PHARMACODYNAMICS OF ANTILEUKEMIC AGENTS IN CHILDREN

儿童抗白血病药物的药效学

• 批准号: 6376788
• 负责人: WILLIAM E EVANS
• 金额: $ 40.57万
• 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/6376788
• 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.

甲氨蝶呤（MTX）是最活跃和广泛使用的药物之一。 治疗儿童急性淋巴细胞白血病（ALL）的药物，但 关于最佳剂量和时间表仍然存在相当大的不确定性 MTX的剂量范围为0.04 gm/m2至8 gm/m2，目前临床上 使用. 高剂量MTX（HDMTX）的基本原理受到质疑， 证明可饱和膜转运的体外研究基础， 多聚谷氨酰化，表明HDMTX不会实现更高的 所有原始细胞中的浓度。 然而，PI已经确定HDMTX 达到更高的活性聚谷氨酰化的淋巴母细胞浓度 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 研究还揭示了MTXPG在B-谱系中的显著更大的积累 vs. T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的积累最终是 但可能需要更高的MTX血浆浓度（Cpss） 以在T系淋巴母细胞中实现最大MTXPG。 临床上 重要的是建立最佳MTX剂量为不同的白血病 谱系和倍性，以避免不必要的高剂量， 脑病和其他严重毒性。 因此，当前的目标 研究的目的是：（目的1）确定在体内，MTX的Cpss产生的最大 MTXPG在儿童白血病淋巴母细胞中的积累以及是否存在MTXPG在儿童白血病淋巴母细胞中的积累。 在白血病亚型（表型和 基因型），（目的2）定义MTXPG浓度之间的关系 白血病原始细胞和MTX的抗白血病作用，以及是否有 白血病亚型之间的显着差异（目的3）以确定 高MTX Cpss是否与（矛盾的） 淋巴母细胞积累的长链MTXPG在体内，和（目的4）， 确定表型和基因型差异的潜在机制 MTXPG在ALL母细胞中的蓄积。 总体而言，这些综合 临床和实验室研究将提供重要的新见解， 合理设计儿童ALL的未来治疗方案。