CHARACTERISTICS OF MULTIDRUG RESISTANCE IN HUMAN TUMORS

描述：（申请人摘要）：耐药性构成了一个主要障碍 肿瘤疾病的治疗。 该项目的长期目标是 多药耐药（multidrug resistance，MDR）机制的研究进展。 的 拟议的研究将集中在MDR与改变表达 DNA拓扑异构酶II（at-MDR）和P-糖蛋白的过度表达 （Pgp-MDR），以及药物介导的机制（即，“信号”） 细胞毒性事件。 新的数据表明， 抗癌药物是通过干扰紧密的 调节细胞周期机制，通常导致诱导程序化的 细胞死亡（PCD）。 有待检验的一个假设是，MDR涉及 细胞周期和PCD相关蛋白的改变， “靶”蛋白减弱细胞毒性信号转导途径 需要充分表达PCD途径。 不同类型的抑制剂 DNA拓扑异构酶II（topo II），包括DNA蛋白质 复合物稳定药物（例如，依托泊苷）和催化抑制剂 (e.g.,甲基巴龙），在野生型（WT）中具有不同的细胞毒性作用， 似乎与DNA损伤或抑制有关的at-MDR细胞 的topo II功能，但很少有人知道的机制（S）， 杀死肿瘤细胞。 第二个有待检验的假设是， topo II抑制剂通过与topo II抑制剂不同的途径激活PCD， 酶的复合物稳定抑制剂。 最后， Pgp-MDR可增加mdr 1和Pgp的表达，但事实上没有什么是已知的 这种效应的信号机制。 最后， 待检验的假设是通过抑制Pgp诱导mdr 1 函数可以中断涉及转录的反馈信号 p53的新功能。 为了验证这些假设， 具体目的如下：（1）明确at-MDR的机制， 通过细胞毒信号转导的研究;（2）确定 催化型与复合稳定型拓扑异构酶II的细胞毒性机制 药物敏感性和at-MDR细胞中的抑制剂;以及（3）识别信号传导 Pgp-MDR调节剂诱导mdr 1表达的机制。

DESCRIPTION: (Applicant's Abstract): Drug resistance poses a major barrier to the cure of neoplastic diseases. The long-term goal of this project has been the dissection of mechanisms of multidrug resistance (MDR). The proposed studies will focus on MDR associated with both altered expression of DNA topoisomerase II (at-MDR) and overexpression of P-glycoprotein (Pgp-MDR), as well as the mechanisms by which drugs mediate (i.e., "signal") cytotoxic events. New data suggest that the cytotoxic effects of many anticancer drugs are mediated through interference with the tightly regulated cell cycle machinery, often leading to induction of programmed cell death (PCD). One hypothesis to be tested is that MDR involves alterations in cell cycle-and PCD-related proteins, and that altered drug "target" proteins attenuate the cytotoxic signal transduction pathways required for full expression of PCD pathways. Different types of inhibitors of DNA topoisomerase II (topo II), including the DNA-protein complex-stabilizing drugs (e.g., etoposide) and the catalytic inhibitors (e.g., merbarone), have different cytotoxic actions in wild-type (wt) and at-MDR cells that appear to be related to either DNA damage or to inhibition of topo II function, but little is known about the mechanism(s) by which they kill tumor cells. A second hypothesis to be tested is that catalytic inhibitors of topo II activate PCD by a different route than that of complex-stabilizing inhibitors of the enzyme. Finally, modulators of Pgp-MDR can increase mdr1 and Pgp expression, but virtually nothing is known about the signaling mechanisms involved in this effect. Thus, the last hypothesis to be tested is that the induction of mdr1 by inhibition of Pgp function may interrupt a feedback signal(s) that involves transcription factors and/or novel functions of p53. To test these hypotheses, the following Specific Aims are proposed: (1) define the mechanism of at-MDR, through studies of cytotoxic signal transduction; (2) determine the mechanism of cytotoxicity of catalytic vs. complex-stabilizing topo II inhibitors in drug-sensitive and at-MDR cells; and (3) identify signalling mechanisms by which Pgp-MDR modulators induce mdr1 expression.