BIOCHEMICAL STRATEGIES TO INCREASE LEUKEMIA RESPONSE

描述：(申请者摘要)本申请的中心目标 是为优化给药开发假说 急性髓系白血病(AML)联合治疗 慢性粒细胞白血病钝性危象的体外实验研究 药理、生化和分子研究。后来， 将设计方案来评估药物动力学和 这些假说的药效学预测及其临床应用 回应。由于Ara-C对AML和CML-BC的治疗很重要， 将尝试通过生物化学来提高其疗效 调制策略、配料和调度，以及通过组合 其他有效的抗白血病药物。在以下情况下进行的试验研究 CA57629研究表明，输注氟达拉滨可提高 Ara-CTP在白血病细胞中的积聚比之前增加了近2倍 在同一患者中单独使用Ara-C。在临床上，这些因素的结合 两个代理导致了比以前更高的应答率 治疗。在本申请中，申请人计划延长这一期限 通过研究Ara-CTP代谢的另外三个调节器进行工作 氟达拉滨和阿糖胞苷的联合用药方案不同。各别 已经设计了一些方案来评估生化调节 克拉曲滨、海德瑞亚和吉西他滨在治疗中的作用 与Ara-C结合使用氟达拉滨和Ara-C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、时间表和持续时间都将仔细考虑 优化和选择以将这种体外方法转化为 药理学指导的临床试验。药代动力学和药动学 调节剂对Ara-CTP代谢和代谢的药效学影响 行动将是这些调查的重点。药代动力学 治疗期间成纤维细胞中Ara-C代谢物的含量将被评估为 确定可能产生的其他细胞毒性代谢物 阿糖胞苷脱氨为阿糖尿嘧啶(Ara-U)。申请者还将 研究这些类似三磷酸盐在体内的分子作用 与Ara-CTP联合应用，了解其协同细胞毒作用。 利用人DNA进行DNA引物延伸的体外模型系统 聚合酶α将被用来研究分子方面的 求婚。将寻求这些研究之间的相关性，以 确定Ara-CTP调控的预后意义 新陈代谢和行动。从这些调查中获得的知识将 用于优化现有方案的药品调度，并 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.