Novel pharmacologic agents in CLL

CLL合作小组药理学部分的目标是在实验室中，利用模型系统和体外原代CLL细胞，了解药物单独作用和基于机制的联合作用的机制。该知识库将为临床试验的设计提供理论依据，这些临床试验将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的药效学作用进行分析，以及在临床环境中对CLL细胞中药物联合作用进行表征的适当程序来实现。这类药物，特别是氟达拉滨和克拉拉宾，在治疗慢性淋巴细胞白血病方面已显示出主要的临床疗效。这类药物的新代表是G2506U78，一种在CLL中表现出主要临床疗效的克拉拉宾。这类药物的新代表是GW506U78，这是一种对CLL有活性的阿拉伯糖基鸟嘌呤的前药，2-氯- 2'-氟阿拉伯糖基鸟嘌呤，目前处于临床开发的初级阶段，具有良好的药动学和药效学特性。2. 信号通路抑制剂。新的药物，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，在体外单独或联合对CLL细胞有活性。这些药物包括：Flavopiridol，一种细胞周期蛋白依赖激酶的抑制剂，已经处于II期评估，UCN-01，一种蛋白激酶C和其他激酶的抑制剂，以及Depsipeptide (FR901228)，一种组蛋白去乙酰化酶的抑制剂。3. 基于机制的细胞毒性药物组合的发展。我们将追求一种基于设计的药物组合策略，即每个成分的作用机制将是互补的，从而产生机制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被纳入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在治疗期间批判性地评估CLL细胞中每种药物的作用机制或组合策略的分析方法，作为验证并最终开发针对该疾病的新疗法的方法。

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.