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作用机制。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。感兴趣的化合物有：1)核苷类似物。这类药物，特别是氟达拉滨和克拉拉宾，已显示出治疗慢性淋巴细胞白血病的主要临床疗效。吉西他滨，一种易于代谢的，长寿命的嘧啶核苷类似物，氯法拉滨，2-氯-2'-弗洛-阿拉伯糖苷，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。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：黄嘌呤醇，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的抑制剂，以及Depsipeptide (FR901228)，一种通过MAP激酶进行细胞周期信号传导的抑制剂。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被纳入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.