Hormonal Modulation of Taxol Action in Solid Tumors

实体瘤中紫杉醇作用的激素调节

• 批准号: 6471948
• 负责人: WEIMIN FAN
• 金额: $ 25.45万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6471948
• 关键词: I kappa B beta; apoptosis; athymic mouse; breast neoplasms; drug resistance; glucocorticoids; hormone regulation /control mechanism; neoplasm /cancer pharmacology; nuclear factor kappa beta; ovary neoplasms; paclitaxel

DESCRIPTION (PROVIDED BY APPLICANT): 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.

描述（由申请人提供）：紫杉醇，一种天然发生的抗魔法 代理，通过 诱导凋亡。但是，紫杉醇介导的细胞死亡和 它与紫杉醇对微管和有丝分裂的众所周知的影响的关系 逮捕并不完全清楚。该实验室的最新研究表明 紫杉醇的细胞杀伤活动（但不是有丝分裂逮捕）是有选择的 如果用糖皮质激素预处理肿瘤细胞，则抑制 紫杉醇诱导的凋亡可能通过独立于信号通路发生 有丝分裂逮捕。另一方面，由于糖皮质激素（例如 地塞米松通常用于紫杉醇的临床应用 预防过敏反应和其他不良反应，这一发现也 提出了一个与临床相关的问题，即是否 糖皮质激素可能会干扰紫杉醇的抗肿瘤功效。 该提案的目标是阐明 糖皮质激素抑制紫杉醇诱导的细胞凋亡，并确定其潜力 对紫杉醇治疗作用的影响。同时，利用独特 糖皮质激素对紫杉醇作用的抑制作用，这项拟议的研究 还试图通过A来确定紫杉醇诱导的凋亡的分子基础 “基因定向”途径。因此，本研究申请将追求两个 主要的特定目标。目标1是评估潜在的抑制 糖皮质激素对紫杉醇和多西他赛在体内的治疗作用 建立适当的动物模型。这个目标将确认或否定 糖皮质激素对紫杉醇或多西他赛的影响的影响 体内。 AIM 2是研究基本的分子机制 紫杉醇诱导的细胞凋亡和糖皮质激素介导的耐药性。基于 最新进展，这项研究将重点阐明 凋亡细胞死亡调节中的NF-KB/IKB-Alpha信号通路 由紫杉醇和人类实体瘤的其他抗魔法剂诱导 细胞。 这项研究的长期目标是提供分子见解 导致紫杉醇引起的细胞死亡的机理和信号途径 糖皮质激素介导的耐药性。从此获得的信息 拟议的研究可能证明对于改善临床应用很有价值 这类抗塑性剂。