Novel pharmacologic agents in CLL

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的作用机制。 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。 感兴趣的化合物的类别是：1）核苷类似物。 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。 吉西他滨（一种易代谢的长效嘧啶核苷类似物）和氯法拉滨（2-氯-2 '-氟-阿拉伯糖基腺嘌呤）目前处于临床前开发的最后阶段，具有良好的药代动力学和药效学特性。 2)信号通路抑制剂。 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的抑制剂，Depsipeptide（FR 901228）是一种通过MAP激酶进行细胞周期信号传导的抑制剂。 3)细胞毒性药物的机制基础组合的开发。 我们将采用一种策略，根据设计将药物配对组合，每个组分的作用机制将互补，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掺入DNA修复补丁提供了机会。 因此，该项目的本质是在治疗期间开发CLL细胞中的组合，作为验证并最终开发这种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 action 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. The classes of compounds of interest are: 1) Nucleoside Analogs. This class of drugs, particularly fludarabine and cladrabine, has demonstrated major clinical efficacy in CLL. Gemcitabine, a readily metabolized, long-lived pyrimidine nucleoside analog, Clofarabine, 2-chloro-2'-flouro- arabinosyladenine, presently in the final stages of preclinical 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 Depsipeptide (FR901228) an inhibitor of cell cycle signaling through MAP kinase. 3) Development of mechanism-base combinations of cytotoxic drugs. We will pursue a strategy that pairs drugs in combination based on the design that the mechanism of action of each component will 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 for combinations in CLL cells during therapy as approaches for validating and ultimately for developing new therapeutics for this disease.