Kishi Shinji, Griener James, Cheng Cheng, Das Soma, Cook Edwin H, Pei Deqing, Hudson Melissa, Rubnitz Jeffrey, Sandlund John T, Pui Ching-Hon, Relling Mary V
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
J Clin Oncol. 2003 Aug 15;21(16):3084-91. doi: 10.1200/JCO.2003.07.056.
Despite its clinical success, methotrexate (MTX) therapy is associated with toxicities such as seizures, the pathogenesis of which remains unclear. It has been suggested that hyperhomocysteinemia is caused by MTX and is responsible for its neurotoxic effects. The purposes of this study were to explore whether hyperhomocysteinemia was related to MTX administration and toxicity and whether homocysteine or MTX toxicity differed by methylenetetrahydrofolate reductase (MTHFR) or reduced folate carrier (RFC) genetic polymorphisms.
We studied 53 children with newly diagnosed acute lymphoblastic leukemia who were consecutively treated on a single clinical protocol that included two courses of high-dose MTX (high-dose methotrexate [HDMTX]; 2.5 or 5.0 g/m2 per day) as consolidation therapy.
The study participants' median plasma homocysteine concentrations at 23 and 44 hours after HDMTX (9.00 micromol/L and 10.12 micromol/L, respectively) were greater than the concentrations immediately before HDMTX (5.77 micromol/L, P <.0001 for both comparisons). Seven days after HDMTX treatment, their plasma concentration returned to baseline. Nine patients experienced seizures, and five patients experienced thrombosis during the first 15 months of therapy, with a tendency for there to be higher plasma homocysteine in patients with seizures across all time points (P =.063) but not in patients with thrombosis (P =.59). We observed no significant differences in plasma or cerebrospinal fluid homocysteine levels or in toxicity based on the MTHFR 677C/T or RFC 80G/A genotypes.
We conclude that homocysteine was transiently elevated after HDMTX and may be related to seizure risk in children with leukemia.
尽管甲氨蝶呤（MTX）治疗在临床上取得了成功，但它与癫痫发作等毒性反应相关，其发病机制尚不清楚。有人提出，高同型半胱氨酸血症是由MTX引起的，并导致其神经毒性作用。本研究的目的是探讨高同型半胱氨酸血症是否与MTX给药及毒性有关，以及同型半胱氨酸或MTX毒性是否因亚甲基四氢叶酸还原酶（MTHFR）或还原型叶酸载体（RFC）基因多态性而有所不同。
我们研究了53例新诊断的急性淋巴细胞白血病儿童，他们按照单一临床方案连续接受治疗，该方案包括两个疗程的高剂量MTX（大剂量甲氨蝶呤[HDMTX]；每天2.5或5.0 g/m²）作为巩固治疗。
HDMTX治疗后23小时和44小时，研究参与者的血浆同型半胱氨酸浓度中位数（分别为9.00 μmol/L和10.12 μmol/L）高于HDMTX给药前即刻的浓度（5.77 μmol/L，两次比较P均<.0001）。HDMTX治疗7天后，其血浆浓度恢复至基线水平。9例患者在治疗的前15个月内发生癫痫发作，5例患者发生血栓形成，在所有时间点癫痫发作患者的血浆同型半胱氨酸有升高趋势（P = 0.063），但血栓形成患者无此趋势（P = 0.59）。基于MTHFR 677C/T或RFC 80G/A基因型，我们未观察到血浆或脑脊液同型半胱氨酸水平及毒性方面的显著差异。
我们得出结论，HDMTX治疗后同型半胱氨酸短暂升高，可能与白血病患儿的癫痫发作风险有关。
