PHARMACODYNAMICS OF ANTILEUKEMIC AGENTS IN CHILDREN

儿童抗白血病药物的药效学

• 批准号: 2896531
• 负责人: WILLIAM E EVANS
• 金额: $ 38.49万
• 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 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2896531
• 关键词: B lymphocyte; T lymphocyte; acute lymphocytic leukemia; antileukemic agent; blood chemistry; child (0-11); clinical research; dosage; folate; genotype; human subject; human therapy evaluation; lymphoblast; methotrexate; pediatric neoplasm /cancer; pediatric pharmacology; pharmacokinetics; phenotype; polyglutamates

DESCRIPTION: Methotrexate (MTX) is one of the most active and widely used drugs for the treatment of childhood acute lymphoblastic leukemia (ALL), yet there remains considerable uncertainty about the optimal dosage and schedule of MTX, with doses ranging from 0.04 gm/m2 to 8 gm/m2 currently in clinical use. The rationale for high-dose MTX (HDMTX) has been questioned on the basis of in vitro studies demonstrating saturable membrane transport and polyglutamylation, indicating that HDMTX would not achieve higher concentrations in ALL blasts. However, the PI has established that HDMTX achieves higher lymphoblast concentrations of the active polyglutamylated metabolites (MTXPG) in patients (JCI 94:1996-2001, 1994), and that this is associated with greater antileukemic effects (JCI, 97:73-80, 1996). These studies also revealed significantly greater MTXPG accumulation in B-lineage vs. T-lineage blasts, and in hyperdiploid vs. non-hyperdiploid lymphoblasts. Our more recent studies suggest that MTXPG accumulation is eventually saturable but that higher MTX plasma concentrations (Cpss) may be required to achieve maximum MTXPG in T-lineage lymphoblasts. It is clinically important to establish the optimal MTX dosage for leukemia of different lineages and ploidy, to avoid unnecessarily high dosages that can induce encephalopathy and other serious toxicities. Therefore, aims of the current studies are: (Aim 1) to define in vivo, the MTX Cpss producing maximum accumulation of MTXPG in leukemic lymphoblasts of children and whether there are significant differences among leukemic subtypes (phenotype and genotype), (Aim 2) to define the relation between MTXPG concentrations in leukemic blasts and the antileukemic effects of MTX and whether there are significant differences among leukemic subtypes, (Aim 3) to determine whether high MTX Cpss is associated with a (paradoxical) decrease in lymphoblast accumulation of long-chain MTXPG in vivo, and (Aim 4) to determine the mechanism(s) underlying phenotypic and genotypic differences in MTXPG accumulation in ALL blasts. Collectively, these integrated clinical and laboratory studies will provide important new insights for the rational design of future treatment protocols for childhood ALL.

描述：甲氨蝶呤 (MTX) 是最活跃和最广泛使用的药物之一 目前尚无治疗儿童急性淋巴细胞白血病（ALL）的药物 最佳剂量和时间表仍存在相当大的不确定性 MTX，目前临床剂量范围为0.04 gm/m2至8 gm/m2 使用。 高剂量 MTX (HDMTX) 的基本原理受到质疑 体外研究的基础证明了饱和膜运输和 多谷氨酰化，表明 HDMTX 不会达到更高的 所有原始细胞中的浓度。 然而，PI 已确定 HDMTX 获得更高的活性聚谷氨酰化淋巴母细胞浓度 患者体内的代谢物 (MTXPG) (JCI 94:1996-2001, 1994)，这是 与更大的抗白血病作用相关(JCI, 97:73-80, 1996)。 这些 研究还表明 B 谱系中 MTXPG 的积累显着增加 与 T 谱系母细胞，以及超二倍体与非超二倍体淋巴母细胞。 我们最近的研究表明 MTXPG 的积累最终会 可饱和，但可能需要更高的 MTX 血浆浓度 (Cpss) 以在 T 系淋巴母细胞中达到最大 MTXPG。 临床上是这样的 确定不同类型白血病的最佳 MTX 剂量非常重要 谱系和倍性，以避免可能诱导的不必要的高剂量 脑病和其他严重毒性。 因此，当前的目标 研究是：（目标 1）定义体内 MTX Cpss 产生的最大 MTXPG在儿童白血病淋巴细胞中的蓄积及其是否存在 白血病亚型（表型和 基因型），（目标 2）定义 MTXPG 浓度之间的关系 白血病母细胞和 MTX 的抗白血病作用以及是否存在 白血病亚型之间的显着差异（目标 3）以确定 高 MTX Cpss 是否与（矛盾的）减少有关 长链 MTXPG 在体内的淋巴母细胞积累，以及（目标 4） 确定表型和基因型差异的潜在机制 所有原始细胞中 MTXPG 的积累。 总的来说，这些综合 临床和实验室研究将为以下方面提供重要的新见解： 合理设计儿童 ALL 的未来治疗方案。