Characteristics of Multidrug Resistance in Human Tumors

人类肿瘤的多药耐药性特征

• 批准号: 7097534
• 负责人: WILLIAM T BECK
• 金额: $ 28.01万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7097534
• 关键词: DNA gyrase; DNA methylation; DNA topoisomerases; antineoplastics; apoptosis; biological signal transduction; cell line; chimeric proteins; chromatin; drug screening /evaluation; enzyme activity; enzyme induction /repression; enzyme inhibitors; genetic promoter element; green fluorescent proteins; microarray technology; multidrug resistance; protooncogene; transcription factor; tumor suppressor genes; DNA gyrase; DNA methylation; DNA topoisomerases; antineoplastics; apoptosis; biological signal transduction; cell line; chimeric proteins; chromatin; drug screening /evaluation; enzyme activity; enzyme induction /repression; enzyme inhibitors; genetic promoter element; green fluorescent proteins; microarray technology; multidrug resistance; protooncogene; transcription factor; tumor suppressor genes

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.

描述（由申请人提供）：尽管癌症遗传学和治疗方面取得了进步，但抗癌药物的耐药性仍然是肿瘤学家和研究人员的巨大问题和挑战。该项目的长期目标是解剖肿瘤多药耐药性机制。以前众所周知，在细胞水平上，即使是单一药物的抗癌耐药性也是多因素现象。在选择对任何特定细胞毒性剂的耐药性中，可能发生多种遗传变化。鉴于这种观点，我们最近了解到，抗癌药物的推定目标和作用的介体在细胞生理和药物反应性中起着复杂的作用。例如，拓扑异构酶对药物治疗进行了翻译后修饰，这些修饰揭示了涉及Sumoylation的复杂信号传导途径，该途径也参与了药物反应。此外，关于介导多药电阻的ABC转运蛋白，我们了解到，该类别的一个成员MRP1/ABCC1似乎受信号分子Notch-1的调节，而另一个成员BCRP/ABCG2则由雌激素调节。因此，研究ABC蛋白表达调节的新型机制可能提供独特的方法来规避耐药性。因此，扩大我们实验室在ABC转运蛋白和拓扑异构酶中的历史焦点，我们希望以过去几年的新知识以及我们在上一家资金期间取得的进步来基于检验以下假设，即表达拓扑异构酶和ABC蛋白的新型监管机制和ABC蛋白会影响抗药性药物反应和新的更便宜的标准。在以前的资助期间，我在这里提供了重点应用，并提出了以下特定目的来检验我们的假设：（1）定义哺乳动物肿瘤中拓扑异构酶调节的分子机制，并通过这些酶通过这些酶进行药物介导的细胞毒性； （2）定义UBC9和蛋白质Sumoylation在抗癌药物反应中的作用； （3）通过Notch-1定义了ABC转运蛋白的表达MRP1/ABCC1的Notch-1的分子机制。