HORMONAL MODULATION OF TAXOL ACTION IN SOLID TUMORS

实体瘤中紫杉醇作用的激素调节

基本信息

批准号：
2769881
负责人：
WEIMIN FAN
金额：
$ 16.97万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-09-01 至 2001-08-31
项目状态：
已结题

项目摘要

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.

最近的研究表明，紫杉醇是一种自然发生的抗魔法剂能够诱导凋亡细胞死亡实体瘤细胞，但尚不清楚该发现是否有提出了一种针对肿瘤或公正的紫杉醇作用机理代表紫杉醇对微管的众所周知影响的最终产物和有丝分裂逮捕。我们实验室的最新实验证明了紫杉醇的杀细胞杀伤活动（但没有有丝分裂逮捕）可能是如果对肿瘤细胞进行预处理，有选择地抑制糖皮质激素，表明紫杉醇诱导的细胞凋亡可能通过一个独立于有丝分裂停滞的信号通路。由于糖皮质激素（例如地塞米松）通常用于临床应用紫杉醇以防止高敏反应，这一发现也提高了关于是否对糖皮质激素实际上可能会干扰紫杉醇的抗肿瘤功效。该建议有两个相互关联的研究目标：1）研究糖皮质激素抑制紫杉醇作用的机制在实体瘤细胞中，2）确定紫杉醇的分子基础诱导的凋亡及其与紫杉醇的其他知名人士的关系细胞对微管和细胞周期停滞的影响。通过利用糖皮质激素对紫杉醇的作用的独特抑制作用，这是一个逐步的步骤实验方法旨在实现这些目标：1）遵循“微管途径”，葡萄糖皮质激素对紫杉醇在此特征良好的途径中的作用被分析； 2）通过同步和其他方法，我们将检查紫杉醇诱导的凋亡与细胞之间的可能相关性循环逮捕，并澄清紫杉醇是否可以通过独立于有丝分裂停滞的单独途径； 3）表征细胞或分子事件发生在有丝分裂停滞和确定糖皮质激素是否可以特别干扰这些事件； 4）通过对紫杉醇有反应的基因克隆和表征，我们将确定表达或修饰改变的基因有可能参与紫杉醇行动和/或的调解糖皮质激素介导的耐药性。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Possible mechanisms of paclitaxel-induced apoptosis.

DOI：
10.1016/s0006-2952(99)00006-4
发表时间：
1999-06
期刊：
Biochemical pharmacology
影响因子：
5.8
作者：
W. Fan
通讯作者：
W. Fan

Antagonistic interplay between antimitotic and G1-S arresting agents observed in experimental combination therapy.

DOI：
发表时间：
1999-09
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
K. Johnson;K. K. Young-K.;W. Fan
通讯作者：
K. Johnson;K. K. Young-K.;W. Fan

Screening and discovery of novel MDR modifiers from naturally occurring bisbenzylisoquinoline alkaloids.

DOI：
发表时间：
2001-07
期刊：
Anticancer research
影响因子：
2
作者：
L. Fu;Z. Deng;Q. Pan;W. Fan
通讯作者：
L. Fu;Z. Deng;Q. Pan;W. Fan

Mitotic chromosomal bcl-2. I. Stable expression throughout the cell cycle and association with isolated chromosomes.

有丝分裂染色体 bcl-2。

DOI：
10.1177/002215549904700203
发表时间：
1999
期刊：
The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society
影响因子：
0
作者：
Schandl,CA;Li,S;Re,GG;Fan,W;Willingham,MC
通讯作者：
Willingham,MC

In vitro evaluation of schedule-dependent interactions between docetaxel and doxorubicin against human breast and ovarian cancer cells.

多西紫杉醇和阿霉素对人乳腺癌和卵巢癌细胞的时间表依赖性相互作用的体外评估。