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合作组药理学部分的目标是在实验室中开发，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组合的药物作用机制。该知识库将为临床试验的设计提供基本原理，该临床试验将在临床试验中检验关于这些药物在CLL细胞中的作用和相互作用的假设。这将通过采用对每种单独药物特异性的药效学作用的测定以及适用于表征临床背景下CLL细胞中药物组合相互作用的程序来实现。这类药物，特别是氟达拉滨和克拉屈滨，已在CLL中显示出主要的临床疗效。这一类的新代表是G2506 U 78，克拉屈滨，已在CLL中显示出主要的临床疗效。这类药物的新代表是GW 506 U 78，一种在CLL中具有活性的阿拉伯糖基鸟嘌呤的前药，以及目前处于临床开发初始阶段的2-氯-2 '-氟-阿拉伯糖基腺嘌呤的氯法拉布林，其具有有利的药代动力学和药效学特性。2.信号通路抑制剂。对细胞周期调节途径的组分具有特异性的新试剂（其中几种处于临床试验中）在体外单独和组合时对CLL细胞具有活性。这些药剂包括：Flavopiridol是一种细胞周期蛋白依赖性激酶的抑制剂，已经处于II期评估中，UCN-01是一种蛋白激酶C和其他激酶的抑制剂，Depsipeptide（FR 901228）是一种组蛋白脱乙酰酶的抑制剂。3.基于机制的细胞毒性药物组合的开发。我们将采用一种策略，根据设计将药物组合在一起，每个组分的作用机制将是互补的，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掺入DNA修复补丁提供了机会。因此，该项目的实质是开发和采用能够在治疗期间批判性地评估CLL细胞中每种药剂或组合策略的作用机制的测定，作为验证并最终开发这种疾病的新疗法的方法。