Development of Mechanism-Based Stratgies for CLL Therapy

开发基于机制的 CLL 治疗策略

• 批准号: 7117532
• 负责人: WILLIAM K PLUNKETT
• 金额: $ 18.48万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-10 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7117532
• 关键词: DNA repair; clinical research; nucleoside analog; proteins

The goals of this project are to develop in the laboratory, using model systems and primary CLL cells in vitro an understanding of the mechanisms of action of anticancer agents acting alone and in mechanism-based combinations. This knowledge base will provide rationales for the design and evaluation of clinical trials that will test hypotheses regarding the actions and interactions of these agents in CLL cells in patients during therapy. Thus, the central hypothesis we will test is that knowledge derived from an understanding of the metabolism, mechanisms of action, and the interactions of new anticancer therapeutics can be used to design and evaluate novel therapeutic regimens for the treatment of patients with CLL. To achieve these goals, we will address the following questions: 1. Do nucleoside analogs with novel actions provide pharmacological and clinical advantages over fludarabine for the treatment of B-CLL? Our focus here will be on the new nucleoside analog, clofarabine which has pharmacologic properties different from fludarabine. 2. Can strategies to reduce survival proteins selectively kill CLL cells? We are developing 8-chloro-adenosine ribonucleotide analog that reduces cellular bioenergy and blocks transcription. Also, we will evaluate the transcription-directed actions of flavopiridol. The actions of each of these agents decreases anti-apoptotic proteins in CLL cells. 3. Will mechanism-based combinations of cytotoxic agents improve outcome in CLL patients? The cellular responses to inhibition of excision DNA repair processes will be investigated in CLL cells, and extended to new DNA damaging agents and drugs that inhibit DNA repair. 4. Can orsaponin, a synthetic natural compound with potent anticancer activity and unique mechanism of action, be used as a novel agent for treatment of CLL? The action mechanism(s) of this novel agent that selectively kills CLL cells independent of p53 status will be investigated in preparation for clinical development. Interactions with other projects in this program will strengthen our investigations.

该项目的目标是在实验室中利用模型系统和体外原代CLL细胞进行开发 对抗癌药物单独作用和作用机理的认识 组合。该知识库将为以下临床试验的设计和评估提供理论基础 将测试有关这些药物在患者的CLL细胞中的作用和相互作用的假说 心理治疗。因此，我们将检验的中心假设是，从对 新的抗癌药物的代谢、作用机制和相互作用可用于 设计和评估治疗慢性淋巴细胞性白血病患者的新治疗方案。要实现这些目标 目标，我们将解决以下问题：1.具有新作用的核苷类似物是否提供 氟达拉滨治疗B-CLL的药理和临床优势？我们在这里的重点将是 关于新的核苷类似物氯法拉滨，它具有不同于氟达拉滨的药理性质。2. 减少存活蛋白的策略能选择性地杀死CLL细胞吗？我们正在开发8-氯腺苷 降低细胞生物能量并阻止转录的核糖核苷酸类似物。此外，我们还将评估 黄烷醇的转录导向作用。这些药物中的每一种都会降低抗凋亡作用。 CLL细胞中的蛋白质。3.基于机制的细胞毒药物联合治疗是否会改善慢性淋巴细胞性白血病的预后 病人？将研究慢性淋巴细胞性白血病细胞对切除DNA修复过程的抑制反应。 细胞，并扩展到新的DNA损伤剂和抑制DNA修复的药物。4.能不能或皂苷，a 人工合成的天然化合物，具有强大的抗癌活性和独特的作用机制，可用作 治疗慢性淋巴细胞白血病的新药物？这种新型药物选择性杀伤CLL的作用机制(S) 独立于P53状态的细胞将被研究，为临床开发做准备。与以下内容交互 该计划中的其他项目将加强我们的调查。