Cytosine arabinoside (ara-C) occupies a central role in the treatment of acute myelogenous leukemia. However, the mechanisms of ara-C action in leukemia cytotoxicity and induction of hematopoietic cell differentiation are not completely understood. We have previously investigated the effects of ara-C incorporation in leukemia cell DNA. Ara-C incorporation is associated with impaired DNA template function, inhibition of DNA synthesis and loss of clonogenic potential. Cytostatic concentrations of ara-C are associated induction of differentiation in K562 leukemia cells are related alterations in specific gene expression. Pharmacology studies with both intravenous and subcutaneous low dose ara-C have demonstrated that clinical efficacy and toxicity may depend on ara-C pharmacokinetic behavior. We have shown that high concentrations of ara-C are required for synergy with cisplatin in vitro and that those concentrations can be achieved and sustained during high dose continuous infusions of ara-C for the treatment of human cancer. This proposal is an extension of these integrated laboratory and clinical studies. We will continue the development and application of analytical techniques to measure in vivo ara-C incorporation into DNA during the therapy of human leukemia and lymphoma. Studies of ara-C induced differentiation in human K562 leukemia cells will be extended. We will examine differentiation related changes in globin gene expression, proto- oncogene expression, DNA methylation and alterations in gene regulation. The effects of ara-C on DNA polymerase and DNA replication of specific genetic sequences will be explored utilizing the M13 DNA sequencing system.
The specific aims of this project are: 1. To develop sensitive methods for the measurement of in vivo ara-C incorporation into DNA during ara-C therapy; 2. To monitor the pharmacodynamics of ara-C during the treatment of AML by the use of sensitive assays to detect ara C incorporation into DNA in vivo; 3. To study the effect of alpha interferon on ara-C pharmacodynamics during treatment of nonHodgkins lymphoma using sensitive in vivo ara-C incorporation studies; 4. To extend our studies on gene expression and DNA methylation during ara-C induced differentiation; and 5. To investigate the effects of ara-CTP on DNA replication of specific genetic sequences.
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