Hum M C, Smith A K, Lark R H, Winick N J, Kamen B A
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas 75235-9063, USA.
Pharmacotherapy. 1997 Nov-Dec;17(6):1260-6.
To explore the value of high-dose methotrexate (MTX).
Blast cells from 15 patients with acute lymphoblastic leukemia.
We compared uptake and polyglutamation of [3H]-MTX by freshly isolated leukemic blasts in vitro after 24-hour exposure to 1, 10, and 50 microM [3H]-MTX.
Mean MTX uptake (pmol/10(6) cells) was 0.78 +/- 0.19, 2.3 +/- 0.54, and 5.9 +/- 1.9, respectively, and mean polyglutamation was 82%, 66%, and 46%. Consequently, mean MTX polyglutamates were 0.68 +/- 0.18, 1.5 +/- 0.47, and 2.2 +/- 0.67 pmol/10(6) cells. Three of 15 patient samples had no detectable polyglutamation of MTX at 50 microM but MTX polyglutamates were detectable at 1 microM. Two of these three had a decrease in MTX polyglutamates at 10 versus 1 microM. In eight precursor B cell samples there was a significant difference in median MTX polyglutamates at 1 versus 10 microM but not 10 versus 50 microM.
Increasing extracellular MTX concentrations may be counterproductive for some patients with acute lymphoblastic leukemia. If MTX polyglutamates are important for efficacy, optimal delivery of MTX may have to be determined by individual metabolism rather than by targeting a specific drug concentration.
探讨大剂量甲氨蝶呤（MTX）的价值。
15例急性淋巴细胞白血病患者的原始细胞。
我们比较了新鲜分离的白血病原始细胞在体外分别暴露于1、10和50微摩尔[3H]-MTX 24小时后对[3H]-MTX的摄取和多聚谷氨酸化情况。
MTX的平均摄取量（皮摩尔/10^6个细胞）分别为0.78±0.19、2.3±0.54和5.9±1.9，平均多聚谷氨酸化率分别为82%、66%和46%。因此，MTX多聚谷氨酸的平均含量分别为0.68±0.18、1.5±0.47和2.2±0.67皮摩尔/10^6个细胞。15例患者样本中有3例在50微摩尔时未检测到MTX的多聚谷氨酸化，但在1微摩尔时可检测到MTX多聚谷氨酸。这3例中有2例在10微摩尔时MTX多聚谷氨酸的含量相较于1微摩尔时有所下降。在8例前体B细胞样本中，1微摩尔与10微摩尔时MTX多聚谷氨酸的中位数有显著差异，但10微摩尔与50微摩尔时无显著差异。
对于一些急性淋巴细胞白血病患者，增加细胞外MTX浓度可能会产生适得其反的效果。如果MTX多聚谷氨酸对疗效很重要，那么MTX的最佳给药方式可能需要根据个体代谢情况来确定，而不是针对特定的药物浓度。
