PHARMACOKINETICS AND PHARMACODYNAMICS IN ACUTE MYELOGENOUS LEUKEMIA

该项目的核心目标是最大限度地提高 核苷酸类似物的细胞内治疗强度 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 反应然而，我们之前的研究表明， 对活性核苷积累的限制 三磷酸盐不能通过简单的剂量规避 升级本申请提出将正在进行的申请扩展到本发明的实施例。 研究表明，生物化学和 生物调节方法成功地增加了 白血病细胞中活性代谢物的浓度， 这与改善的临床反应有关。具体地说， 设计了一个试验方案，以评估 粒细胞集落刺激因子（G-CSF）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- ATP）的白血病细胞。这项调查将在 在连续输注araC的情况下， 生长调节分子对稳态 将定量ara-CTP的浓度。第二 研究将集中在细胞药代动力学 核苷酸类似物三磷酸，以确定最低剂量的 氟达拉滨，其将使ara-CTP在小鼠中的积累最大化。 爆炸声这些信息将用于阶段的设计 我的研究是允许每日多次氟达拉滨联合给药 间歇性注射阿糖胞苷将寻求相关性 缓解诱导治疗的临床反应与 DNA断裂的动力学和程度以及凋亡形态 在白血病细胞中。最终，这些信息将提供一个 临床方案设计的全面原理， 联合收割机生长调节分子与细胞毒性抗白血病 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.