Smith A, Hum M, Winick N J, Kamen B A
Departments of Pediatrics and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9063, USA.
Clin Cancer Res. 1996 Jan;2(1):69-73.
Clinical and laboratory investigations during the past four decades have resulted in numerous schedules, doses, and routes of delivery for methotrexate (MTX). It remains as an important drug for the treatment of children with acute lymphoblastic leukemia (ALL). Aminopterin (AMT) was the initial antifolate showing promise as an anticancer drug. It is more potent than MTX and also is known to be accumulated more efficiently than MTX in model systems. Because Whitehead et al. (Blood, 76: 44-49, 1990) have shown that MTX accumulation by blasts at diagnosis is of prognostic significance in children with ALL, we reasoned that if accumulation of a "stoichiometric inhibitor" of dihydrofolate reductase by leukemic blasts was of prognostic importance, then whether it was AMT or MTX may be relevant only with respect to the absolute dose. To compare MTX and AMT metabolism, we incubated lymphoblasts with 1 microM radiolabeled drug in vitro. MTX and AMT accumulation by ALL cells (n = 24) was 0.7 +/- 0.7 and 1.47 +/- 0.9 pmol/10(6) cells, respectively. Based on the data of Whitehead et al., this predicts pharmacological success in 59 and 84% of the MTX and AMT groups, respectively. Moreover, 5 of 10 patients considered poor risks based on MTX accumulation would be "cures" based on AMT uptake. Even at only 0.1 microM AMT, a concentration at which there is little accumulation of MTX, 5 of 11 patients studied would be "pharmacological cures" based on AMT uptake. Accumulation of AMT by blasts from 11 patients with T-cell-lineage ALL and 5 patients with acute myelogenous leukemia was also found to be twice the uptake of MTX. These data allow the suggestion that AMT, despite increased potential for toxicity, may be useful in children who are identified as poor risks with respect to MTX uptake.
在过去的四十年里，临床和实验室研究得出了多种甲氨蝶呤（MTX）的给药方案、剂量和途径。它仍然是治疗儿童急性淋巴细胞白血病（ALL）的一种重要药物。氨基蝶呤（AMT）是最初显示出有望成为抗癌药物的抗叶酸剂。它比MTX更有效，并且在模型系统中已知比MTX更有效地积累。因为怀特黑德等人（《血液》，76：44 - 49，1990年）已经表明，诊断时原始细胞对MTX的积累在ALL儿童中具有预后意义，我们推断，如果白血病原始细胞对二氢叶酸还原酶的“化学计量抑制剂”的积累具有预后重要性，那么无论是AMT还是MTX可能仅在绝对剂量方面相关。为了比较MTX和AMT的代谢，我们在体外将淋巴母细胞与1微摩尔放射性标记药物一起孵育。ALL细胞（n = 24）对MTX和AMT的积累分别为0.7±0.7和1.47±0.9皮摩尔/10⁶个细胞。根据怀特黑德等人的数据，这分别预测MTX组和AMT组的药理学成功率为59%和84%。此外，基于MTX积累被认为是高风险的10名患者中有5名基于AMT摄取将被“治愈”。即使在仅0.1微摩尔AMT（MTX几乎没有积累的浓度）时，所研究的11名患者中有5名基于AMT摄取将是“药理学治愈”。还发现11例T细胞系ALL患者和5例急性髓性白血病患者的原始细胞对AMT的积累是对MTX摄取的两倍。这些数据表明，尽管AMT的毒性潜力增加，但对于那些被确定为MTX摄取高风险的儿童可能是有用的。
