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剂量升级的I期临床试验中确定，对晚期紫杉醇 - 抗甲醇 - 难治性卵巢癌患者的临床试验。我们将评估BMS-24755对其分子靶标微管（特别是β-微管蛋白）的作用，并研究其在调节定义的生物学标记的表达和功能中的作用，这些定义生物学标记调节药物转运，细胞骨骼完整性和细胞死亡。所有结果将与使用单变量和多元分析的药代动力学，临床病理学和患者反应相关，而这项试验研究的发现适用于大规模研究。如果有的话，将从治疗前和治疗后患者以及恶性液中收获肿瘤活检。总RNA，DNA和蛋白质将从所有标本中分离出来，并存储在70厘米。将确定BMS-247550剂量药代动力学与微管束和外周血单核细胞（PBMC）中的Aster形成的相关性。这项科学探索性研究的主要目的是：1。评估肿瘤反应和（a）突变在I类β-微管蛋白的I类突变的发生和（b）β-微管蛋白同型分布。 β-微管蛋白的突变已经在抗紫杉醇癌细胞系中分离出来，β-微管蛋白的GTP结合区域的突变与NSCLC患者的紫杉醇单一疗法的反应/存活率差有关。 2。为了研究MDR1，MRP和CMOAT mRNA和蛋白表达是肿瘤对BMS-247550的反应的预后。 3。为了关联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（凋亡的侵袭者）成员，例如Survivin和p53。线粒体膜电位的变化（一种早期凋亡指标）将通过流式细胞仪进行评估，并在治疗前和治疗后肿瘤样品中进行比较，并与反应相关。 4。确定斯塔明蛋白表达与磷酸化状态之间的关系随反应的函数。