PHARMACOLOGIC STUDIES OF ACUTE LYMPHOBLASTIC LEUKEMIA

急性淋巴细胞性白血病(ALL)是儿童最常见的疾病 恶毒。它约占所有确诊儿童的25% 得了癌症。在过去的40年里，中国取得了长足的进步 对这些孩子的治疗。诱导缓解率超过95% 在时间和强度上，多药物治疗的结果是65%-70% 无病生存5年。在过去的十年里，POG开始 调查强化注射用甲氨蝶呤(MTX)和6-甲氨蝶呤(6-MTX)的使用 硫代嘌呤(6-MP)作为持续阶段的独家制剂 心理治疗。该设计是基于两种制剂的已知协同作用， 非肠道穿透避难所的潜在好处 比口服药物和经验知识更重要的是MTX和6-MP是两种 最有效的持续治疗药物。的初步结果。 ALINC 15(第三阶段)令人兴奋。对于标准风险儿童来说，疾病 自由存活率(DFS)为85%，高危患者为70%。下一次POG试验 (ALINC 16)包括进一步加强肠外和 6-MP治疗的口服成分。对致病机理的认识 这两种药物结合生化技术(如高效液相色谱)的作用 和放射性配基结合分析)来研究它们的药效学 让我们理解为什么治疗会让一些孩子失败。基因的克隆 一些重要的酶(如二氢叶酸还原酶和 最近的叶基多谷氨酸合成酶)也让我们有可能找到 在分子水平上治疗失败的原因。我们的目标是 研究的目的是定义儿童或儿童的“药理学表型” 白血病细胞将预测治疗的成败或毒性 甲氨蝶呤和6-甲基-4-羟色胺联合治疗。将分析甲氨蝶呤的原始细胞代谢 在诊断和RBC代谢时，MTX和6-MP的代谢产物将是 在治疗过程中进行了分析。在复发时，患者和 白血病母细胞将参照甲氨蝶呤和6-甲基-4-羟色胺的代谢进行研究。

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. It accounts for approximately 25% of all children diagnosed with cancer. During the past 4 decades great strides have been made in the therapy for these children. Induction of a remission occurs more than 95% of the time and intensive, multi-agent therapy has resulted in a 65-70% disease free survival of 5 years. In the past decade the POG began investigating the use of intensive, parenteral methotrexate (MTX) and 6- mercaptopurine (6-MP) as the sole agents in the continuation phase of therapy. The design was based upon the known synergy of the two agents, the potential benefit of sanctuary site penetration by parenteral rather than oral drug and the empiric knowledge that MTX and 6-MP are the two most effective agents for continuation therapy. The preliminary results of ALINC 15 (Phase III) are exciting. For standard risk children the disease free survival (DFS) is 85% and for high risk 70%. The next POG trial (ALINC 16) includes further intensification of both the parenteral and oral components of 6-MP therapy. An understanding of the mechanism of action of the two drugs coupled with the biochemical techniques (e.g. HPLC and radio-ligand binding assays) for studying their pharmacodynamics may allow us to understand why therapy fails some children. The cloning of some of the important enzymes (e.g. dihydrofolate reductase and very recently folylpolyglutamate synthetase) also allows us to possibly find reasons for treatment failure at a molecular level. The goal of our studies is to define a "pharmacologic phenotppe" of either the child or of the leukemic blasts that will predict success, failure or toxicity of treatment with MTX and 6-MP. Blast cell metabolism of MTX will be analyzed at the time of diagnosis and rbc metabolites of both MTX and 6-MP will be analyzed during therapy. At the time of relapse the patient and the leukemic blasts will be studied with reference to MTX and 6-MP metabolism.