Characteristics of Multidrug Resistance in Human Tumors

描述（由申请人提供）：尽管癌症遗传学和治疗取得了进展，但抗癌药物耐药性仍然是肿瘤学家和研究人员面临的一个巨大问题和挑战。该项目的长期目标是解剖肿瘤多药耐药机制。以前我们知道，在细胞水平上的抗癌药物耐药性，即使是对单一药物的耐药性，是一个多因素现象；多种遗传变化可发生在肿瘤细胞选择抵抗任何特定的细胞毒性剂。为了补充这一观点，我们最近了解到，假定的抗癌药物靶点及其作用介质在细胞生理学和药物反应中起着复杂的作用。例如，拓扑异构酶在对药物治疗的反应中经历翻译后修饰，这些修饰揭示了一种复杂的信号通路，包括与药物反应有关的聚合化。此外，关于介导多药耐药的ABC转运蛋白，我们已经了解到这类转运蛋白中的一个成员MRP1/ABCC1似乎受到信号分子Notch-1的调节，而另一个成员BCRP/ABCG2则受到雌激素的调节。因此，对ABC蛋白表达调控新机制的研究可能为规避耐药性提供独特的方法。因此，扩展我们在ABC转运体和拓扑异构酶方面的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之前的资助期所取得的进展的基础上，以测试拓扑异构酶和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。在之前资助期所做的工作的基础上，我在这里提供一个重点应用，并提出以下具体目标来验证我们的假设：(1)定义哺乳动物肿瘤中拓扑异构酶的调节分子机制和通过这些酶介导的药物介导的细胞毒性；(2)明确Ubc9和蛋白summoylation在抗癌药物反应中的作用；(3)明确Notch-1调控ABC转运蛋白MRP1/ABCC1表达的分子机制。

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.