PHARMACODYNAMICS OF ANTILEUKEMIC AGENTS IN CHILDREN

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，基本上是全世界所有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的甲氨喋呤的剂量和输注时间范围为100倍，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短时间静脉输注HDMTX（例如，4H），以便在门诊环境中提供治疗，但临床前研究表明，长时间接触效果更大。因此，我们目前的研究旨在确定24H输注HDMTX是否优于4H输注，对于所有谱系和倍体亚型（目的1），并阐明HDMTX细胞内配置和作用的遗传决定因素（目的2-4）。目的1在一项随机研究中得到解决，该研究将4H和24H输注HDMTX （1 gm/m2）作为新诊断ALL儿童的初始治疗，比较骨髓（BM）白血病细胞和外周血系列ALL细胞中活性MTX多谷氨酸代谢物的细胞积累和作用。治疗前后ALL细胞基因表达的全基因组评估用于确定HDMTX细胞配置的基因组决定因素（Aim 2），并确定治疗引起的基因表达变化，以区分具有良好反应的患者（即，完全抑制新生嘌呤合成，第3天ALL细胞减少bbb60 %，第19天无亚显微疾病，第42天完全缓解，长期无病生存）。来自不良反应的患者（目标3）。目的4将确定与候选基因的基因组反应差异相关的遗传多态性，这些基因可区分药物效应。初步数据表明，基因表达的变化可以区分反应良好和不良的患者，为细胞耐药机制提供了新的见解，并揭示了潜在的新靶点，以增强当前的治疗。

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.