The central goals of this application are to test hypotheses developed in the preclinical setting using nucleotide analogues for the therapy of leukemias, and to optimize dosing and scheduling of a new and effective nucleoside analog, arabinosylguanine (ara-G). Protocols have been designed to evaluate the pharmacokinetic and pharmacodynamic predictions of these hypothesis and for clinical responses. Specifically, the applicant plans to investigate new mechanism based strategies with inhibitors of the ribonucleotide reductase. Because cladribine has been proven effective in the treatment of pediatric AML, this ribonucleotide reductase inhibitor will be tested to modulate ara-C triphosphate accumulation in this patient population (Aim 1a). To use ribonucleotide reductase inhibitor as an enhancer of drug action, fludarabine and continuous infusion ara-C therapy will be combined with i.v. hydrea.
(Aim 1 b). This is based on the data that hydrea infusion consistently and exclusively results in 50% decline in the dATP pool. Because fludarabine triphosphate competes with dATP, addition of hydrea will enhance incorporation and hence action of fludarabine. The third use of an ribonucleotide reductase inhibitor will test the effectiveness of gemcitabine as an inhibitor of DNA repair induced by agents such as carboplatin which has been proven effective in AML (Aim 1c). The applicant hypothesizes that the depletion would result in mechanistic synergy. The entire Aim 2 is devoted to developing and testing different strategies for optimization of a new nucleoside analog, ara-G, administered as a prodrug compound 506U. In the applicant's Phase I trial with 506U, she learned that the response to this agent is directly related to the intracellular level of ara-G triphosphate. Three approaches have evolved based on her recently published preclinical work in primary leukemia cells. These include maximization of the rate of ara-G phosphorylation (Aim 2a), biochemical modulation of ara-G triphosphate metabolism by fludarabine (Aim 2b), and increasing the ara-G exposure duration (Aim 2c). The pharmacokinetic and pharmacodynamic endpoints will be correlated with clinical responses for future interventions. These rationale based approaches for the single and combination drug development would provide knowledge for optimal therapy.
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