CHARACTERISTICS OF MULTIDRUG RESISTANCE IN HUMAN TUMORS

人类肿瘤的多药耐药性特征

• 批准号: 6613759
• 负责人: WILLIAM T BECK
• 金额: $ 27.95万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6613759
• 关键词: DNA gyrase; DNA methylation; DNA topoisomerases; antineoplastics; apoptosis; biological signal transduction; cell line; chimeric proteins; chromatin; drug screening /evaluation; enzyme activity; enzyme induction /repression; enzyme inhibitors; genetic promoter element; green fluorescent proteins; microarray technology; multidrug resistance; protooncogene; transcription factor; tumor suppressor genes

DESCRIPTION: (Applicant's Abstract) Despite recent breathtaking advances in cancer genetics and treatment, anticancer drug resistance remains a formidable problem and challenge to oncologists and researchers alike. The long-term goal of this project has been the dissection of mechanisms of antitumor multidrug resistance. It is now clear that anticancer drug resistance at the cellular level, even to a single agent, is a multifactorial phenomenon; multiple genetic changes can occur in a tumor cell selected for resistance to any particular cytotoxic agent. Not known, however, is whether these alterations are a cause or consequence of selection for resistance. Thus the hypothesis to be tested in this application is that anticancer drug treatment perturbs many cellular components that can provide a selective advantage for tumor cell survival and contribute to the anticancer drug resistance phenotype. Building on work done in the prior funding period, the applicant proposes a focused application to test this hypothesis, using different classes of topoisomerase inhibitors and his unique panel of tumor cell lines, selected for resistance to them as a paradigm for cytotoxic drug action and resistance. These novel cell lines will provide the platform for the proposed genetic and biochemical studies. To test the hypothesis, the following specific aims are proposed: 1) characterize the functions of topoisomerase (topo) II-alpha and beta and topo I in drug sensitive and resistant cells through the use of molecularly-engineered enzymes and accessory proteins; 2) describe the regulation of expression of topo II alpha and beta in drug sensitive and resistant cells through the studies of transcription factors, chromatin accessibility, and promoter methylation; 3) identify elements in the cytotoxic signaling pathways induced by complex-stabilizing and catalytic topoisomerase inhibitors through selective studies of cDNA array technology; and 4) utilize knowledge of these resistance mechanisms to develop novel approaches to circumvent resistance to these inhibitors, including gene therapy.

描述：（申请人的摘要）尽管最近令人叹为观止 癌症遗传学和治疗，抗癌药物耐药性仍然是强大的 肿瘤学家和研究人员的问题和挑战。长期目标 该项目的解剖是抗肿瘤多药的机制 反抗。现在很明显，抗癌药在细胞处的耐药性 即使对单个代理来说，水平也是多因素现象。多遗传 可以在选择对任何特定的肿瘤细胞中发生变化 细胞毒性剂。但是，尚不清楚这些改变是否是原因 或选择阻力的结果。因此，要检验的假设 该应用是抗癌药物治疗许多细胞 可以为肿瘤细胞存活提供选择性优势的组件和 有助于抗癌耐药性表型。基于完成的工作 在以前的资助期间，申请人提出了重点申请 使用不同类别的拓扑异构酶抑制剂和 他独特的肿瘤细胞系面板，被选为阻力 细胞毒性药物作用和抗性的范式。这些新颖的细胞系将 为拟议的遗传和生化研究提供平台。测试 提出了以下特定目的的假设：1）表征 拓扑异构酶（Topo）II-Alpha和beta和Topo I在药物中的功能 通过使用分子设计酶，敏感和抗性细胞 和配件蛋白； 2）描述TOPO II表达的调节 通过研究 转录因子，染色质可及性和启动子甲基化； 3） 识别由细胞毒性信号通路中的元素 通过选择性 cDNA阵列技术的研究； 4）利用这些抵抗的知识 开发新方法来规避这些方法的机制 抑制剂，包括基因治疗。