BIOCHEMICAL STRATEGIES TO INCREASE LEUKEMIA RESPONSE

描述：(申请者摘要)本申请的中心目标 是使用核苷酸测试在临床前环境中开发的假说 治疗白血病的类似物，并优化剂量和 一种新型有效核苷类似物--阿拉伯糖鸟嘌呤的合成 (Ara-G)。已经设计了方案来评估药物动力学和 这些假说和临床反应的药效学预测。 具体地说，申请人计划调查新的基于 使用核糖核苷酸还原酶抑制剂的策略。因为 克拉曲滨已被证明对治疗儿童急性髓细胞白血病有效，这 将测试核苷酸还原酶抑制剂来调节Ara-C 该患者群体中的三磷酸盐蓄积(目标1a)。要使用 核糖核苷酸还原酶抑制剂作为药物作用的增强剂， 氟达拉滨和持续输注阿糖胞苷联合静脉注射治疗。 海德里亚。(目标1b)。这是基于海德鲁输液的数据 持续且唯一地导致dATP池下降50%。 因为三磷酸氟达拉滨与dATP竞争，所以加入Hydrea将 提高氟达拉滨的合并度，从而发挥作用。第三次使用 核糖核苷酸还原酶抑制剂将测试其有效性 吉西他滨作为药物诱导的DNA修复的抑制剂 卡铂，已被证明对急性髓细胞白血病有效(目标1c)。申请人 假设耗尽将导致机械协同作用。这个 整个目标2致力于开发和测试不同的策略 一种新型核苷类似物Ara-G作为前药给药的优化 化合物506U。在申请人与506U的第一阶段试验中，她了解到 对这种药物的反应直接与细胞内的 阿糖胞苷-G三磷酸。最近，基于她的三种方法得到了发展 发表了在原发白血病细胞上的临床前工作。这些措施包括 最大化Ara-G磷酸化速率(目标2a)，生化 氟达拉滨对Ara-G三磷酸代谢的调节(目标2b)，以及 增加Ara-G暴露时间(目标2c)。药代动力学和药动学 药效学终点将与临床反应相关 未来的干预措施。这些基于原理的方法适用于单一和 联合药物的开发将为最佳治疗提供知识。

DESCRIPTION: (Applicant's Abstract) The central goals of this application are to test hypotheses developed in the preclinical setting using nucleotide analogues for the therapy of leukemias, and to optimize dosing and scheduling of a new and effective nucleoside analog, arabinosylguanine (ara-G). Protocols have been designed to evaluate the pharmacokinetic and pharmacodynamic predictions of these hypothesis and for clinical responses. Specifically, the applicant plans to investigate new mechanism based strategies with inhibitors of the ribonucleotide reductase. Because cladribine has been proven effective in the treatment of pediatric AML, this ribonucleotide reductase inhibitor will be tested to modulate ara-C triphosphate accumulation in this patient population (Aim 1a). To use ribonucleotide reductase inhibitor as an enhancer of drug action, fludarabine and continuous infusion ara-C therapy will be combined with i.v. hydrea. (Aim 1b). This is based on the data that hydrea infusion consistently and exclusively results in 50% decline in the dATP pool. Because fludarabine triphosphate competes with dATP, addition of hydrea will enhance incorporation and hence action of fludarabine. The third use of an ribonucleotide reductase inhibitor will test the effectiveness of gemcitabine as an inhibitor of DNA repair induced by agents such as carboplatin which has been proven effective in AML (Aim 1c). The applicant hypothesizes that the depletion would result in mechanistic synergy. The entire Aim 2 is devoted to developing and testing different strategies for optimization of a new nucleoside analog, ara-G, administered as a prodrug compound 506U. In the applicant's Phase I trial with 506U, she learned that the response to this agent is directly related to the intracellular level of ara-G triphosphate. Three approaches have evolved based on her recently published preclinical work in primary leukemia cells. These include maximization of the rate of ara-G phosphorylation (Aim 2a), biochemical modulation of ara-G triphosphate metabolism by fludarabine (Aim 2b), and increasing the ara-G exposure duration (Aim 2c). The pharmacokinetic and pharmacodynamic endpoints will be correlated with clinical responses for future interventions. These rationale based approaches for the single and combination drug development would provide knowledge for optimal therapy.