Clofarabine: Cytarabine Activation for Leukemia Response

氯法拉滨：阿糖胞苷激活白血病反应

• 批准号: 6800995
• 负责人: STEFAN FADERL
• 金额: $ 26.88万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-22 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6800995
• 关键词: acute lymphocytic leukemia; acute myelogenous leukemia; antineoplastics; biochemistry; blood cell count; clinical research; clinical trial phase II; combination chemotherapy; dosage; human subject; human therapy evaluation; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nucleoside analog; patient oriented research; pharmacokinetics; ribonucleotide reductase

DESCRIPTION (provided by applicant): The goal of this proposal is to further characterize the role of clofarabine in combination with cytarabine (ara-C) in the treatment of patients with acute leukemias who have relapsed or have become refractory to conventional therapy. Clofarabine is a novel nucleoside analog that was found to be active in phase I clinical trials of patients with hematologic malignancies. Activity in patients with advanced acute leukemias has been confirmed in phase II studies which are currently ongoing. Clofarabine acts through inhibition of DNA synthesis and repair. Importantly, clofarabine is also a potent inhibitor of ribonucleotide reductase (RnR) and thus ideally suited for biochemical modulation strategies with other nucleoside analogs such as ara-C. We have previously shown that RnR inhibitors (fludarabine, cladribine) can be used successfully to modulate ara-C triphosphate accumulation in leukemic cells. We therefore hypothesize that inhibition of RnR by clofarabine will result in a decrease in the levels of deoxynucleotides causing a subsequent decrease in the feedback inhibition of deoxycytidine kinase, the rate-limiting step in the synthesis of ara-CTP. We further hypothesize that the combination of clofarabine with ara-C leads to increased retention of ara-CTP in leukemic cells so that the antileukemic activity of clofarabine is complemented by a biochemical synergy between these agents that should result in greater clinical efficacy. The biochemical properties of clofarabine and data of its clinical efficacy in our target population determine the aims of the study. Specifically, we plan to investigate the safety and efficacy of the combination of clofarabine with ara-C (Aim1). Pharmacodynamic and pharmacokinetic measurements will determine intracellular concentrations of clofarabine triphosphate, clofarabine-triphosphate-mediated inhibition of RnR, and modulation of ara-CTP accumulation in leukemia cells (Aim 2). The pharmacodynamic and pharmacokinetic endpoints will then be correlated with clinical response to create a valuable knowledge base for future investigations of this agent (Aim 3) This study constitutes a rationally-designed attempt to utilize new and effective nucleoside analogs for single and combination drug development to achieve optimum therapeutic efficacy in a poor-prognosis group of patients.

描述（由申请人提供）：本提案的目的是进一步描述氯法拉滨与阿糖胞苷（ara-C）联合治疗复发或对常规治疗难治的急性白血病患者的作用。氯法拉滨是一种新型核苷类似物，在血液系统恶性肿瘤患者的 I 期临床试验中被发现具有活性。目前正在进行的 II 期研究已证实对晚期急性白血病患者的活性。氯法拉滨通过抑制 DNA 合成和修复发挥作用。重要的是，氯法拉滨也是核糖核苷酸还原酶 (RnR) 的有效抑制剂，因此非常适合与其他核苷类似物（例如 ara-C）一起实施生化调节策略。我们之前已经证明，RnR 抑制剂（氟达拉滨、克拉屈滨）可成功用于调节白血病细胞中 ara-C 三磷酸盐的积累。因此，我们假设氯法拉滨对 RnR 的抑制将导致脱氧核苷酸水平降低，从而导致脱氧胞苷激酶的反馈抑制随后降低，脱氧胞苷激酶是 ara-CTP 合成中的限速步骤。我们进一步假设氯法拉滨与 ara-C 的组合导致白血病细胞中 ara-CTP 的保留增加，因此氯法拉滨的抗白血病活性通过这些药物之间的生化协同作用得到补充，从而产生更好的临床疗效。氯法拉滨的生化特性及其在目标人群中的临床疗效数据决定了本研究的目的。具体来说，我们计划研究氯法拉滨与ara-C联合用药的安全性和有效性（目标1）。药效学和药代动力学测量将确定氯法拉滨三磷酸的细胞内浓度、氯法拉滨三磷酸介导的 RnR 抑制以及白血病细胞中 ara-CTP 积累的调节（目标 2）。然后将药效学和药代动力学终点与临床反应相关联，为该药物的未来研究创建有价值的知识库（目标 3）。这项研究构成了一项合理设计的尝试，旨在利用新的有效核苷类似物进行单一和组合药物开发，以在预后不良的患者群体中取得最佳治疗效果。