PHARMACOLOGIC STUDIES OF ACUTE LYMPHOBLASTIC LEUKEMIA

急性淋巴细胞白血病的药理学研究

• 批准号: 2101167
• 负责人: BARTON A. KAMEN
• 金额: $ 14.35万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-01 至 1997-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2101167
• 关键词: 6 thiopurine; acute lymphocytic leukemia; child (0-11); combination cancer therapy; cooperative study; dihydrofolate reductase; drug metabolism; drug resistance; enzyme activity; folate; high performance liquid chromatography; human subject; human therapy evaluation; methotrexate; molecular oncology; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplasm /cancer relapse /recurrence; pediatric neoplasm /cancer; pharmacokinetics; phenotype; polymerase chain reaction; prognosis; statistics /biometry; urinalysis

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.

急性淋巴细胞白血病（ALL）是最常见的儿童 恶性肿瘤它约占所有确诊儿童的25% 得了癌症在过去的40年里， 治疗这些孩子。诱导缓解发生率超过95% 的时间和强度，多药治疗已导致65-70% 无病生存5年。在过去的十年里，POG开始 研究使用密集的，胃肠外甲氨蝶呤（MTX）和6- 巯基嘌呤（6-MP）作为唯一的药物在继续阶段， 疗法该设计基于两种药剂的已知协同作用， 通过胃肠外注射而不是通过肠外注射而渗透保护区部位的潜在益处 口服药物和经验知识，MTX和6-MP是两个 最有效的药物继续治疗。的初步结果 ALINC 15（第三阶段）令人兴奋。对于标准风险儿童， 无瘤生存率（DFS）为85%，高危组为70%。下一次POG审判 （ALINC 16）包括进一步强化胃肠外和 6-MP治疗的口服成分。了解其机制， 两种药物的作用与生物化学技术（如HPLC）相结合 和放射性配体结合测定）用于研究其药效学， 让我们明白为什么治疗会让一些孩子失败的克隆 一些重要的酶（例如二氢叶酸还原酶和 最近Folylpolyglutamate合成酶）也使我们有可能发现 在分子水平上治疗失败的原因。我们的目标 研究的目的是确定儿童或儿童的“药理学表型”， 白血病原始细胞可以预测白血病治疗的成功、失败或毒性 MTX和6-MP治疗。将分析MTX的原始细胞代谢 MTX和6-MP的红细胞代谢产物将被 在治疗过程中分析。在复发时，患者和 将参照MTX和6-MP代谢来研究白血病原始细胞。