Recent studies have demonstrated that taxol, a naturally occurring antimitotic agent, was able to induce apoptotic cell death in a number of solid tumor cells, but it is unclear whether this finding has suggested a novel mechanism of action for taxol against tumors or just represents an end product of taxol's well-known effects on microtubules and mitotic arrest. Recent experiments in our laboratory demonstrated that taxol's cell-killing activity (but not mitotic arrest) could be selectively inhibited if tumor cells were pretreated with glucocorticoids, suggesting that taxol-induced apoptosis might occur via a signaling pathway independent of mitotic arrest. Since glucocorticOids (such as dexamethasone) are routinely used in the clinical application of taxol to prevent hypersensitivity reactions, this finding also raises a clinically relevant question as to whether pretreatment with glucocorticoids might actually interfere with taxol's antitumor efficacy. There are two interrelated research goals for this proposal: 1) to investigate the mechanism by which glucocorticoids inhibit taxol's action in solid tumor cells, and 2) to determine the molecular basis of taxol- induced apoptosis and its relationship with taxol's other well-known cellular effects on microtubules and cell cycle arrest. By utilizing the unique inhibitory feature of glucocorticoids on taxol's action, a step-by- step experimental approach is designed to accomplish these objectives: 1) Following the """"""""microtubule pathway"""""""", the potential influence of glucocorticoids on taxol's action in this well-characterized pathway will be analyzed; 2) Through pre-synchronization and other approaches, we will examine the possible correlation between taxol-induced apoptosis and cell cycle arrest, and clarify if taxol can exert its cell-killing activity via a separate pathway independent of mitotic arrest; 3) To characterize the cellular or molecular events occurring downstream of mitotic arrest and determine if glucocorticoids can specifically interfere with these events; 4) Through cloning and characterization of genes responsive to taxol, we will identify genes whose altered expression or modification are potentially involved in the mediation of taxol's action and/or glucocorticoid-mediated drug resistance.
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