PHARMACODYNAMICS OF ANTILEUKEMIC AGENTS IN CHILDREN

儿童抗白血病药物的药效学

• 批准号: 7069691
• 负责人: WILLIAM E EVANS
• 金额: $ 48.24万
• 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/7069691
• 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(申请人提供)：急性淋巴细胞性白血病(ALL)是儿童中最常见的癌症，尽管在治疗ALL方面取得了显著进展(治愈率从10%提高到75%)，但癌症仍然是美国1至15岁儿童因疾病死亡的主要原因。甲氨蝶呤(MTX)是使用最广泛的抗白血病药物之一，几乎是全世界所有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相对于低剂量的优势，T系ALL需要更高的剂量，以及谱系和倍体差异的机制。然而，目前用于治疗儿童ALL的MTX的剂量和输注时间有100倍的范围，没有考虑治疗反应的遗传决定因素。此外，医学经济学促使人们使用短时间静脉输注HDMTX(例如4H)，以便在门诊环境下进行治疗，但临床前研究表明，长时间使用HDMTX的效果更好。因此，我们目前的研究旨在确定对于ALL的每个谱系和倍体亚型(目标1)，24H是否优于4H输注HDMTX(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)。目的1在一项随机研究中，将HDMTX(1gm/m2)4h和24h输注作为初诊急性淋巴细胞白血病(ALL)患儿的初始治疗，比较活性MTX多谷氨酸代谢物在骨髓(BM)白血病细胞和系列外周血ALL细胞中的蓄积和作用。利用对治疗前后所有细胞中基因表达的全基因组评估来确定HDMTX细胞处置的基因组决定因素(目标2)，并确定治疗诱导的基因表达变化，以区分反应良好的患者(即，完全抑制从头合成嘌呤，&GT；到第3天所有细胞减少60%，BM第19天没有亚微观疾病，第42天完全缓解，长期无病生存)，从反应差的患者(目标3)。目标4将确定与区分药物效果的候选基因的基因组反应差异有关的遗传多态。初步数据表明，基因表达的变化可以区分反应良好和反应差的患者，为细胞耐药机制提供新的见解，并揭示潜在的新靶点，以加强当前的治疗。