The goals of this project are to develop in the laboratory, using model systems and primary CLL cells in vitroan understanding of the mechanisms of action of anticancer agents acting alone and in mechanism-basedcombinations. This knowledge base will provide rationales for the design and evaluation of clinical trials thatwill test hypotheses regarding the actions and interactions of these agents in CLL cells in patients duringtherapy. Thus, the central hypothesis we will test is that knowledge derived from an understanding of themetabolism, mechanisms of action, and the interactions of new anticancer therapeutics can be used todesign and evaluate novel therapeutic regimens for the treatment of patients with CLL. To achieve thesegoals, we will address the following questions: 1. Do nucleoside analogs with novel actions providepharmacological and clinical advantages over fludarabine for the treatment of B-CLL? Our focus here will beon the new nucleoside analog, clofarabine which has pharmacologic properties different from fludarabine. 2.Can strategies to reduce survival proteins selectively kill CLL cells? We are developing 8-chloro-adenosineribonucleotide analog that reduces cellular bioenergy and blocks transcription. Also, we will evaluate thetranscription-directed actions of flavopiridol. The actions of each of these agents decreases anti-apoptoticproteins in CLL cells. 3. Will mechanism-based combinations of cytotoxic agents improve outcome in CLLpatients? The cellular responses to inhibition of excision DNA repair processes will be investigated in CLLcells, and extended to new DNA damaging agents and drugs that inhibit DNA repair. 4. Can orsaponin, asynthetic natural compound with potent anticancer activity and unique mechanism of action, be used as anovel agent for treatment of CLL? The action mechanism(s) of this novel agent that selectively kills CLLcells independent of p53 status will be investigated in preparation for clinical development. Interactions withother projects in this program will strengthen our investigations.
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