1,5,2,4-dioxadithiepane-2,2,4,4-tetraoxide (cyclidisone, NSC- 348948) is an active antitumor agent that is being considered for phase I clinical trials in humans and is currently under toxicological evaluation. The mechanism of action of this compound is unknown, therefore, the major aim of this proposal is to identify the mechanism by which cyclidisone elicits its antitumor activity. The chemistry of cyclidisone suggests that it is an alkylating agent with bifunctional capabilities. This proposal will thus concentrate on the ability of cyclidisone to react with DNA and/or nuclear proteins. Specific interests include the identification of the nuclear reactions of cyclidisone in order to pinpoint which particular lesions may be responsible for its selective toxicity against human tumor cells. This will be achieved by a comparison of the macromolecular DNA damage induced by cyclidisone in a sensitive (BE) and resistant (HT-29) human colon carcinoma cell lines by the technique of alkaline elution. A more detailed analysis of these lesions at the molecular level will be performed. DNA base adducts will be analysed by high pressure liquid chromatography and DNA-protein crosslinks will be identified by cesium chloride gradients and gel electorphoresis. A human cell line with acquired resistance to cyclidisone will be established. The importance of DNA repair as a mechanism of drug resistance will be assessed. The effect that structural modifications of the parent compound have upon toxicity and nuclear reactivity will be determined. The elucidation of the mechanism by which cyclidisone selectively kills human tumor cells is very important to the future development of this new class of anticancer agent.
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