Suzuki Ryoko, Fukushima Hiroko, Noguchi Emiko, Tsuchida Masahiro, Kiyokawa Nobutaka, Koike Kazutoshi, Ma Enbo, Takahashi Hideto, Kobayashi Chie, Nakajima-Yamaguchi Ryoko, Sakai Aiko, Saito Makoto, Iwabuchi Atsushi, Kato Keisuke, Nakao Tomohei, Yoshimi Ai, Sumazaki Ryo, Fukushima Takashi
Department of Child Health, Graduate School of Comprehensive Human Sciences.
Departments of Child Health.
Pediatr Int. 2015 Aug;57(4):572-7. doi: 10.1111/ped.12682.
Management of the adverse effects of chemotherapy is essential to improve outcome of children with leukemia. Some genetic polymorphisms can predict treatment-related toxicity, and be used individually in dose modification of 6-mercaptopurine (6-MP) and methotrexate (MTX) in maintenance therapy for childhood acute lymphoblastic leukemia (ALL). We investigated associations between clinical course and candidate gene polymorphisms less evaluated in Japanese patients.
Fifty-three children who received maintenance chemotherapy were enrolled in this study. The scheduled dose of oral 6-MP was 40 mg/m(2) daily and that of oral MTX was 25 mg/m(2) weekly. The doses were adjusted according to white blood cell count (target range, 2.5-3.5 × 10(9) /L) and aspartate aminotransferase and alanine aminotransferase level (< 750 IU/L). Eight polymorphisms in six candidate genes, TPMT, ITPA, MRP4, MTHFR, RFC1, and SLCO1B1, were genotyped using the Taqman PCR method. Clinical course was reviewed retrospectively from medical records.
The average dose of 6-MP was lower in the patients with at least one variant allele at SLCO1B1 c.521 T > C than in the patients with wild homozygous genotype. The other analyzed polymorphisms were not associated with toxicity, 6-MP, or MTX dose.
Polymorphism of SLCO1B1 c.521 T > C could be a strong predictor of 6-MP dose reduction in maintenance chemotherapy in childhood ALL.
化疗不良反应的管理对于改善白血病患儿的治疗结局至关重要。一些基因多态性可预测治疗相关毒性，并可单独用于儿童急性淋巴细胞白血病（ALL）维持治疗中6-巯基嘌呤（6-MP）和甲氨蝶呤（MTX）的剂量调整。我们研究了日本患者中较少评估的临床病程与候选基因多态性之间的关联。
本研究纳入了53例接受维持化疗的儿童。口服6-MP的预定剂量为每日40mg/m²，口服MTX的预定剂量为每周25mg/m²。根据白细胞计数（目标范围，2.5 - 3.5×10⁹/L）以及天冬氨酸转氨酶和丙氨酸转氨酶水平（<750IU/L）调整剂量。使用Taqman PCR方法对6个候选基因TPMT、ITPA、MRP4、MTHFR、RFC1和SLCO1B1中的8个多态性进行基因分型。从病历中回顾性分析临床病程。
SLCO1B1基因c.521 T>C位点至少有一个变异等位基因的患者，其6-MP的平均剂量低于野生纯合基因型患者。其他分析的多态性与毒性、6-MP或MTX剂量无关。
SLCO1B1基因c.521 T>C多态性可能是儿童ALL维持化疗中6-MP剂量降低的有力预测指标。
