Millot F, Dhondt J L, Mazingue F, Mechinaud F, Ingrand P, Guilhot F
Service d'Hématologie et Oncologie Médicale, CHU, Poitiers, France.
Pediatr Res. 1995 Feb;37(2):151-4. doi: 10.1203/00006450-199502000-00004.
Acute or subacute neurologic disorders can be observed in patients receiving high-dose methotrexate therapy for lymphoblastic leukemia or malignant tumor. Impairment of biopterin metabolism leading to decreased availability of monoamine neurotransmitters has been suggested to explain methotrexate neurotoxicity. To investigate such a mechanism, we have measured prospectively by HPLC the concentrations of total biopterin, homovanillic acid, and 5-hydroxyindolacetic acid in cerebrospinal fluid of 57 children with acute lymphoblastic leukemia. A sequential analysis of cerebrospinal fluid was performed for each patient: cerebrospinal fluid samples were obtained before therapy and after each of the four high-dose methotrexate infusions during the CNS prophylaxis phase. A significant increase of total biopterin concentrations in cerebrospinal fluid was observed after high-dose methotrexate therapy compared with the pretreatment values. No cumulative effect was noted. In contrast, no significant variation of the homovanillic acid and 5-hydroxyindolacetic acid levels was observed in cerebrospinal fluid. However, individual analysis revealed a transient decrease of homovanillic acid and 5-hydroxyindolacetic acid concentrations in cerebrospinal fluid of six children. The increase of total biopterin mimicking that observed in inherited dihydropteridine reductase deficiencies suggests that methotrexate inhibits the regenerating system of biopterin in the brain of patients undergoing high-dose methotrexate therapy.
在接受高剂量甲氨蝶呤治疗淋巴细胞白血病或恶性肿瘤的患者中，可观察到急性或亚急性神经功能障碍。有人提出，生物蝶呤代谢受损导致单胺类神经递质可用性降低，以此来解释甲氨蝶呤的神经毒性。为了研究这一机制，我们前瞻性地采用高效液相色谱法测定了57例急性淋巴细胞白血病患儿脑脊液中总生物蝶呤、高香草酸和5-羟吲哚乙酸的浓度。对每位患者的脑脊液进行了连续分析：在中枢神经系统预防阶段，于治疗前以及四次高剂量甲氨蝶呤输注中的每次输注后采集脑脊液样本。与治疗前值相比，高剂量甲氨蝶呤治疗后脑脊液中总生物蝶呤浓度显著升高。未观察到累积效应。相比之下，脑脊液中高香草酸和5-羟吲哚乙酸水平未观察到显著变化。然而，个体分析显示，6名儿童脑脊液中的高香草酸和5-羟吲哚乙酸浓度出现短暂下降。总生物蝶呤的增加与遗传性二氢蝶呤还原酶缺乏症中观察到的情况相似，这表明甲氨蝶呤抑制了接受高剂量甲氨蝶呤治疗患者大脑中生物蝶呤的再生系统。
