Taxol, a naturally occurring antimitotic agent, has shown significant cell-killing activity against tumor cells by induction of apoptosis. However, the mechanism of taxol mediated cell death and its relationship with taxol's well-known effects on microtubules and mitotic arrest is not entirely clear. Recent studies in this laboratory demonstrated that taxol's cell-killing activity (but not mitotic arrest) is selectively inhibited if tumor cells were pretreated with glucocorticoids, suggesting that taxol-induced apoptosis might occur via a signaling pathway independent of mitotic arrest. On the other hand, since glucocorticoids (such as dexamethasone) are routinely used in the clinical application of taxol to prevent hypersensitivity reactions and other adverse effects, this finding also raises a clinically relevant question as to whether the pretreatment with glucocorticoids might interfere with taxol's antitumor efficacy. The objectives of this proposal are to elucidate the mechanism by which glucocorticoids inhibit taxol-induced apoptosis and determine its potential influence on taxol's therapeutic effect. Meanwhile, utilizing the unique inhibitory effect of glucocorticoids on taxol's action, this proposed research also tries to determine the molecular basis of taxol-induced apoptosis via a """"""""gene-directed"""""""" pathway. Therefore, this research application will pursue two major specific aims.
Aim 1 is to evaluate the potential inhibition of glucocorticoids on taxol and docetaxel's therapeutic effects in vivo through establishment of appropriate animal models.
This aim will confirm or negate the implication of glucocorticoid's effect on taxol or docetaxel's administration in vivo.
Aim 2 is to investigate the molecular mechanism underlying taxol-induced apoptosis and glucocorticoid-mediated drug resistance. Based on the latest progress, this study will focus on elucidating the possible role of the NF-kB/IkB-alpha signaling pathway in the regulation of apoptotic cell death induced by taxol and possibly other antimitotic agents in human solid tumor cells. The long-term goal of this research is to provide molecular insight into the mechanism and signal pathways that lead to taxol-induced cell death and glucocorticoid-mediated drug resistance. The information obtained from this proposed research may prove valuable for improving in the clinical application of this class of antineoplastic agents.
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