MODIFICATION OF HYPERTHERMIA RESPONSE

热疗反应的改变

• 批准号: 6350108
• 负责人: DENNIS B. LEEPER
• 金额: $ 114.19万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-04-23 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6350108
• 关键词: acidity /alkalinity; cellular pathology; extracellular; hyperglycemia; hyperthermia; intracellular

Reduction of intracellular pH (pHi) by acute reduction of extracellular pH (PhE) leads to hyperthermia sensitization and sensitization to certain chemotherapeutic agents. The global hypothesis of this program is that acute acidification provides a mechanisms by which melanoma can be sensitized by chemical means to pH-dependent therapeutic agents such as hyperthermia. We have shown that hyperglycemia alone is unlikely to provide significant sensitization to hyperthermia. Strategies have been developed to enhance melanoma to hyperthermia by acute tumor acidification. This research program will provide new mechanistic insights into: The effects of acidification alone or combined with hyperthermia on DNA replication in a defined molecular system (Project 1); The regulation of pHi and methods to inhibit proton transport in melanoma cells adapted at growth at low pHe (Project 2); The cytoskeletal resistance and upregulation of hsp27, hsp60 and hsp72 that accompany growth of melanoma cells at low pHe (Project 3); The chemical methods to enhance hyperglycemia-induced acidification in human melanoma xenografts (Project 4) and The sensitization by acute acidification of the response of melanoma xenografts to hyperthermia relative to normal tissues (Project 4). A subcontract to the University of Pennsylvania will measure xenograft pHi and other metabolic parameters by non-invasive magnetic resonance techniques. This research plan is an outgrowth of the progress made with previous N.C.I. support. Four interactive projects and two cores are proposed. Projects 1 & 3 provide molecular and cellular mechanisms of effects of acidification on response to hyperthermia. Project 2 seeks to understand regulation of pHi and identify novel drugs to inhibit proton pumping mechanisms to induce intracellular acidification. Project 2 measures pHi for all projects. Project 4 validates the molecular and cellular findings in vivo by determining pHe, pHi, pO2, blood flow and glucose metabolites in xenografts and by comparing the response of xenografts and normal tissue to hyperthermia. Furthermore, Project 4 provides melanoma cells and response of xenografts and normal tissue to hyperthermia. Furthermore, Project 4 provides melanoma cells and tissues to Projects 1, 2 & 3 to test the hypotheses proposed in vitro. The Administrative Core provides administrative support, statistical & data management and external review for all projects. The Animal Care Core purchases and provides care for animals for xenografts to provide melanoma cells and tumors for all projects.

通过急剧降低细胞外 pH 值来降低细胞内 pH (pHi) (PhE) 导致热敏化和对某些物质的敏化 化疗剂。该计划的全局假设是 急性酸化提供了一种机制，可以通过这种机制来治疗黑色素瘤 通过化学手段对 pH 依赖性治疗剂敏感，例如 高热。我们已经证明，仅靠高血糖不太可能 对高热具有显着的敏感性。策略已 开发用于增强黑色素瘤对急性肿瘤的高热反应 酸化。该研究计划将提供新的机制见解 成：单独酸化或与热疗结合的效果 DNA 在特定分子系统中的复制（项目 1）；法规 pHi 的研究和抑制黑色素瘤细胞中质子转运的方法 在低 pHe 条件下生长（项目 2）；细胞骨架抵抗力和 伴随黑色素瘤生长的 hsp27、hsp60 和 hsp72 上调 低 pHe 条件下的细胞（项目 3）；化学方法增强 高血糖诱导的人类黑色素瘤异种移植物酸化（项目 4) 急性酸化反应致敏 黑色素瘤异种移植物相对于正常组织的高温（项目 4).宾夕法尼亚大学的分包合同将测量异种移植物 通过无创磁共振检测 pHi 和其他代谢参数 技术。该研究计划是所取得进展的产物 以前的 N.C.I.支持。四个互动项目和两个核心是 建议的。项目 1 和 3 提供了分子和细胞机制 酸化对高热反应的影响。项目 2 旨在 了解 pHi 的调节并识别抑制质子的新型药物 诱导细胞内酸化的泵机制。项目2 测量所有项目的 pHi。项目 4 验证了分子和 通过测定 pHe、pHi、pO2、血流量和 异种移植物中的葡萄糖代谢物并通过比较 异种移植物和正常组织进行高温治疗。此外，项目4 提供黑色素瘤细胞以及异种移植物和正常组织的反应 高热。此外，项目4提供黑色素瘤细胞和组织 项目 1、2 和 3 在体外测试提出的假设。这 行政核心提供行政支持、统计和数据 所有项目的管理和外部审查。动物护理核心 购买并照顾用于异种移植的动物以提供黑色素瘤 所有项目的细胞和肿瘤。