Novel pharmacologic agents in CLL

CLL合作组的药理学部分的目标是在实验室利用模型系统和体外原代CLL细胞，了解单独作用的药物和以机制为基础的组合的作用机制。这个知识库将为临床试验的设计提供理论基础，这些临床试验将检验关于这些药物在临床试验中在CLL细胞中的作用和相互作用的假说。这将通过采用针对每个单独药物的药效学作用的分析，以及适合于在临床背景下表征CLL细胞中联合药物的相互作用的程序来实现。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性白血病方面已显示出重大的临床疗效。这一类的新代表是G2506U78，一种已在CLL中显示出主要临床疗效的枝拉宾。这一类的新代表是GW506U78，一种具有CLL和Clofarabine活性的阿拉伯糖鸟嘌呤前体药物，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性质。2.信号通路的抑制物。针对细胞周期调节通路成分具有特异性的新药物，在体外单独和联合使用时对CLL细胞具有活性，其中几种正在进行临床试验。这些药物包括：细胞周期蛋白依赖性激酶的抑制剂黄吡哆醇，已经进入第二阶段评估的药物，蛋白激酶C和其他激酶的抑制剂UCN-01，以及组蛋白脱乙酰酶的抑制剂Depsi多肽(FR901228)。3.发展以机制为基础的细胞毒药物组合。我们将奉行一种策略，即根据每个成分的作用机制将互补的设计，将药物配对成组合，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试剂的活性，但DNA修复过程为核苷类似物进入DNA修复补丁提供了机会。因此，这个项目的实质是开发和使用能够批判性地评估治疗期间CLL细胞中每种药物或结合策略的作用机制的分析方法，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 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.