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）：急性淋巴细胞性白血病（ALL）是儿童中最常见的癌症，尽管在所有人治疗方面取得了显着进展（治愈已从<10％提高到> 75％），但癌症仍然是1至15岁之间美国儿童疾病的主要死亡原因。甲氨蝶呤（MTX）是使用最广泛的抗白血病药物之一，是全球所有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优于低剂量的优势，T-linege全部需要更高剂量的剂量，以及谱系和倍增性差异的机制。但是，目前在用于治疗儿童时期的MTX的剂量和输注时间中，没有考虑治疗反应的遗传决定因素。此外，医学经济学促使使用HDMTX（例如4H）的短静脉内输注，因此可以在门诊环境中进行治疗，但临床前研究表明，延长暴露的临床研究更大。因此，我们目前的研究旨在确定24H是否优于HDMTX的4H输注，对于所有谱系和倍型亚型（AIM 1），并阐明了HDMTX细胞内处置和效应的遗传决定因素（AIMS 2-4）。 AIM 1在4H与24H输注HDMTX（1 gm/m2）的随机研究中被解决，作为对所有新诊断的儿童的初步疗法，比较了活性MTX聚谷氨酸代谢物在骨髓（BM）白血病细胞中的细胞积累和影响。 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长期无疾病的生存），来自反应较差的患者（AIM 3）。 AIM 4将确定与区分药物作用的候选基因基因组反应差异有关的遗传多态性。初步数据表明，基因表达的变化可以区分良好反应和反应良好的患者，从而提供了对细胞抗性机制的新见解，并揭示了潜在的新靶标，以增加当前治疗。