BIOCHEMICAL STRATEGIES TO INCREASE LEUKEMIA RESPONSE

描述：（申请人的摘要）本申请的中心目标 是发展一种假设， 用于治疗急性骨髓性白血病（AML）的组合， 慢性髓细胞白血病钝性危象（CML-BC）的体外研究 药理学、生物化学和分子研究。随后，委员会注意到， 将设计方案以评价药代动力学， 这些假设和临床的药效学预测 反应因为ara-C对于AML和CML-BC的治疗是重要的， 将尝试通过生物化学方法来提高其功效。 调节策略、给药和时间安排，以及 其他有效的抗白血病药物。根据以下准则开展的试点研究 CA 57629已经证明氟达拉滨输注增加了 ara-CTP在白血病母细胞中的积累几乎是在 阿糖胞苷单独给药。临床上，这些因素的结合 两个代理人导致了比我们以前更高的响应率 治疗。在本申请中，申请人计划将 通过研究ara-CTP代谢的另外三种调节剂， 以及不同的氟达拉滨和阿糖胞苷联合用药方案。单独 已经设计了方案来评估生物化学调节 克拉屈滨、Hydrea和吉西他滨在 与阿糖胞苷联合使用。氟达拉滨和阿糖胞苷的组合将是 在K562体外模型系统中作为持续输注方案进行评价。 每种药物的剂量、时间表和持续时间将仔细研究。 优化和选择，以将这种体外方法转化为 指导临床试验。的药代动力学和 调节剂对ara-CTP代谢的药效学作用， 行动将是这些调查的重点。药代动力学 将评价治疗期间原始细胞中阿糖胞苷代谢产物的含量， 确定可能产生的其他细胞毒性代谢产物 ara-C脱氨为阿拉伯糖基尿嘧啶（ara-U）。申请人还将 研究这些类似物三磷酸盐在 与ara-CTP组合以理解协同细胞毒性。 人DNA引物延伸的体外模型 聚合酶α将被用来研究分子方面的 提议将寻求这些研究之间的相关性， 确定ara-CTP调节的预后意义 代谢和行动。从这些调查中获得的知识将 用于优化现有方案的药物调度， 设计和评估新的治疗方法。

DESCRIPTION: (Applicant's Abstract) The central goal of this application is to develop hypotheses for optimized administration of drug combinations for the therapy of acute myelogenous leukemia (AML) and chronic myelogenous leukemia in blunt crisis (CML-BC) 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 and CML-BC, 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 CA57629 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 an improved response rate than our previous treatments. In this application, the applicant plans to extend that work by investigating three additional modulators of ara-CTP metabolism and a different schedule of fludarabine and ara-C combination. Separate protocols have been designed to evaluate biochemical modulation strategies effected by cladribine, hydrea, and gemcitabine in combination with ara-C. The fludarabine and ara-C combination will be evaluated in K562 in vitro model system as continuous infusion regimen. The doses, schedule, and duration of each drug will be carefully optimized and selected to translate this in vitro approach as a pharmacologically guided clinical trial. The pharmacokinetic and pharmacodynamic effects of the modulators on ara-CTP metabolism and actions will be the focus of these investigations. The pharmacokinetics of ara-C metabolites in blasts during therapy will be evaluated to determine additional cytotoxic metabolites which may be generated by ara-C deamination to arabinosyluracil (ara-U). The applicant will also investigate molecular action of these analog triphosphates in combination with ara-CTP to understand the synergistic cytotoxicity. An in vitro model system of DNA primer extension using human DNA polymerase alpha will be used to investigate the molecular aspect of the proposal. Correlations will be sought between these studies to determine the prognostic significance of modulation of ara-CTP metabolism and actions. Knowledge gained from these investigations will be used to optimize scheduling of drugs for the existing protocol and to design and evaluate new treatments.