Peeters M, Poon A
Division of Haematology and Oncology, Hospital for Sick Children, Toronto, Ontario, Canada.
Eur J Pediatr. 1987 Jul;146(4):416-22. doi: 10.1007/BF00444952.
Twenty-four patients with Down syndrome and leukemia were studied. A strong male predominance (79%) was found. Age ranged between 18 months and 15 years (mean: 5 6/12); 54% of the patients were less than 4 years of age at the time of diagnosis. A preleukemic phase was noted in 6/24 patients. This phase, characterized essentially by thrombocytopenia, lasted from 2-8 months. Patients with preleukemia had unusual blast cell morphology and involvement of more than one cell line (dyserythropoiesis, hypolobulated megakaryocytes) and were probably M7 leukemias. All patients demonstrated severe methotrexate toxicity at standard methotrexate doses. Toxicity, manifesting as mouth ulcerations and bone marrow depression was seen regardless of the route of administration (oral, intrathecal or intravenous). A 30%-50% reduction of the standard dose was tolerated. Methotrexate absorption and clearance were studied in two patients and were found to be normal. We postulate that the observed toxicity of methotrexate may be due to a gene dosage effect for enzymes known to be on chromosome 21 and intervening in purine metabolism. Increased purine synthesis implies greater tetrahydrofolic acid demands and therefore greater sensitivity to an antifolate agent.
对24例患有唐氏综合征和白血病的患者进行了研究。发现男性占主导地位（79%）。年龄在18个月至15岁之间（平均：5岁6个月）；54%的患者在诊断时年龄小于4岁。24例患者中有6例出现白血病前期。该阶段主要表现为血小板减少，持续2 - 8个月。白血病前期患者具有异常的原始细胞形态，且累及不止一种细胞系（异常红细胞生成、低叶巨核细胞），可能为M7型白血病。所有患者在标准甲氨蝶呤剂量下均表现出严重的甲氨蝶呤毒性。无论给药途径（口服、鞘内或静脉注射）如何，均出现了表现为口腔溃疡和骨髓抑制的毒性。标准剂量减少30% - 50%可耐受。对两名患者进行了甲氨蝶呤吸收和清除研究，发现均正常。我们推测，观察到的甲氨蝶呤毒性可能是由于已知位于21号染色体上且参与嘌呤代谢的酶的基因剂量效应所致。嘌呤合成增加意味着对四氢叶酸的需求更大，因此对抗叶酸剂更敏感。
