CHARACTERISTICS OF MULTIDRUG RESISTANCE IN HUMAN TUMORS

描述：（申请人的摘要）尽管最近在 癌症遗传学和治疗，抗癌药物耐药性仍然是一个可怕的 问题和挑战的肿瘤学家和研究人员一样。远景目标 本项目的主要内容是对多药抗肿瘤作用机制的研究， 阻力现在很清楚，细胞内的抗癌药物耐药性 水平，即使是一个单一的代理，是一个多因素的现象;多基因 肿瘤细胞对任何一种特定的抗肿瘤药物都有抵抗力， 细胞毒性剂。然而，不知道这些变化是否是导致 或者是抗性选择的结果。因此，要检验的假设 这种应用是抗癌药物治疗扰乱许多细胞 可以为肿瘤细胞存活提供选择性优势的组分， 有助于抗癌药物抗性表型。在已完成工作的基础上 在上一个资助期内，申请人提出一项重点申请， 测试这一假设，使用不同类别的拓扑异构酶抑制剂， 他的独特的肿瘤细胞系小组，选择对它们具有抗性， 细胞毒性药物作用和耐药性的范例。这些新的细胞系将 为拟议的遗传和生物化学研究提供平台。测试 假设，提出了以下具体目标：1）表征 拓扑异构酶II-α和β以及拓扑异构酶I在药物中的作用 通过使用分子工程酶， 和辅助蛋白; 2）描述了topo II表达的调节 α和β在药物敏感和耐药细胞中的作用， 转录因子、染色质可及性和启动子甲基化; 3） 识别细胞毒性信号传导途径中的元件， 复合物稳定和催化拓扑异构酶抑制剂， cDNA阵列技术的研究;以及4）利用这些抗性的知识 开发新的方法来规避这些耐药性的机制 抑制剂，包括基因治疗。

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.