Characteristics of Multidrug Resistance in Human Tumors

描述(申请人提供)：尽管在癌症遗传学和治疗方面取得了进展，但抗癌耐药性仍然是肿瘤学家和研究人员面临的一个艰巨的问题和挑战。该项目的长期目标一直是剖析肿瘤多药耐药的机制。人们已经知道，抗癌药物在细胞水平上的耐药性是一种多因素现象，即使对单一药物也是如此；在对任何特定细胞毒剂产生耐药性的肿瘤细胞中，可能会发生多个基因变化。作为对这一观点的补充，我们最近了解到，抗癌药物的假定靶标及其作用的介体在细胞生理和药物反应中扮演着复杂的角色。例如，拓扑异构酶对药物治疗的反应经历了翻译后的修饰，这些修饰揭示了一个复杂的信号通路，包括苏莫化，它也参与了药物的反应。此外，关于介导多药耐药的ABC转运蛋白，我们了解到其中一个成员MRP1/ABCC1似乎受信号分子Notch-1调控，另一个成员BCRP/ABCG2受雌激素调控。因此，研究ABC蛋白表达调控的新机制可能为规避耐药提供独特的方法。因此，扩展我们在ABC转运体和拓扑异构酶实验室工作的历史重点，我们希望建立在过去几年的新知识和我们在前一个资助期取得的进展的基础上，以检验拓扑异构酶和ABC蛋白表达的新调控机制影响抗癌药物反应的假设，并为新的治疗范例提供见解。在前一个资助期所做工作的基础上，我在这里提供一个有针对性的应用，并提出以下具体目标来检验我们的假设：(1)确定哺乳动物肿瘤中拓扑异构酶调控的分子机制和通过这些酶的药物介导的细胞毒性；(2)定义Ubc9和蛋白质总合作用在抗癌药物反应性中的作用；(3)定义Notch-1对ABC转运体MRP1/ABCC1表达的新调控的分子机制。

DESCRIPTION (provided by applicant): Despite 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 tumor multidrug resistance. It was known previously that anticancer drug resistance at the cellular level, even to a single agent, is a multifactor phenomenon; multiple genetic changes can occur in a tumor cell selected for resistance to any particular cytotoxic agent. Complementing this view, we have learned more recently that the putative targets of anticancer agents and mediators of their actions play complex roles in cellular physiology and drug responsiveness. For example, topoisomerases undergo post- translational modifications in response to drug treatments, and these modifications have revealed a complex signaling pathway involving sumoylation that is also involved in drug responses. Further, with regard to ABC transporters, which mediate multidrug resistance, we have learned that one member of this class, MRP1/ABCC1, appears to be regulated by the signaling molecule Notch-1, and that another member, BCRP/ABCG2, is regulated by estrogen. Accordingly, study of novel mechanisms of regulation of ABC protein expression may afford unique methods to circumvent drug resistance. Thus, expanding on the historical focus of our laboratory efforts in ABC transporters and topoisomerases, we wish to build on the new knowledge of the past few years and on the progress we have made in the prior funding period to test the hypothesis that novel regulatory mechanisms for expression of topoisomerases and ABC proteins affect anticancer drug responses and offer insights into new therapeutic paradigms. Building on work done in the prior funding period, I offer here a focused application and propose the following specific aims to test our hypothesis: (1) Define the molecular mechanisms of regulation of topoisomerases in mammalian tumors and drug-mediated cytotoxicity through these enzymes; (2) Define the role of Ubc9 and protein sumoylation in anticancer drug responsiveness; and (3) Define the molecular mechanisms of novel regulation by Notch-1 of expression of the ABC transporter, MRP1/ABCC1.