PHARMACODYNAMICS OF ANTILEUKEMIC AGENTS IN CHILDREN

儿童抗白血病药物的药效学

• 批准号: 6751958
• 负责人: WILLIAM E EVANS
• 金额: $ 46.92万
• 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/6751958
• 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 <10% 提高到 >75%），但癌症仍然是导致儿童死亡的主要原因。美国 1 至 15 岁儿童因疾病死亡的情况。甲氨蝶呤 (MTX) 是最广泛使用的抗白血病药物之一，并且是全球几乎所有 ALL 治疗方案的组成部分。我们之前的工作已经确定了高剂量 (HD) MTX 相对于低剂量的优势、T 谱系 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 剂量和输注时间的范围超过 100 倍，且没有考虑治疗反应的遗传决定因素。此外，医疗经济学促使使用 HDMTX 短时间静脉输注（例如 4H），以便可以在门诊环境中进行治疗，但临床前研究表明，长期暴露效果更大。因此，我们当前的研究旨在确定对于 ALL 的每个谱系和倍性亚型，24 小时输注 HDMTX 是否优于 4 小时输注（目标 1），并阐明 HDMTX 细胞内处置和影响的遗传决定因素（目标 2-4）。目标 1 在一项随机研究中得到解决，该研究采用 4 小时与 24 小时输注 HDMTX (1 gm/m2) 作为新诊断 ALL 儿童的初始治疗，比较活性 MTX 聚谷氨酸代谢物在骨髓 (BM) 白血病中的细胞积累和作用细胞和来自外周血的连续 ALL 原始细胞。对治疗前后 ALL 细胞的基因表达进行全基因组评估，用于识别 HDMTX 细胞处置的基因组决定因素（目标 2），并识别治疗诱导的基因表达变化，以区分具有良好反应的患者（即完全抑制）嘌呤从头合成，第 3 天 ALL 细胞减少 > 60%，第 19 天 BM 不存在亚显微疾病，第 42 天完全缓解，并且长期无疾病生存率），来自反应不佳的患者（目标 3）。目标 4 将识别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不良的患者，为细胞耐药机制提供新的见解，并揭示增强当前治疗的潜在新靶标。