CHARACTERISTICS OF MULTIDRUG RESISTANCE IN HUMAN TUMORS

描述：(申请者摘要)：抗药性是一大障碍 来治愈肿瘤疾病。这个项目的长期目标是 对多药耐药(MDR)机制进行了剖析。这个 拟议的研究将集中在与这两种表达改变相关的MDR DNA拓扑异构酶II与P-糖蛋白的过表达 (PGP-MDR)，以及药物的调节机制(即“信号”)。 细胞毒性事件。新数据表明，许多药物的细胞毒作用 抗癌药物是通过与细胞紧密结合而介导的 调节细胞周期机制，通常导致程序化诱导 细胞死亡(PCD)。需要检验的一个假设是，MDR涉及 细胞周期和PCD相关蛋白的改变，以及改变的药物 “靶”蛋白减弱细胞毒信号转导途径 完整表达PCD通路所必需的。不同类型的抑制剂 DNA拓扑异构酶II(Topo II)，包括DNA蛋白 稳定络合物的药物(如依托泊苷)及其催化抑制剂 (例如，Merbarone)，在野生型(Wt)和 与DNA损伤或抑制有关的AT-MDR细胞 TOPO II的功能，但对其作用机制(S)知之甚少 它们杀死肿瘤细胞。需要检验的第二个假设是，催化作用 Topo II抑制剂激活PCD的途径与TOPO II不同 酶的复合体稳定抑制剂。最后，调制器 Pgp-MDR可以增加mdr1和Pgp的表达，但几乎什么都不知道 关于这一效应所涉及的信号机制。因此，最后一个 有待检验的假设是通过抑制Pgp诱导MDR1 功能可能会中断涉及转录的反馈信号(S P53的因子和/或新功能。为了检验这些假设， 提出了以下具体目标：(1)定义AT-MDR机制， 通过对细胞毒信号转导的研究；(2)确定 催化剂与络合物稳定剂TOPO II的细胞毒性机制 药物敏感和at-mdr细胞中的抑制物；以及(3)识别信号转导 PGP-MDR调节剂诱导MDR1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.