BIOCHEMICAL STRATEGIES TO INCREASE LEUKEMIA RESPONSE

该提案的中心目标是发展优化的假设 用于治疗急性骨髓性白血病的药物组合的施用 白血病（AML）的基础上，在体外药理学，生化， 分子研究 随后，将设计方案来评估 这些假设的药代动力学和药效学预测 和临床反应。 因为阿糖胞苷对于治疗 AML，将尝试通过以下方式提高其疗效： 生化调节策略、给药和时间安排，以及 联合其他有效的抗白血病药物。 根据R 03 CA 53311进行的初步研究表明， 氟达拉滨输注增加了ara-CTP的蓄积率， 2-在白血病原始细胞中， 病人 在临床上，这两种药物的组合导致 比我们之前的治疗有更好的反应率 本 我们计划通过调查 通过氟达拉滨和通过研究 这两种类似物三磷酸盐的分子作用，以了解 协同细胞毒性。 我们已经修改了协议， 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，我们将实施一个新的协议：ara-C和 氟达拉滨与DNA损伤剂米托蒽醌。 药代动力学 将分析白血病原始细胞中ara-CTP的积累，以评价 氟达拉滨和米托蒽醌的调节作用。 研究将 进行分析DNA损伤引入体内未标记的 接受米托蒽醌治疗的患者的白血病细胞。 生化 研究了这些药物对ara-CTP代谢的相互作用， 同一患者白血病原始细胞DNA损伤的体外研究 将进行补充和扩展体内研究。 将寻求这些研究之间的相关性，以确定 ara-CTP代谢调节的预后意义。 知识 从这些调查中获得的信息将用于优化 药物的现有协议，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.