MODIFICATION OF HYPERTHERMIA RESPONSE

通过急性降低细胞外pH值降低细胞内pH值（pHi） (PhE)导致高温致敏和对某些 化疗剂。这个项目的总体假设是， 急性酸化提供了一种机制， 通过化学方法对pH依赖性治疗剂敏感， 体温过高我们已经证明，单独的高血糖不太可能 对体温过高有显著的敏感性。策略已经 开发用于增强黑色素瘤对急性肿瘤的热疗 酸化这项研究计划将提供新的机制见解 酸化单独或与高温结合对 定义的分子系统中的DNA复制（项目1）; 以及抑制黑素瘤细胞中质子转运的方法 在低pHe下生长（项目2）;细胞骨架阻力和 伴随黑色素瘤生长的Hsp 27、Hsp 60和Hsp 72的上调 细胞在低pHe（项目3）;化学方法，以提高 人黑素瘤异种移植物中高血糖诱导的酸化 4)和急性酸化反应的致敏作用， 相对于正常组织的热疗的黑素瘤异种移植物（项目 4）。宾夕法尼亚大学的一名研究人员将测量异种移植 pHi和其他代谢参数，通过非侵入性磁共振 技术.这项研究计划是随着科技进步而产生的。 前N.C.I.支持.四个互动项目和两个核心是 提出了项目1和3提供了分子和细胞机制， 酸化对体温过高反应的影响。项目2旨在 了解pHi的调节并确定抑制质子的新药 泵送机制以诱导细胞内酸化。计划2 测量所有项目的pHi。项目4验证了分子和 通过测定pHe、pHi、pO 2、血流量和 葡萄糖代谢物在异种移植，并通过比较反应， 异种移植物和正常组织的高温。此外，项目4 提供黑色素瘤细胞和异种移植物和正常组织对 体温过高此外，项目4提供黑色素瘤细胞和组织， 项目1、2和3，以测试体外提出的假设。的 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 购买和提供照顾动物异种移植提供黑色素瘤 细胞和肿瘤的所有项目。

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.