TRANSLATIONAL CORRELATES OF AN EPOTHILONE B ANALOG

埃坡霉素 B 类似物的翻译相关性

• 批准号: 6152969
• 负责人: SUSAN BAND HORWITZ
• 金额: $ 8.38万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6152969
• 关键词: BCL2 gene /protein; HeLa cells; analog; antineoplastics; apoptosis; biological signal transduction; clinical research; clinical trial phase I; drug metabolism; drug resistance; female; gene induction /repression; gene mutation; human subject; human therapy evaluation; membrane transport proteins; multidrug resistance; neoplasm /cancer chemotherapy; ovary neoplasms; p53 gene /protein; paclitaxel; pharmacokinetics; phosphoproteins; tubulin

The optimum dose, clinical toxicity and antitumor activity of BMS-247550 will be determined in a dose-escalation phase I clinical trial of patients with advanced Taxol-refractory ovarian cancer. We will evaluate the effects of BMS-24755 on its molecular target, the microtubule, specifically beta- tubulin and investigate its role in modulating the expression and function of defined biological markers that regulate drug transport, cytoskeletal integrity and cell death. All results will be correlated with pharmacokinetics, clinicopathology and patient response using univariate and multivariate analyses, and the findings from this pilot study applied to a large-scale study. Tumor biopsies will be harvested from pre- and post- treatment patients, together with malignant fluid, when available. Total RNA, DNA and protein will be isolated from all specimens and stored at 70 centigrade. Correlates of BMS-247550 dose pharmacokinetics with microtubule bundle and aster formation in peripheral blood mononuclear cells (PBMC's ) will be determined. The primary aims of this scientific exploratory study are: 1. To evaluate the relationship between tumor response and (a) the occurrence of mutation in the class I isotype of beta-tubulin and (b) beta- tubulin isotype distribution. Mutations in beta-tubulin have been isolated in Taxol-resistant cancer cell lines, and mutations in the GTP-binding regions of beta-tubulin have been associated with poor response/survival to Taxol monotherapy in NSCLC patients. 2. To investigate MDR1, MRP and cMOAT mRNA and protein expression as prognosticators of tumor response to BMS-247550. 3. To correlate the effects of BMS-247550 on the expression of proteins which regulate apoptosis, such as bcl-2 family members and IAP (inhitors of apoptosis) members, e.g. survivin and p53. Changes in mitochondrial membrane potential, an early indicator of apoptosis, will be evaluated by flow cytometry and compared in pre-and post-treatment tumor samples and correlated with response. 4. To determine the relationship between stathmin expression and phosphorylation status as a function of response.

BMS-247550的最佳剂量、临床毒性和抗肿瘤活性将在晚期紫杉醇难治性卵巢癌患者的剂量递增I期临床试验中确定。我们将评价BMS-24755对其分子靶点微管（特别是β-微管蛋白）的影响，并研究其在调节药物转运、细胞骨架完整性和细胞死亡的定义生物标志物的表达和功能中的作用。所有结果将使用单变量和多变量分析与药代动力学、临床病理学和患者反应相关，并且该初步研究的结果适用于大规模研究。将从治疗前和治疗后的患者中采集肿瘤活检标本，并在可用时采集恶性液体。将从所有标本中分离总RNA、DNA和蛋白质，并在70 ℃下储存。将确定BMS-247550剂量药代动力学与外周血单核细胞（PBMC）中微管束和星形细胞形成的相关性。本科学探索性研究的主要目的是：1。评价肿瘤缓解与（a）β-微管蛋白I类同种型突变的发生和（B）β-微管蛋白同种型分布之间的关系。已在泰素耐药癌细胞系中分离出β-微管蛋白突变，并且β-微管蛋白的GTP结合区突变与NSCLC患者对泰素单药治疗的不良反应/生存期相关。2.研究MDR 1、MRP和cMOAT mRNA和蛋白表达作为肿瘤对BMS-247550反应的指示剂。3.关联BMS-247550对调节细胞凋亡的蛋白质表达的影响，例如bcl-2家族成员和IAP（细胞凋亡抑制剂）成员，例如生存素和p53。将通过流式细胞术评价线粒体膜电位（细胞凋亡的早期指标）的变化，并在治疗前和治疗后肿瘤样本中进行比较，并与缓解相关。4.确定stathmin表达和磷酸化状态之间的关系作为响应的函数。