CHARACTERISTICS OF MULTIDRUG RESISTANCE IN HUMAN TUMORS

描述：(申请人摘要)尽管最近在以下方面取得了惊人的进展 癌症遗传学和治疗，抗癌耐药性仍然是一个令人敬畏的问题 对肿瘤学家和研究人员来说，这是一个问题和挑战。长期目标 该项目的主要内容是对抗肿瘤多药的作用机制进行剖析。 抵抗。现在清楚的是，细胞内的抗癌药物耐药性 水平，甚至对单一因素来说，是一个多因素的现象；多基因 选择对任何特定药物具有抵抗力的肿瘤细胞可能会发生变化 细胞毒剂。然而，目前尚不清楚这些变化是否是一种原因 或选择抗药性的后果。因此，将在以下方面测试的假设 这一应用是抗癌药物治疗扰乱多细胞的。 可为肿瘤细胞存活提供选择性优势的成分 与抗癌耐药表型有关。以已完成的工作为基础 在之前的资助期内，申请人提出重点申请 使用不同类别的拓扑异构酶抑制剂和 他的独特的肿瘤细胞系小组，选择对它们的耐药性作为 细胞毒药物作用和耐药性的范例。这些新的细胞系将 为拟议的遗传和生化研究提供平台。为了测试 这一假设提出了以下具体目的：1)描述 拓扑异构酶II-α、β和Topo I在药物中的作用 通过使用分子工程酶获得敏感和耐药细胞 和辅助蛋白；2)描述Topo II的表达调控 通过研究药物敏感和耐药细胞中的α和β 转录因子、染色质可及性和启动子甲基化；3) 确定细胞毒信号通路中的元件 选择性络合稳定和催化拓扑异构酶抑制剂 基因芯片技术的研究；4)利用这些抗性的知识 开发新的方法来规避对这些疾病的抵抗力的机制 抑制剂，包括基因疗法。

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.