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Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western world. Flavopiridol (Alvocidib, NSC 649890), as a pan cyclin-dependent kinases inhibitor (CDKI), initiates cell cycle arrest and p53-independent apoptosis through down-regulation of Mcl-1 and X-linked inactivator of apoptosis (XIAP). A novel pharmacokinetically (PK)-based dosing schedule with a 30-minute intravenous bolus loading dose (IVB) followed by a 4-hour continuous intravenous infusion (CIVI) in patients with refractory CLL produced an approximately 50% overall response rate. A major flavopiridol metabolite, flavopiridol glucuronide (flavo-G), was as also evaluated in this study. In order to fully understand the inter-individual variability between patients, a phase 1 CLL patient data set (OSU0055) was evaluated and a two-compartment flavopiridol PK model followed by first-order elimination was developed by nonlinear mixed effects modeling. Bilirubin level was shown as a significant covariate, and OATP1B1 was first time discovered having a significant correlation with flavopiridol PK parameters. A functional analysis in vitro study was done to confirm that flavopiridol and flavo-G are substrates of OATP1B1. Since cellular redox status is important on cell survival and previous studies showed that flavopiridol can induce the decrease of intracellular GSH levels in transformed cells, glutathione (GSH) level was evaluated among leukemia cell models and patient’s CLL cells. The change in GSH level compared to baseline after flavopiridol treatment varied among cell models and individual patient. In order to evaluate flavo-G with flavopiridol treatment, a linked parent-metabolite population PK model was developed. This model was expanded to include a pharmacodynamic logistic-regression component linked to flavopiridol exposure level. This developing PK-PD-PG model of flavopiridol will help to characterize the factors associated with inter-individual variability in drug disposition and outcomes, and provide us better understanding of the mechanisms and factors governing the balance between safety and efficacy.

My studies are based on the hypothesis that Rac GTPase signaling contributes to the p53 deficiency-mediated tumorigenesis through a functional connection of Rac with the p53-regulated cell growth and survival network. Combined methods of dominant negative Rac1 expression and pharmacologic treatment with a Rac-specific small molecule inhibitor, NSC23766, were applied. In human BL41 and mouse J3D cells in which p53 is defective, p53 functional expression caused a reduction of Rac1-GTP level. Expression of N17Rac1 mutant or treatment with NSC23766 resulted in decreased Rac1 activity accompanied by decreased proliferation of these cells. The suppression of lymphoma cell proliferation by Rac1 inhibition was associated with increased apoptosis and decreased S-phase transition, as well as reduced signaling activities of Rac-downstream effectors PAK1 and AKT. These results suggest Rac1 activity is inversely regulated by p53 in the lymphoma cells, and that targeting Rac-signaling pathway may be beneficial in suppressing lymphomagenesis associated with p53-pathway deficiency.