The central objective of this project is to maximize the intracellular therapeutic intensity of nucleotide analogues to leukemia cells. This is desirable because greater intracellular exposure to the active triphosphates is associated with clinical response. Our previous studies, however, have demonstrated limitations to the accumulation of the active nucleoside triphosphates that cannot be circumvented by simple dose escalation. The present application proposes to extend ongoing studies which have demonstrated that both biochemical and biological modulation approaches successfully increase the concentrations of active metabolites in leukemia cells, and that this is associated with improved clinical response. Specifically, a pilot protocol has been designed to evaluate the ability of granulocyte colony-stimulating factor (G-CSF) or all-trans retinoic acid (ATRA) to serve as biological modulators of the active triphosphates of ara-C (ara-CTP) and fludarabine (F-ara- ATP) in leukemia cells. This investigation will be conducted in the context of a continuous infusion of araC, during which the action of the growth regulatory molecules on the steady-state concentrations of ara-CTP will be quantitated. A second investigation will focus on the cellular pharmacokinetics of nucleotide analogue triphosphates to determine the minimum dose of fludarabine that will maximize the accumulation of ara-CTP in blasts. This information will be utilized in the design of a phase I study to permit combining multiple daily doses of fludarabine with intermittent ara-C infusions. Correlations will be sought between clinical response to remission induction therapy and the kinetics and extent of DNA fragmentation and apoptotic morphology in leukemia blasts. Ultimately, this information will provide a comprehensive rationale for the design of clinical protocols that combine growth regulatory molecules with cytotoxic antileukemia drugs.
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