Development of Mechanism-Based Stratgies for CLL Therapy

本项目的目标是在实验室开发，使用模型系统和体外原代CLL细胞 了解单独作用和基于机制的抗癌剂的作用机制 组合。该知识库将为临床试验的设计和评价提供依据， 将测试关于这些药物在患者的CLL细胞中的作用和相互作用的假设， 疗法因此，我们将检验的中心假设是，从对知识的理解中获得的知识， 新的抗癌治疗剂的代谢、作用机制和相互作用可用于 设计和评估治疗CLL患者的新治疗方案。实现这些 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 与氟达拉滨相比治疗B-CLL的药理学和临床优势？我们的重点是 新的核苷类似物氯法拉滨的药理学特性与氟达拉滨不同。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 核糖核苷酸类似物，减少细胞生物能量并阻断转录。此外，我们将评估 flavopiridol的转录导向作用。这些药剂中的每一种的作用降低了抗细胞凋亡作用。 CLL细胞中的蛋白质。3.基于机制的细胞毒性药物联合治疗能否改善CLL的结局 病人？将在CLL中研究细胞对抑制切除DNA修复过程的反应 细胞，并扩展到新的DNA损伤剂和药物，抑制DNA修复。4.人参皂甙， 具有有效抗癌活性和独特作用机制的合成天然化合物，可用作 治疗慢性淋巴细胞白血病的新药物？这种选择性杀死CLL的新型药物的作用机制 将研究不依赖于p53状态的细胞以准备临床开发。相互作用 这个计划中的其他项目将加强我们的调查。

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.