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.

描述：甲氨蝶呤（MTX）是最活跃和广泛使用的 治疗儿童急性淋巴细胞白血病的药物（全部） 最佳剂量和时间表仍然存在很大的不确定性 MTX的剂量范围从0.04 gm/m2到8克/m2 使用。 高剂量MTX（HDMTX）的理由已在 体外研究的基础证明了饱和膜转运和 聚谷氨酸，表明HDMTX无法达到更高 所有爆炸中的浓​​度。 但是，PI已经确定HDMTX 实现较高的活性聚谷氨酸的淋巴细胞浓度 患者的代谢物（MTXPG）（JCI 94：1996-2001，1994），这是 与更大的抗血症作用有关（JCI，97：73-80，1996）。 这些 研究还显示，B-linege中MTXPG的积累明显更大 与T-Linege爆炸，在高二倍体中与非二倍体淋巴细胞。 我们最近的研究表明，MTXPG的积累最终是 可能需要饱和但MTX血浆浓度（CPS）较高 为了实现T-Linege淋巴细胞中最大的MTXPG。 它在临床上 重要的是建立不同的白血病的最佳MTX剂量 谱系和倍曲，以避免不必要的高剂量 脑病和其他严重毒性。 因此，目前的目标 研究是：（目标1）要定义体内，MTX CPS产生最大 MTXPG在儿童白血病淋巴细胞中的积累以及是否存在 白血病亚型之间存在显着差异（表型和 基因型），（目标2）定义MTXPG浓度之间的关系 白血病爆炸和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）确定 高MTX CPS是否与（悖论）减少有关 长链MTXPG在体内积累的淋巴细胞和（目标4） 确定基本表型和基因型差异的机制 在所有爆炸中的MTXPG积累中。 总的来说，这些集成了 临床和实验室研究将为 童年的未来治疗方案的合理设计。