gamma-Glutamyl hydrolase and folylpolyglutamate synthetase activities predict polyglutamylation of methotrexate in acute leukemias.
gamma-Glutamyl hydrolase and folylpolyglutamate synthetase activities predict polyglutamylation of methotrexate in acute leukemias.
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发表时间：
1997-12
影响因子：
3.1
通讯作者：
Giuseppe Longo;R. Gorlick;William P. Tong;Silan Lin;P. Steinherz;J. R. Bertino
中科院分区：
文献类型：
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作者：
Giuseppe Longo;R. Gorlick;William P. Tong;Silan Lin;P. Steinherz;J. R. Bertino
甲氨蝶呤（MTX）长链聚谷氨酸形成减少与MTX耐药相关，而在对治疗有反应并改善预后的白血病患者的原始细胞中发现高水平的MTX聚谷氨酸蓄积。长链MTX多聚谷氨酸盐的稳态水平取决于两种酶活性的平衡：叶酰多聚谷氨酸盐合成酶（FPGS），其将谷氨酸盐以γ-羧基键加到MTX上，和γ-谷氨酰水解酶（GGH）或缀合酶，其依次去除MTX多聚谷氨酸盐的末端谷氨酸盐残基。在15个急性白血病（髓系和淋巴系）患者的原始细胞样本中与[3 H]MTX孵育后，测定了FPGS和GGH活性以及总MTX和长链MTX聚谷氨酸盐的形成。与单独测定任一活性相比，GGH和FPGS活性之间的比率在预测24小时[3 H]MTX测定中聚谷氨酸盐累积量方面更好。长链多聚谷氨酸盐/总多聚谷氨酸盐的相对水平与GGH/FPGS比值的线性回归曲线显示r值为0.81（P < 0.001）。这些数据表明，这两种酶在诊断的评价可用作MTX多聚谷氨酰胺化的预测因子，因此对MTX治疗的反应和结果。
Decreased methotrexate (MTX) long-chain polyglutamate formation is associated with MTX resistance whereas high levels of MTX polyglutamate accumulation are found in the blasts of leukemia patients who respond to therapy and have improved outcome. The steady-state level of long-chain MTX polyglutamates depends on the balance of activities of two enzymes: folylpolyglutamate synthetase (FPGS), which adds glutamates to MTX in a gamma-carboxyl linkage, and gamma-glutamyl hydrolase (GGH) or conjugase, which sequentially removes the terminal glutamate residue of MTX polyglutamates. FPGS and GGH activities as well as the formation of total and long-chain MTX polyglutamates were measured after incubation with [3H]MTX in 15 blast samples from patients with acute leukemias (myeloid and lymphoid). The ratio between GGH and FPGS activities was better at predicting the amount of polyglutamate accumulated in the 24-h [3H]MTX assay compared to the determination of either activity alone. The linear regression curve relating the relative levels of long-chain polyglutamates/total polyglutamates with the ratio of GGH/FPGS showed an r value of 0.81 (P < 0.001). These data suggest that the evaluation of both these enzymes at diagnosis may be used as a predictor of MTX polyglutamylation and therefore for response to MTX therapy and outcome.