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.
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