PHARMACOKINETICS AND PHARMACODYNAMICS IN ACUTE MYELOGENOUS LEUKEMIA

该项目的中心目标是最大化 核苷酸类似物在细胞内的治疗强度 白血病细胞。这是可取的，因为更大的细胞内 暴露于活性三磷酸盐与临床相关 回应。然而，我们之前的研究表明， 活性核苷积累的局限性 简单剂量不能绕过的三磷酸盐 升级。本申请提议将正在进行的 研究表明，无论是生物化学还是 生物调制方法成功地增加了 白血病细胞中活性代谢产物的浓度，以及 这与改善临床反应有关。具体来说， 已经设计了一个试点协议来评估 粒细胞集落刺激因子或全反式 维甲酸(ATRA)作为生物调节剂 活性三磷酸阿糖胞苷(Ara-CTP)和氟达拉滨(F-Ara-CTP) 三磷酸腺苷)。这项调查将在 持续输注Arac的背景，在此期间 生长调节分子在稳态中的作用 Ara-CTP的浓度将被定量。一秒钟 研究将集中在细胞药代动力学上。 核苷酸类似物三磷酸测定最小剂量 氟达拉滨将在体内最大限度地积累Ara-CTP 爆炸。这些信息将被用于设计一个阶段 我研究允许将多种剂量的氟达拉滨联合使用 间歇性地输注阿糖胞苷。我们将寻找相关信息 诱导缓解治疗的临床反应与 DNA断裂的动力学和程度以及细胞凋亡的形态 在白血病爆炸中。最终，这些信息将提供一个 设计临床方案的全面理论基础 生长调节分子与细胞毒性抗白血病药物的结合 毒品。

The central objective of this project is to maximize the intracellular therapeutic intensity of nucleotide analogues to leukemia cells. This is desirable because greater intracellular exposure to the active triphosphates is associated with clinical response. Our previous studies, however, have demonstrated limitations to the accumulation of the active nucleoside triphosphates that cannot be circumvented by simple dose escalation. The present application proposes to extend ongoing studies which have demonstrated that both biochemical and biological modulation approaches successfully increase the concentrations of active metabolites in leukemia cells, and that this is associated with improved clinical response. Specifically, a pilot protocol has been designed to evaluate the ability of granulocyte colony-stimulating factor (G-CSF) or all-trans retinoic acid (ATRA) to serve as biological modulators of the active triphosphates of ara-C (ara-CTP) and fludarabine (F-ara- ATP) in leukemia cells. This investigation will be conducted in the context of a continuous infusion of araC, during which the action of the growth regulatory molecules on the steady-state concentrations of ara-CTP will be quantitated. A second investigation will focus on the cellular pharmacokinetics of nucleotide analogue triphosphates to determine the minimum dose of fludarabine that will maximize the accumulation of ara-CTP in blasts. This information will be utilized in the design of a phase I study to permit combining multiple daily doses of fludarabine with intermittent ara-C infusions. Correlations will be sought between clinical response to remission induction therapy and the kinetics and extent of DNA fragmentation and apoptotic morphology in leukemia blasts. Ultimately, this information will provide a comprehensive rationale for the design of clinical protocols that combine growth regulatory molecules with cytotoxic antileukemia drugs.