Novel pharmacologic agents in CLL

CLL 的新型药物

• 批准号: 6594419
• 负责人: WILLIAM K PLUNKETT
• 金额: $ 16.54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-31 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6594419
• 关键词: antimetabolites; antineoplastics; chronic lymphocytic leukemia; clinical research; combination chemotherapy; cytotoxicity; drug screening /evaluation; enzyme inhibitors; human subject; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nucleoside analog; pharmacokinetics

The goals of the Pharmacology Component of the CLL Cooperative Group are to develop in the laboratory, using model systems and primary CLL cells in vitro, an understanding of the mechanisms of ation of agents acting alone and in mechanism-based combinations. This knowledge base will provide rationale for the design of clinical trials that will test hypothesis regarding the actions and interactions of these agents in CLL cells in clinical trials. This will be achieved by employing assays of the pharmacodynamic actions specific to each individual agent, and procedures that are appropriate for characterization of the interactions of agents in combination in CLL cells in the clinical context. This class of drugs, particularly fludarabine and cladrabine, has demonstrated major clinically efficacy in CLL. New representatives of this class are G2506U78, a cladrabine, has demonstrated major clinical efficacy in CLL. New representatives of this class are GW506U78, a pro-drug of arabinosylguanine, which has activity in CLL and Clofarabrine, 2-chloro- 2'-fluoro-arabinosyladenine, presently in the initial stages of clinical development, that has favorable pharmacokinetic and pharmacodynamic properties. 2. Inhibitors of Signaling Pathways. New agents, several of which are in clinical trials, that have specificity against components of the cell cycle regulatory pathways have activity against CLL cells in vitro alone and also in combinations. These agents include: Flavopiridol, an inhibitor of cyclin dependent kinases, is already in phase II evaluation, UCN-01, an inhibitor of protein kinase C and other kinase, and Depsipeptide (FR901228) an inhibitor of histone deacetylase. 3. Development of mechanism-based combinations of cytotoxic drugs. We will pursue a strategy that pairs drugs in combinations based on the design that the mechanism of action of each component will be complementary, thereby resulting in mechanistic synergism and greater cytotoxicity. Our hypothesis is that the indolent nature of CLL limits the activity of these agents, but the process of DNA repair offers an opportunity for the nucleoside analogs to be incorporated into DNA repair patches. Thus, the essence of this project is to develop and employ assays capable of critically evaluating the mechanisms of action of each agent or strategy for combinations in CLL cells during therapy as approaches for validating and ultimately for developing new therapeutics for this disease.

CLL 合作小组药理学部分的目标是在实验室中使用模型系统和体外原代 CLL 细胞进行开发，了解单独作用的药物和基于机制的组合的作用机制。该知识库将为临床试验的设计提供基本原理，这些临床试验将在临床试验中检验有关这些药物在 CLL 细胞中的作用和相互作用的假设。这将通过对每种药物特有的药效学作用进行分析，并采用适合于临床背景下 CLL 细胞中药物组合相互作用表征的程序来实现。这类药物，特别是氟达拉滨和克拉拉滨，已在 CLL 中表现出主要的临床疗效。该类别的新代表是 G2506U78，一种克拉拉滨，已在 CLL 中显示出主要的临床疗效。该类药物的新代表是GW506U78，一种阿拉伯糖鸟嘌呤前药，对慢性淋巴细胞白血病（CLL）具有活性；氯法拉滨（2-氯-2'-氟-阿拉伯糖腺嘌呤）目前处于临床开发的初始阶段，具有良好的药代动力学和药效学特性。 2.信号通路抑制剂。新药物（其中一些正在临床试验中）对细胞周期调节途径的成分具有特异性，在体外单独或联合使用时对 CLL 细胞具有活性。这些药物包括：Flavopiridol，一种细胞周期蛋白依赖性激酶抑制剂，已进入 II 期评估；UCN-01，一种蛋白激酶 C 和其他激酶抑制剂；以及 Depsipeptide (FR901228)，一种组蛋白脱乙酰酶抑制剂。 3.基于机制的细胞毒性药物组合的开发。我们将采取一种基于每个成分的作用机制互补的设计将药物配对的策略，从而产生机械协同作用和更大的细胞毒性。我们的假设是，CLL 的惰性性质限制了这些药物的活性，但 DNA 修复过程为核苷类似物并入 DNA 修复补丁提供了机会。因此，该项目的本质是开发和采用能够严格评估治疗期间 CLL 细胞中每种药物的作用机制或组合策略的测定方法，作为验证并最终开发针对该疾病的新疗法的方法。