PHARMACODYNAMICS OF ANTILEUKEMIC AGENTS IN CHILDREN

儿童抗白血病药物的药效学

• 批准号: 6680569
• 负责人: WILLIAM E EVANS
• 金额: $ 47.59万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6680569
• 关键词: acute lymphocytic leukemia; adolescence (12-20); antileukemic agent; blood tests; child (0-11); clinical research; dosage; drug administration rate /duration; drug metabolism; gene expression; genetic polymorphism; genotype; human subject; human therapy evaluation; lymphoblast; methotrexate; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplastic cell; patient oriented research; pediatric neoplasm /cancer; pediatric pharmacology; pharmacogenetics; pharmacokinetics; polyglutamates

DESCRIPTION (provided by applicant): Acute lymphoblastic leukemia (ALL) is the most common cancer in children, and despite remarkable progress in the treatment of ALL (cure has improved from <10 percent to >75 percent), cancer remains the leading cause of death by disease in US children between 1 and 15 years of age. Methotrexate (MTX) is one of the most widely used antileukemic agents and is a component of essentially every ALL treatment protocol worldwide. Our previous work has established the advantage of high-dose (HD) MTX over low-dose, the need for higher doses in T-lineage ALL, and mechanisms for lineage and ploidy differences. However, there is currently >100-fold range in the dosage and infusion time of MTX used to treat childhood ALL, with no consideration of the genetic determinants of treatment response. Furthermore, medical economics have prompted the use of short intravenous infusions of HDMTX (e.g., 4H), so that the treatment can be delivered in an outpatient setting, yet pre clinical studies indicate greater effects with prolonged exposure. Our current research is therefore designed to determine whether 24H is superior to 4H infusion of HDMTX, for each lineage and ploidy subtype of ALL (Aim 1), and to elucidate the genetic determinants of HDMTX intracellular disposition and effects (Aims 2-4). Aim 1 is addressed in a randomized study of 4H vs. 24H infusions of HDMTX (1 gm/m2) as initial therapy of children with newly diagnosed ALL, comparing cellular accumulation and effects of the active MTX polyglutamate metabolites in bone marrow (BM) leukemia cells and in serial ALL blasts from peripheral blood. Genome-wide assessment of gene expression in ALL cells before and after treatment is used to identify genomic determinants of HDMTX cellular disposition (Aim 2), and identify treatment induced changes in gene expression that discriminate patients who have a good response (i.e., complete inhibition of de novo purine synthesis, >60 percent decrease in ALL cells by day 3, absence of submicroscopic disease in day 19 BM, complete remission at day 42, and long-term disease free survival), from patients who have a poor response (Aim 3). Aim 4 will identify genetic polymorphisms linked to differences in genomic response of candidate genes that discriminate drug effects. Preliminary data indicate that changes in gene expression can discriminate patients with a good vs. poor response, providing new insights into mechanisms of cellular resistance and revealing potential new targets to augment current treatment.

描述（由申请人提供）：急性淋巴细胞白血病（ALL）是儿童中最常见的癌症，尽管ALL的治疗取得了显着进展（治愈率从75%提高<10 percent to >），但癌症仍然是1至15岁美国儿童疾病死亡的主要原因。甲氨蝶呤（MTX）是最广泛使用的抗白血病药物之一，是世界上几乎所有ALL治疗方案的组成部分。我们以前的工作已经确定了高剂量（HD）MTX优于低剂量，T细胞系ALL需要更高剂量，以及谱系和倍性差异的机制。然而，目前用于治疗儿童ALL的MTX剂量和输注时间范围&gt;100倍，未考虑治疗反应的遗传决定因素。此外，医疗经济学已经促使使用HDMTX的短静脉内输注（例如，4 H），因此可以在门诊进行治疗，但临床前研究表明，长期暴露的影响更大。因此，我们目前的研究旨在确定对于ALL的每个谱系和倍性亚型，2 - 4 H输注HDMTX是否上级4 H输注（目的1），并阐明HDMTX细胞内分布和作用的遗传决定因素（目的2-4）。目的1是在一项随机研究中进行的，该研究将HDMTX（1 gm/m2）的4 H与24 H输注作为新诊断的ALL儿童的初始治疗，比较了骨髓（BM）白血病细胞和外周血连续ALL原始细胞中活性MTX聚谷氨酸代谢物的细胞蓄积和作用。治疗前后ALL细胞中基因表达的全基因组评估用于鉴定HDMTX细胞分布的基因组决定因素（目的2），并鉴定治疗诱导的基因表达变化，其区分具有良好反应的患者（即，完全抑制从头嘌呤合成，第3天ALL细胞减少&gt; 60%，第19天BM无亚显微疾病，第42天完全缓解，长期无病生存）。目的4将确定与区分药物作用的候选基因的基因组反应差异相关的遗传多态性。初步数据表明，基因表达的变化可以区分反应良好与反应不良的患者，为细胞耐药机制提供了新的见解，并揭示了增强当前治疗的潜在新靶点。