Characteristics of Multidrug Resistance in Human Tumors

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一个可怕的问题 对肿瘤学家和研究人员都是一个挑战。这个项目的长期目标是解剖 肿瘤多药耐药的机制。先前已知，在肿瘤细胞中的抗癌药物抗性是由肿瘤细胞的细胞毒性引起的。 细胞水平，即使是一个单一的代理，是一个多因素的现象;多种遗传变化可以发生在一个 选择对任何特定细胞毒性剂具有抗性的肿瘤细胞。为了补充这一观点，我们有 最近我了解到，抗癌药物的假定靶点和它们的作用介质起着重要的作用， 在细胞生理学和药物反应中的复杂作用。例如，拓扑异构酶经历后- 翻译修饰响应于药物治疗，这些修饰揭示了一个复杂的 涉及类小泛素化的信号通路，也参与药物反应。此外，关于 ABC转运蛋白，介导多药耐药性，我们已经了解到，这类成员之一， MRP 1/ABCC 1似乎受到信号分子Notch-1的调节，而另一个成员， BCRP/ABCG 2受雌激素调节。因此，研究ABC调节的新机制， 蛋白质表达可以提供独特的方法来规避耐药性。因此，扩大 我们在ABC转运蛋白和拓扑异构酶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，以及我们在上一个资助期内为测试 拓扑异构酶和ABC蛋白表达新调控机制影响 抗癌药物的反应，并提供新的治疗模式的见解。在联合国各机构所做工作的基础上， 上一个资助期，我在这里提供一个重点应用程序，并提出以下具体目标，以测试我们的 假设：（1）定义哺乳动物肿瘤中拓扑异构酶调节的分子机制， （2）确定Ubc 9和蛋白质类小泛素化在药物介导的细胞毒性中的作用。 抗癌药物反应性;和（3）定义Notch-1新型调节的分子机制 ABC转运蛋白MRP 1/ABCC 1的表达。

Despite advances in cancer genetics and treatment, anticancer drug resistance remains a formidableproblem and challenge to oncologists and researchers alike. The long-term goat 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 multifactorial 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 cytotoxiciry 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.