TUBULIN GENES AND DRUG RESISTANCE

微管蛋白基因和耐药性

• 批准号: 2429864
• 负责人: BRANIMIR I SIKIC
• 金额: $ 20.58万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-06-05 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2429864
• 关键词: breast neoplasms; clinical research; drug resistance; gene expression; human genetic material tag; human subject; laboratory mouse; microtubules; multidrug resistance; mutant; neoplasm /cancer chemotherapy; neoplastic cell; nonHodgkin's lymphoma; nucleic acid sequence; oligonucleotides; ovary neoplasms; paclitaxel; phenotype; polymerase chain reaction; protein isoforms; tissue /cell culture; transfection; tubulin; vinca alkaloids; western blottings

DESCRIPTION: (taken from investigator s abstract) Given that taxanes and vinca alkaloids are substrates for the mdr1 gene product, P-glycoprotein (Pgp), and given that Pgp is not expressed in all clinical tumor specimens, the investigator postulates that other mechanisms of resistance to these classes of drugs may be expressed. Tubulins are the targets of the taxanes and vinca alkaloids. Accordingly, the goal of this revised application is to explore other mechanisms of resistance to these agents, with a focus on tubulin genes. In support of this idea, some cell lines selected for resistance to taxol express altered beta-tubulin. The investigator therefore postulates that alterations in tubulin isoform expression, especially changes in relative abundance, are responsible for this form of resistance, and proposes 4 specific aims to test this hypothesis: (1) to determine tubulin isoform expression in non-MDR models of resistance to tubulin-targeted cytotoxins in leukemia, breast and ovarian carcinoma; (2)to study the effects of altered tubulin gene expression on drug sensitivity and microtubule assembly dynamics in transfected cells; (3) to modulate drug sensitivity by down-regulation of specific tubulin gene expression with antisense constructs and oligonucleotides; and (4) to study tubulin isoform expression in tumor specimens obtained from patients before and after therapy with taxanes or vinca alkaloids.

描述：（摘自研究者摘要）鉴于紫杉烷类和 长春花生物碱是mdr 1基因产物P-糖蛋白的底物 (Pgp)并且考虑到Pgp并非在所有临床肿瘤标本中表达， 研究者推测，对这些药物的其他抗性机制 可以表示药物的种类。 微管蛋白是紫杉烷类药物的靶点 和长春花生物碱。 因此，本修订版应用程序的目标是 探索对这些药物耐药的其他机制，重点是 微管蛋白基因 为了支持这一想法，选择了一些细胞系， 对紫杉醇的抗性表达改变的β-微管蛋白。 研究者 因此假设微管蛋白同种型表达的改变， 特别是相对丰度的变化，是造成这种形式的 阻力，并提出了4个具体目标来测试这一假设：（1） 确定微管蛋白同种型在耐药的非MDR模型中的表达 白血病、乳腺癌和卵巢癌中的微管蛋白靶向细胞毒素;（2） 研究微管蛋白基因表达改变对药物敏感性的影响， 转染细胞中的微管组装动力学;（3）调节药物 通过特异性微管蛋白基因表达下调敏感性 反义构建体和寡核苷酸;和（4）研究微管蛋白亚型 在治疗前后从患者获得的肿瘤标本中的表达 用紫杉烷类或长春花生物碱治疗。