The central goal of this proposal is to develop hypotheses for optimized administration of drug combinations for the therapy of acute myelogenous leukemia (AML) based on in vitro pharmacological, biochemical, and molecular studies. Subsequently, protocols will be designed to evaluate the pharmacokinetic and pharmacodynamic predictions of these hypotheses and for clinical response. Because ara-C is important for the therapy of AML, attempts will be directed toward enhancing its efficacy by biochemical modulation strategies, dosing and scheduling, and by combination of other effective antileukemic drugs. Pilot studies conducted under R03 CA53311 have demonstrated that fludarabine infusion increased the rate of ara-CTP accumulation nearly 2-fold in leukemia blasts over that after ara-C alone in the same patient. Clinically, the combination of these two agents resulted in better response rates than our previous treatments. In the present proposal we plan to extend that work by investigating the mechanism of potentiation of ara-CTP metabolism by fludarabine and by studying the molecular action of these two analogue triphosphates to understand the synergistic cytotoxicity. We have amended the protocol based on the pharmacology studies and will investigate the cellular pharmacokinetics and pharmacodynamics to seek correlations with clinical response. Additionally, we will implement a new protocol: combination of ara-C and fludarabine with a DNA damaging agent, mitoxantrone. Pharmacokinetics of ara-CTP accumulation in leukemic blasts will be analyzed to evaluate the modulatory action of fludarabine and mitoxantrone. Studies will be performed to analyze the DNA damage introduced in vivo into unlabeled leukemia cells from patients receiving mitoxantrone therapy. Biochemical studies of the interaction of these agents for ara-CTP metabolism and for DNA damage in vitro in leukemic blasts isolated from the same patient will be conducted to complement and extend in vivo investigations. Correlations will be sought between these studies to determine the prognostic significance of modulation of ara-CTP metabolism. Knowledge gained from these investigations will be used to optimize scheduling of drugs for the existing protocol and to design and evaluate new treatments.
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