BIOCHEMICAL STRATEGIES TO INCREASE LEUKEMIA RESPONSE

描述：（申请人的摘要）本申请的中心目标 是为了测试在临床前环境中开发的假设， 类似物用于治疗白血病，并优化给药和 一种新的有效的核苷类似物阿拉伯糖基鸟嘌呤的排序 （ara-G）。 已设计方案来评价药代动力学和 这些假设的药效学预测和临床反应。 具体而言，申请人计划研究基于 策略与抑制剂的核糖核苷酸还原酶。 因为 克拉屈滨已被证明在治疗儿童AML中有效， 将测试核糖核苷酸还原酶抑制剂调节ara-C 该患者人群中的三磷酸盐蓄积（目的1a）。 使用 作为药物作用增强剂的核糖核苷酸还原酶抑制剂， 氟达拉滨和连续输注阿糖胞苷治疗将与静脉内给药相结合。 Hydrea。 (Aim 1 b）。 这是基于Hydrea输液的数据， 一致且唯一地导致dATP池下降50%。 由于三磷酸氟达拉滨与dATP竞争，因此添加氢将 增强氟达拉滨的掺入并因此增强其作用。 第三种用法是 核糖核苷酸还原酶抑制剂将测试的有效性 吉西他滨作为DNA修复的抑制剂， 卡铂已被证明对AML有效（目的1c）。 申请人 假设消耗将导致机械协同作用。 的 整个Aim 2致力于开发和测试不同的策略， 一种新的核苷类似物ara-G作为前药给药的优化 化合物506 U。 在申请人的506 U I期试验中，她了解到， 对该试剂的反应与细胞内的 ara-G三磷酸盐 根据她最近的研究， 发表了在原代白血病细胞中的临床前工作。 这些包括 ara-G磷酸化速率最大化（目标2a），生化 通过氟达拉滨调节ara-G三磷酸代谢（Aim 2b），和 增加阿糖胞苷暴露持续时间（目标2c）。 的药代动力学和 药效学终点将与以下各项的临床应答相关： 未来的干预措施。 这些基于原理的方法， 联合药物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.