The goal is to utilize an understanding of the metabolism and action of antitumor drugs in cancer cells during chemotherapy to optimize the design of treatment regimens for individuals and for specific hematologic diseases. Strong correlations have been established between the response of patients with refractory acute leukemia to high-dose araC therapy and the pharmacokinetics of the active metabolite araCTP in leukemic cells during treatment. These observations were confirmed prospectively and used to design treatment protocols that utilize the cellular pharmacology of araCTP a) to direct the intervals between intermittent doses of araC and b) to indicate the rate of araC administration during a continuous infusion regimen. This application proposes to extend these studies in several directions. First, the cellular pharmacology of araCTP will be evaluated with respect to the response of other hematologic malignancies to high-dose araC to determine the scope of these findings. Second, the cellular metabolism and action of F-araAMP shares many similarities with araC. Therefore, the cellular pharmacology of the active metabolite F-araATP will be evaluated with respect to clinical response during Phase II trials. Third, high-dose araC treatment will be combined with mitoxantrone and with cisplatin to seek higher response rates. This provides the opportunity to determine whether the cellular pharmacology of araCTP continues to provide independent prognostic information during combination chemotherapy, and to investigate if these drugs affect araCTP metabolism. Fourth, DNA damage induced in leukemic cells during therapy with mitoxantrone or with cisplatin will be quantitated by alkaline elution procedures coupled with fluorescence detection. The prognostic value of this evidence of drug action will be evaluated. Finally, knowledge gained in these studies of the metabolism and action of antileukemic drugs in tumor cell during therapy will be used to design new treatment protocols.
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