We have proposed to study the mechanism of action and toxicity of sesquiterpene lactones, a naturally occurring class of antineoplastic agents. These compounds are thought to exert their therapeutic effect by alkylating sensitive sulfhydryl groups in the cell. Our recent experiments have suggested that sesquiterpene lactones at therapeutic doses have a very rest icted range of enzyme targets in P-388 tumor cells. In particular, the sesquiterpene lactones helenalin and bishelenalinyl malonate appear to inactivate the enzyme IMP dehydrogenase and the protein synthesis initiation factor eIF-3 at therapeutic levels. Other data suggest that DNA polymerase alpha and eIF-2alpha kinase may also be important target enzymes. We plan to: 1) determine the target enzymes for a selected group of therapeutically effective sesquiterpene lactones. These studies will include in vivo and in vitro experiments to correlate loss of enzyme activity with therapeutic effectiveness and experiments with purified enzymes to confirm the enzyme target; 2) carry out SAR study to determine the structural features of sesquiterpene lactones which make them particularly effective inhibitors of the target enzymes; 3) determine the extent and basic mechanism(s) of toxicity for these compounds, and 4) investigate the role of reduced glutathione in lowering the toxicity and increasing the therapeutic effectiveness of these compounds. These experiments should provide information which will be useful in the selection and/or design of second generation sesquiterpene lactones with improved selectivity for target enzymes and reduced toxicity. These experiments should also provide the data base necessary to move these compound into the clinical trial stage.
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