PHARMACODYNAMICS OF ANTILEUKEMIC AGENTS IN CHILDREN

说明：甲氨蝶呤(MTX)是最活跃和应用最广泛的药物之一。 治疗儿童急性淋巴细胞白血病(ALL)的药物 关于最佳剂量和时间表，仍存在相当大的不确定性 目前临床上使用的剂量从0.04克/平方米到8克/平方米不等 使用。大剂量甲氨蝶呤(HDMTX)的理论基础在 体外研究表明可饱和膜转运和 多谷氨酰化，表明HDMTX不会达到更高的 所有爆炸中的浓度。然而，PI已经确定HDMTX 达到更高的淋巴母细胞活性聚谷氨酰化浓度 患者体内的代谢产物(MTXPG)(JCI 94：1996-2001,1994)，这是 与更强的抗白血病作用相关(JCI，97：73-80,1996)。这些 研究还显示，MTXPG在B细胞系中的积聚显著增加 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 饱和，但可能需要更高的MTX血浆浓度(CPSS) 在T细胞系中获得最大的MTXPG。这是临床上的 重要的是确定治疗不同类型白血病的最佳MTX剂量 血统和倍性，以避免不必要的高剂量可能导致 脑病和其他严重毒性反应。因此，当前的目标是 研究内容如下：(1)在体内确定MTX CPSS最大产生量 MTXPG在儿童白血病淋巴母细胞中的蓄积及其是否存在 白血病亚型之间有显著差异(表型和 基因)，(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有 白血病亚型之间的显著差异，(目标3)以确定 高MTX CPSS是否与(矛盾的) 淋巴母细胞在体内蓄积长链MTXPG，以及(目标4) 确定表型和遗传型差异的机制(S) 在所有爆炸中积累的MTXPG。总体而言，这些集成了 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未来治疗方案。

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.