Ara-C is one of the most effective agents in the treatment of acute myelogenous leukemia. The mechanism(s) of action of ara-C and the basis for selectivity against leukemic cells, however, remains unclear. We have previously studied the effects of ara-C incorporation into leukemic cell DNA. The incorporated ara-C residue acts as a relative chain terminator and the extent of incorporation correlates with inhibition of DNA synthesis. Cytostatic concentrations of ara-C induce human leukemic cell differentiation in vitro and alter specific gene expression. Lethal effects at higher ara-C concentration are associated with termination of DNA chain elongation. The work will extend these findings by studying the mechanism(s) responsible for ara-C induced globin gene expression in human K562 erythroleukemia cells. We will extend preliminary studies demonstrating that ara-C alters proto-oncogene expression in human leukemic cells. These effects on specific gene expression will be further studied by monitoring ara-C induced changes in chromatin structure. The effects of ara-C on gene amplification, rereplication of previously replicated DNA segments and chromosomal aberrations will also be studied as events related to the accumulation of DNA replication intermediates. Finally, we will study the in vivo metabolism of ara-C during high dose continuous infusion therapy.
The specific aims are: 1) To study the molecular mechanisms of ara-C induced K562 cell differentiation by monitoring specific globin gene expression, DNA methylation and nuclease hypersensitive sites; 2) To monitor the effects of ara-C on proto-oncogene expression in human leukemic cell lines; 3) To study the effects of ara-C on DNA chain elongation, histone expression and chromatin structure; 4) To study the effects of ara-C on gene amplification, endoreduplication and chromosomal aberrations; 5) To study the pharmacodynamics of ara-C in a Phase II trial of high dose continuous infusion therapy for myeloid leukemia.
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