The central goal of this application is to develop hypotheses for optimized administration of drug combinations for the therapy of acute myelogenous leukemia (AML) and chronic myelogenous leukemia in blunt crisis (CML-BC) 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 and CML-BC, 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 CA57629 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 an improved response rate than our previous treatments. In this application, the applicant plans to extend that work by investigating three additional modulators of ara-CTP metabolism and a different schedule of fludarabine and ara-C combination. Separate protocols have been designed to evaluate biochemical modulation strategies effected by cladribine, hydrea, and gemcitabine in combination with ara-C. The fludarabine and ara-C combination will be evaluated in K562 in vitro model system as continuous infusion regimen. The doses, schedule, and duration of each drug will be carefully optimized and selected to translate this in vitro approach as a pharmacologically guided clinical trial. The pharmacokinetic and pharmacodynamic effects of the modulators on ara-CTP metabolism and actions will be the focus of these investigations. The pharmacokinetics of ara-C metabolites in blasts during therapy will be evaluated to determine additional cytotoxic metabolites which may be generated by ara-C deamination to arabinosyluracil (ara-U). The applicant will also investigate molecular action of these analog triphosphates in combination with ara-CTP to understand the synergistic cytotoxicity. An in vitro model system of DNA primer extension using human DNA polymerase alpha will be used to investigate the molecular aspect of the proposal. Correlations will be sought between these studies to determine the prognostic significance of modulation of ara-CTP metabolism and actions. 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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