The purpose of this proposal is to investigate the cell killing mechanism and associated DNA damage responses of a number of clinically important antitumor drugs that are known to target DNA topoisomerase II. Many lines of evidence have strongly supported the argument that the primary cellular lesion induced by these drugs is a new and uncharacterized class of DNA damage: a reversible drug-topoisomerase-DNA cleavable complex. Preliminary studies have suggested that the cleavable complexes are likely to be responsible for, in addition to cell killing, the increased frequencies of sister chromatid exchanges, the stimulation of the differentiation of murine erythroleukemic cells in vitro, and the induction of heat shock hsp70 gene expression. In order to understand this new type of DNA damage and its biological consequences associated with the antitumor action of these topoisomerase-specific drugs, we propose the following experiments: (a) to investigate the regulation of the drug target, DNA topoisomerase II, in normal and neoplastic cells. (b) to characterize drug-enzyme-DNA cleavable complexes in cultured cells and purified systems. (c) to study the cellular responses to topoisomerase-specific antitumor drugs. (d) to study the cell killing mechanism by genetic approaches. The understanding of the mechanism of action of topoisomerase II- specific antitumor drugs is likely to shed light on the cell killing mechanism of other antitumor drugs and improve drug efficacy in cancer chemotherapy.
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