Characteristics of Multidrug Resistance in Human Tumors

尽管在癌症遗传学和治疗方面取得了进展，但抗癌药物耐药性仍然是一个严峻的问题 对肿瘤学家和研究人员都提出了挑战。这个项目的长期目标是解剖 肿瘤多药耐药机制的研究。以前已经知道，抗癌药物耐药性在 细胞水平，甚至对单个因素来说，都是一个多因素的现象；多个基因变化可能发生在 对任何特定细胞毒剂产生抗药性的肿瘤细胞。补充这一观点，我们有 最近了解到抗癌药物的假定靶点和它们的作用介体发挥作用 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- 翻译修饰对药物治疗的反应，这些修饰揭示了一种复杂的 涉及相扑的信号通路，也参与药物反应。此外，关于 ABC转运蛋白，介导多药耐药，我们已经了解到，这一类中的一名成员， MRP1/ABCC1似乎受信号分子Notch-1的调控，而另一个成员， BCRP/ABCG2受雌激素调节。因此，对农业银行监管新机制的研究 蛋白表达可能为规避耐药提供独特的方法。因此，在 我们实验室在ABC转运蛋白和拓扑异构酶方面的历史焦点，我们希望在此基础上 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蛋白表达的新调控机制影响 抗癌药物的反应，并提供对新的治疗范例的见解。基于在 在之前的资助期内，我在这里提供一个有重点的申请，并提出以下具体目标来测试我们的 假设：(1)定义哺乳动物肿瘤中拓扑异构酶调节的分子机制和 药物通过这些酶介导的细胞毒作用；(2)确定Ubc9和蛋白质苏莫化在 抗癌药物反应性；以及(3)确定Notch-1调控新的分子机制 ABC转运蛋白MRP1/ABCC1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.