Adenosine Analogs: Therapeutics for Hematologic Cancers

腺苷类似物：血液癌症的治疗方法

• 批准号: 7034380
• 负责人: STEVEN Terry ROSEN
• 金额: $ 34.04万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-26 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7034380
• 关键词: DNA directed DNA polymerase; adenine analog; adenosine; antineoplastics; apoptosis; cell line; chronic myelogenous leukemia; clinical research; cysteine endopeptidases; drug screening /evaluation; enzyme activity; flow cytometry; gene mutation; high performance liquid chromatography; human subject; mitochondria; multiple myeloma; neoplasm /cancer pharmacology; nuclear magnetic resonance spectroscopy; nucleic acid biosynthesis; nucleoside analog; nucleoside triphosphate; oxidative phosphorylation; pharmacokinetics; polymerase chain reaction; ribonucleotide reductase

DESCRIPTION (provided by applicant): Multiple myeloma and chronic lymphocytic leukemia are composed of non- or slowly- replicating quiescent cell populations. Therefore, therapeutic approaches that do not target replicating DNA, but rather focus on transcription, translation, cellular bioenergy production, and critical molecular pathways may prove to be more effective. We have previously developed a halogenated ATP analog, 8-chloro-adenosine (8-CI-Ado) that has a unique RNA-directed mechanism of action. The special properties of this agent, two successful RAID awards, and availability of the GMP material has resulted in a clinical trial targeting patients with hematologic malignancies. The success of 8-CI-Ado stimulated our investigation of related analogs. We identified 8-amino-adenosine (8-NH2-Ado) and 8-azido-adenosine (8-N3-Ado) in this screen as having similar RNA-directed actions as the 8-CI-Ado halogenated congener. In preliminary studies, we have shown that 8-NH2-Ado actions are more potent and rapid than the halogenated congener. Most impressively, 8- NH2-Ado causes a massive accumulation of 8-NH2-ATP with a concomitant decrease in the endogenous ATP pools. In addition, there is a striking decrease in RNA synthesis, which is followed by a concurrent decrease in DNA synthesis. In this grant proposal, we will focus on the unique properties of 8-NH2-Ado and 8-N3-Ado in order to move these drugs forward to the clinical setting. In Aim I of this proposal, we will characterize the metabolism of these drugs, dissect their effects on mitochondria I function and the subsequent depletion of cellular bioenergy, and explore how these alterations may act on nucleic acid synthesis. In Aim II, we will further dissect the inhibitory actions toward RNA by examining changes in transcription and poly-adenylation. Finally, in Aim III, we will pursue the novel observation of decreased phosphorylation of key signaling pathways and how that impacts on apoptosis. Understanding the mechanisms underlying the actions of 8-modified adenosine analogs will allow for further rational drug design and lead to an identification of compounds that may complement the activity of these drugs in a therapeutic setting. Relevance to public health: These studies propose to investigate the mechanism of action of novel therapeutics that may be effective in treating slowly proliferating cancers of the blood such as multiple myeloma and chronic lymphocytic leukemia; cancers which are currently incurable.

描述（由申请人提供）：多发性骨髓瘤和慢性淋巴细胞性白血病由非或缓慢复制的静止细胞群组成。因此，不靶向复制DNA的治疗方法，而是专注于转录，翻译，细胞生物能源产生和关键分子途径可能更有效。我们以前已经开发了具有独特的RNA指导作用机理的卤代A​​TP类似物，8-氯腺苷（8-Ci-Ado）。该试剂的特殊特性，两个成功的RAID奖项以及GMP材料的可用性导致了针对血液学恶性肿瘤患者的临床试验。 8-Ci-Ado的成功刺激了我们对相关类似物的研究。我们在此筛选中鉴定出8-氨基 - 腺苷（8-NH2-ADO）和8-齐多腺苷（8-N3-Ado），它们的RNA指导作用与8-Ci-Ado卤代同源物具有类似的RNA指导作用。在初步研究中，我们表明8-NH2-ADO的作用比卤代同类物更有效和快速。最令人印象深刻的是，8-NH2-ADO会导致8-NH2-ATP的大量积累，内源性ATP池的伴随下降。另外，RNA合成的降低显着降低，随后是DNA合成的同时降低。在这项赠款建议中，我们将重点关注8-NH2-ADO和8-N3-ADO的独特性能，以将这些药物转向临床环境。在该提案的目标中，我们将表征这些药物的代谢，剖析它们对线粒体I功能的影响以及随后的细胞生物能源耗尽，并探索这些改变如何对核酸合成作用。在AIM II中，我们将通过检查转录和多腺苷酸化的变化来进一步剖析对RNA的抑制作用。最后，在AIM III中，我们将追求对关键信号途径磷酸化降低以及如何影响凋亡的新观察。了解8修饰的腺苷类似物作用的基础机制将允许进一​​步的合理药物设计，并导致对可能在治疗环境中这些药物活性补充的化合物的鉴定。与公共卫生有关：这些研究建议研究新型治疗剂的作用机理，这些疗法可能有效地治疗血液的缓慢增殖癌，例如多发性骨髓瘤和慢性淋巴细胞性白血病；目前无法治愈的癌症。