Winick N J, Kamen B A, Balis F M, Holcenberg J, Lester C M, Poplack D G
Cancer Drug Deliv. 1987 Spring;4(1):25-31. doi: 10.1089/cdd.1987.4.25.
Methotrexate (MTX), a mainstay in the treatment of acute lymphoblastic leukemia, is associated with both hepatic and neurologic toxicity. Like a folate, MTX is metabolized to polyglutamated derivatives (MTXGlun) with long intracellular half-lives. These metabolites may contribute to MTX toxicity through a direct effect on cellular metabolism or indirectly through a perturbation of folate homeostasis. To better define the effects of chronic MTX treatment, tissue levels of MTX, MTXGlun, and folate were measured in three monkeys treated with weekly intramuscular MTX for 1 year. Greater than 80% of the total tissue MTX found was in the form of polyglutamated derivatives. Most of these derivatives were MTXGlu3-5 but Glu6-7 were easily detectable. Total tissue folates were measured in liver, kidney, brain and testis with MTX treated animals having a 90% loss of total folate in brain tissue. This is of special interest since inborn errors of folate metabolism are often associated with severe neurologic abnormalities.
甲氨蝶呤（MTX）是治疗急性淋巴细胞白血病的主要药物，与肝脏和神经毒性均有关联。MTX如同叶酸一样，会代谢为具有较长细胞内半衰期的多聚谷氨酸化衍生物（MTXGlun）。这些代谢产物可能通过对细胞代谢的直接作用或通过干扰叶酸稳态间接导致MTX毒性。为了更好地明确慢性MTX治疗的影响，对三只每周接受一次肌肉注射MTX，持续1年的猴子的组织中甲氨蝶呤、MTXGlun和叶酸的水平进行了测量。所发现的总组织MTX中超过80%为多聚谷氨酸化衍生物形式。这些衍生物大多是MTXGlu3 - 5，但Glu6 - 7也易于检测到。在肝脏、肾脏、大脑和睾丸中测量了总组织叶酸，接受MTX治疗的动物脑组织中的总叶酸损失了90%。这一点特别值得关注，因为叶酸代谢的先天性缺陷常常与严重的神经异常相关。
