BIOCHEMICAL STRATEGIES TO INCREASE LEUKEMIA RESPONSE

提高白血病反应的生化策略

• 批准号: 2894954
• 负责人: VARSHA GANDHI
• 金额: $ 20.32万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-15 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2894954
• 关键词: DNA repair; DNA replication; acute myelogenous leukemia; antileukemic agent; apoptosis; carboplatin; clinical research; clinical trial phase I; combination cancer therapy; cytotoxicity; drug administration rate /duration; drug interactions; drug metabolism; drug screening /evaluation; enzyme inhibitors; fludarabine; gemcitabine; human subject; human therapy evaluation; hydroxyurea; neoplastic cell; nucleoside analog; pharmacokinetics; prodrugs; ribonucleotide reductase

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.

描述：（申请人摘要）本申请的中心目标 是使用核苷酸来测试在临床前环境中提出的假设 用于治疗白血病的类似物，并优化剂量和 一种新的有效核苷类似物阿拉伯糖鸟嘌呤的调度 (ara-G)。 方案旨在评估药代动力学和 这些假设和临床反应的药效学预测。 具体来说，申请人计划研究基于新机制 核糖核苷酸还原酶抑制剂的策略。 因为 克拉屈滨已被证明可有效治疗小儿 AML， 将测试核糖核苷酸还原酶抑制剂调节 ara-C 该患者群体中三磷酸盐蓄积（目标 1a）。 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 ara-C 治疗将与静脉注射相结合。 水螅。 （目标 1b）。 这是基于水螅输液的数据 持续且唯一地导致 dATP 池下降 50%。 由于氟达拉滨三磷酸与 dATP 竞争，添加水螅会 增强氟达拉滨的掺入，从而增强其作用。 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 修复抑制剂 卡铂已被证明对 AML 有效（目标 1c）。 申请人 假设耗尽将导致机械协同作用。 这 整个目标 2 致力于开发和测试不同的策略 作为前药给药的新型核苷类似物 ara-G 的优化 化合物506U。 在申请人对506U的一期试验中，她了解到 对这种药物的反应与细胞内的水平直接相关 阿糖胞苷-G 三磷酸。 最近在她的基础上发展了三种方法 发表了原发性白血病细胞的临床前工作。 这些包括 ara-G 磷酸化率最大化（目标 2a），生化 氟达拉滨调节 ara-G 三磷酸代谢（目标 2b），以及 增加 ara-G 暴露持续时间（目标 2c）。 药代动力学和 药效学终点将与临床反应相关 未来的干预措施。 这些基于基本原理的方法适用于单一和 联合药物开发将为最佳治疗提供知识。