Elucidation of adverse events of methotrexate based on genomic and proteomic analysis in childhood leukemia patients

甲氨蝶呤是管理在高剂量治疗儿童急性淋巴细胞白血病和恶性淋巴瘤。然而，肝毒性和骨髓抑制往往限制了它的使用。我们试图确定与甲氨蝶呤肝毒性和消除相关的遗传多态性。谷胱甘肽S-转移酶（GST）基因的遗传多态性，包括GSTT 1阳性/无效、GSTM 1阳性/无效和GSTP 1 A313 G，以及还原型叶酸载体1G 80 A基因（RFC 1 G80 A），亚甲基四氢叶酸还原酶C677 T（MTHFR C677T），用聚合酶链反应（PCR）法或直接测序法检测26例乳腺癌患者血清中乳腺癌耐药蛋白C421 A（BCRP C421 A）。GSTM 1阳性和RFC 1 AA（80）的患者肝毒性发生率较高（P = 0.035），MTHFR TT（677）基因型患者输注开始后48 h的甲氨蝶呤血清浓度较高（P = 0.028）。总之，GSTM 1阳性/无效和RFC 1 G80 A多态性可能是肝毒性的预测因子，MTHFR C677 T与甲氨蝶呤的消除相关。此外，天冬酰胺酶诱导的急性胰腺炎是维持治疗的关键问题。polymorphism.is我们试图阐明与胰腺炎相关的基因多态性，但没有发现预测胰腺炎的多态性。这些结果可以为儿童急性淋巴细胞白血病和恶性淋巴瘤的治疗提供有用的信息。

Methotrexate is administered in high doses to treat childhood acute lymphoblastic leukemia and malignant lymphoma. Hepatotoxicity and bone marrow suppression often limit its use, however. We tried to determine the genetic polymorphisms associated with the hepatotoxicity and elimination of methotrexate. Genetic polymorphisms of glutathione S-transferase (GST) genes including GSTT1 positive/null, GSTM1 positive/null, and GSTP1 A313G, and genes for reduced folate carrier 1G80A (RFC1 G80A), methylenetetrahydrofolate reductase C677T (MTHFR C677T), and breast cancer resistant protein C421A (BCRP C421A) were determined for 26 patients by the polymerase chain reaction (PCR) method or by direct sequencing. A high frequency of hepatotoxicity (P = 0.035) was observed for patients with GSTM1 positive and RFC1 AA(80), and serum concentrations of methotrexate 48 h after the start of infusion were higher for patients with the TT(677) genotype of MTHFR (P = 0.028). In conclusion, GSTM1 positive/null and RFC1 G80A polymorphisms could be predictors for hepatotoxicity, and the MTHFR C677T polymorphism.is associated with elimination of methotrexate.In addition, asparaginase-induced acute pancreatitis is a critical problem in maintenance therapy. We tried to clarify the genetic polymorphisms associated with pancreatitis, but no polymorphism to predict pancreatitis was found.Theses results could be useful information in treatment for childhood acute lymphoblastic leukemia and malignant lymphoma.