BIOCHEMICAL STRATEGIES TO INCREASE LEUKEMIA RESPONSE

这项提议的中心目标是开发优化的假设 急性髓系白血病的联合用药治疗 白血病(AML)的体外药理、生化和 分子研究。随后，将设计方案以评估 这些假说的药代动力学和药效学预测 并用于临床反应。因为Ara-C对于治疗糖尿病很重要 AML，将通过以下方式努力增强其效力 生化调节策略、给药和调度，以及 联合其他有效的抗白血病药物。 根据R03 CA53311进行的试点研究表明 氟达拉滨输注可提高Ara-CTP的蓄积率 白血病发病率是单独使用Ara-C后的2倍 有耐心的。在临床上，这两种药物的结合导致了 比我们以前的治疗有更好的有效率。在现在 建议我们计划通过调查 氟达拉滨对Ara-CTP代谢的增强作用及其机制的研究 这两种类似的三磷酸酯的分子作用 协同细胞毒性。我们已经修改了基于 药理学研究并将研究细胞药代动力学 和药效学，以寻求与临床反应的相关性。 此外，我们还将实现一个新的协议：Ara-C和Ara-C的组合 氟达拉滨和DNA损伤剂米托蒽醌。阿司匹林的药代动力学 将分析白血病原始细胞中Ara-CTP的积聚，以评估 氟达拉滨和米托蒽醌的调节作用。研究将会是 分析体内引入未标记的DNA损伤 接受米托蒽醌治疗的患者的白血病细胞。生化 这些药物对Ara-CTP代谢和For的相互作用的研究 同一患者白血病细胞体外DNA损伤的研究 将进行补充和扩大体内研究。 将在这些研究之间寻找相关性，以确定 Ara-CTP代谢调控的预后意义。知识 从这些调查中获得的信息将用于优化 用于现有方案的药物，并设计和评估新的 治疗。

The central goal of this proposal is to develop hypotheses for optimized administration of drug combinations for the therapy of acute myelogenous leukemia (AML) based on in vitro pharmacological, biochemical, and molecular studies. Subsequently, protocols will be designed to evaluate the pharmacokinetic and pharmacodynamic predictions of these hypotheses and for clinical response. Because ara-C is important for the therapy of AML, attempts will be directed toward enhancing its efficacy by biochemical modulation strategies, dosing and scheduling, and by combination of other effective antileukemic drugs. Pilot studies conducted under R03 CA53311 have demonstrated that fludarabine infusion increased the rate of ara-CTP accumulation nearly 2-fold in leukemia blasts over that after ara-C alone in the same patient. Clinically, the combination of these two agents resulted in better response rates than our previous treatments. In the present proposal we plan to extend that work by investigating the mechanism of potentiation of ara-CTP metabolism by fludarabine and by studying the molecular action of these two analogue triphosphates to understand the synergistic cytotoxicity. We have amended the protocol based on the pharmacology studies and will investigate the cellular pharmacokinetics and pharmacodynamics to seek correlations with clinical response. Additionally, we will implement a new protocol: combination of ara-C and fludarabine with a DNA damaging agent, mitoxantrone. Pharmacokinetics of ara-CTP accumulation in leukemic blasts will be analyzed to evaluate the modulatory action of fludarabine and mitoxantrone. Studies will be performed to analyze the DNA damage introduced in vivo into unlabeled leukemia cells from patients receiving mitoxantrone therapy. Biochemical studies of the interaction of these agents for ara-CTP metabolism and for DNA damage in vitro in leukemic blasts isolated from the same patient will be conducted to complement and extend in vivo investigations. Correlations will be sought between these studies to determine the prognostic significance of modulation of ara-CTP metabolism. Knowledge gained from these investigations will be used to optimize scheduling of drugs for the existing protocol and to design and evaluate new treatments.