HYPOXIC STRESS MECHANISMS IN RADIATION AND CHEMOTHERAPY

放射治疗和化疗中的缺氧应激机制

• 批准号: 6831609
• 负责人: BRIAN J MURPHY
• 金额: $ 36.17万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-12 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6831609
• 关键词: antineoplastics; biological signal transduction; cesium; drug resistance; hypoxia; intracellular transport; laboratory mouse; microarray technology; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer radiation therapy; neoplasm /cancer transplantation; neoplastic process; oxidation reduction reaction; phosphorylation; radiation resistance; tissue /cell culture; transcription factor

A growing body of evidence suggests that many human solid tumors contain a significant fraction of hypoxic cells which can directly affect a number of malignant phenotypes, including therapeutic resistance, sustained angiogenesis, evasion of programmed cell death, tissue invasion and metastasis, and self-sufficiency in growth signals. This scenario is supported by clinical studies that correlate hypoxia with poor prognosis in a number of solid tumor types. These hypoxia-dependent phenotypic alterations are believed to involve, in part, a set of diverse hypoxic stress genes whose expression is controlled by specific hypoxia-sensitive transcription factors. The proposed research is based on the findings that the metal transcription factor-1 (MTF-1) is activated by hypoxia and that tumor expansion in hypoxic mouse fibrosarcomas requires MTF-1 expression. Furthermore, hypoxia-activated MTF-1 contributes to the development of cisplatin resistance in vitro. This ubiquitous transcription factor controls a number of hypoxic stress genes that, if overexpressed, could contribute to the development of clinically important malignant phenotypes in tumors containing transiently hypoxic microregions. The first set of studies (Aim 1) proposed in this competitive renewal is designed to clearly define the mechanisms associated with MTF-1 activation by hypoxia, including analysis of potential signaling pathways, phosphorylation events, regulation of the redox state of the MTF- 1 DNA binding domain, and nuclear translocation. Aim 2 uses microarray technology to identify other hypoxic stress genes that are controlled by MTF-1 and involves transcriptional analysis of a selected number of these MTF-dependent genes. The studies in Aim 3, utilizing both tumor xenograft and in vitro models will address the functional significance of hypoxia-mediated activation of MTF-1 in malignant progression. An understanding of these mechanisms will aid in the development of novel prognostic and therapeutic modalities, including gene therapy approaches, for solid tumors containing significant regions of recurring or transient hypoxia.

越来越多的证据表明，许多人类实体瘤含有很大一部分缺氧细胞，这些细胞可以直接影响许多恶性表型，包括治疗耐药、持续血管生成、逃避程序性细胞死亡、组织侵袭和转移以及自给自足在增长信号中。 这种情况得到了临床研究的支持，这些临床研究将缺氧与多种实体瘤类型的不良预后相关联。 这些缺氧依赖性表型改变被认为部分涉及一组不同的缺氧应激基因，其表达受到特定缺氧敏感转录因子的控制。 拟议的研究基于以下发现：缺氧会激活金属转录因子-1 (MTF-1)，并且缺氧小鼠纤维肉瘤中的肿瘤扩张需要 MTF-1 表达。此外，缺氧激活的 MTF-1 有助于体外顺铂耐药性的发展。 这种普遍存在的转录因子控制着许多缺氧应激基因，如果这些基因过度表达，可能会导致含有短暂缺氧微区域的肿瘤中临床上重要的恶性表型的发展。 本次竞争性更新中提出的第一组研究（目标1）旨在明确定义缺氧引起的MTF-1激活相关机制，包括分析潜在的信号通路、磷酸化事件、MTF-1氧化还原状态的调节DNA 结合域和核易位。 目标 2 使用微阵列技术来鉴定受 MTF-1 控制的其他缺氧应激基因，并涉及对这些 MTF 依赖性基因中选定数量的转录分析。 目标 3 中的研究利用肿瘤异种移植和体外模型，将探讨缺氧介导的 MTF-1 激活在恶性进展中的功能意义。 了解这些机制将有助于开发新的预后和治疗方式，包括基因治疗方法，用于含有显着反复或短暂缺氧区域的实体瘤。