PHARMACODYNAMICS OF ANTILEUKEMIC AGENTS IN CHILDREN

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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.