Lennard L, Lewis I J, Michelagnoli M, Lilleyman J S
Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield, U.K.
Med Pediatr Oncol. 1997 Oct;29(4):252-5. doi: 10.1002/(sici)1096-911x(199710)29:4<252::aid-mpo3>3.0.co;2-l.
Daily 6-mercaptopurine (6MP) forms the backbone of continuing chemotherapy for childhood lymphoblastic leukaemia (ALL). A major metabolic route is catalysed by thiopurine methyltransferase (TPMT). TPMT deficiency occurs in 1 in 300 individuals and results in high concentrations of thioguanine nucleotides (TGNs), cytotoxic 6MP metabolites. A leukaemic child taking 6MP repeatedly developed profound pancytopenias. TPMT deficiency was confirmed. TGN formation was then studied on attenuated 6MP dosages. Four weekly oral doses of 75 mg/m2 6MP produced TGNs of 2348 pmol/8 x 10(8) red cells, nearly double the maximum TGNs recorded in ALL children with TPMT activity taking long term daily 75 mg/m2 6MP. Grossly elevated TGN concentrations were also produced at 10% standard 6MP dosage (7.5 mg/m2 daily), accompanied by unacceptable 6MP toxicity (neutropenia, diarrhoea, vomiting). The child was eventually stabilised on 10% alternate day therapy and after 15 weeks TGNs were 1670 pmol, just above the upper end of the TGN range for ALL children with TPMT activity.
每日服用6-巯基嘌呤（6MP）是儿童淋巴细胞白血病（ALL）持续化疗的主要手段。一条主要的代谢途径由硫嘌呤甲基转移酶（TPMT）催化。每300人中就有1人存在TPMT缺乏，这会导致硫鸟嘌呤核苷酸（TGNs）（具有细胞毒性的6MP代谢产物）浓度升高。一名接受6MP治疗的白血病患儿反复出现严重的全血细胞减少症。TPMT缺乏得到确诊。随后研究了降低6MP剂量时TGN的形成情况。每周口服4次、每次剂量为75mg/m²的6MP，会使每8×10⁸个红细胞产生2348pmol的TGNs，几乎是长期每日服用75mg/m² 6MP且具有TPMT活性的ALL患儿所记录到的最高TGNs的两倍。在6MP标准剂量的10%（每日7.5mg/m²）时也会产生显著升高的TGN浓度，同时伴有难以接受的6MP毒性（中性粒细胞减少、腹泻、呕吐）。该患儿最终通过10%的隔日疗法实现病情稳定，15周后TGNs为1670pmol，略高于具有TPMT活性的ALL患儿TGN范围的上限。
