - 至少对于本质上具有高 TPMT 活性的患者而言。我们试图通过比较这两种药物在一小群患有淋巴细胞白血病 (ALL) 的儿童中的药代动力学来评估其作为替代方案的适用性。纳入的患者包括第二次或随后的缓解期患者，否则本应接受 6-MP，并且在之前的缓解期收集了有关 6-MP 代谢的药代动力学数据。口服40 mg m-2剂量后测定血浆6-TG浓度，并在每日口服治疗期间定期测量细胞内（红细胞，RBC）6-TG核苷酸（6-TGN）的积累和波动。研究了七名儿童。血浆 6-TG 浓度较低，并在口服给药后 6 小时内清除。 7 天时，6-TGN 浓度范围为 959 至 2361 pmol 8 x 10(-8) RBC，在所有情况下均显着高于 (P = 0.002) 相同患者使用 6-MP 时产生的浓度。在 35 个月的总治疗时间后，有一次观察到丙氨酸氨基转移酶适度升高，除骨髓抑制外，没有遇到任何毒性。在使用的情况下，6-TG 似乎具有良好的耐受性，并产生比 6-MP 更高浓度的细胞内细胞毒性代谢物。对于天生对传统药物有“抵抗力”的儿童（即使不是全部）来说，它可能是更好的选择。
The cytotoxic activity of 6-mercaptopurine (6-MP) is affected by thiopurine methyltransferase (TPMT), a genetically regulated and variable intracellular enzyme. 6-Thioguanine (6-TG), a closely related thiopurine, is less affected by that enzyme and so it may be a more reliable drug - at least for patients with constitutionally high TPMT activity. We attempted to assess its suitability as an alternative by comparing the pharmacokinetics of both drugs in a small group of children with lymphoblastic leukaemia (ALL).Patients were included who were in their second or subsequent remission, who would otherwise have received 6-MP, and on whom pharmacokinetic data concerning 6-MP metabolism had been collected in a previous remission. Plasma 6-TG concentrations were assayed following an oral dose of 40 mg m-2, and the accumulation and fluctuation of intracellular (erythrocyte, RBC) 6-TG nucleotides (6-TGNs) were measured at regular intervals during daily oral therapy.Seven children were studied. Plasma 6-TG concentrations were low and cleared within 6 h of oral dosing. At 7 days, 6-TGN concentrations ranged from 959 to 2361 pmol 8 x 10(-8) RBCs, in all cases significantly higher (P = 0.002) than those produced by the same patients on 6-MP. After a total therapy time of 35 patient months, a modest rise of alanine aminotransferase was seen on one occasion, otherwise no toxicity apart from myelosuppression was encountered.In the context used, 6-TG appears well tolerated and produces higher concentrations of intracellular cytotoxic metabolites than 6-MP. For children constitutionally 'resistant' to the traditional drug, if not all, it may be a preferable alternative.