MODIFICATION OF HYPERTHERMIA RESPONSE

通过急性降低胞外pH来降低胞内pH(Phi) (苯丙氨酸)导致体温过高致敏和一定程度的致敏 化疗药物。这一计划的总体假设是 急性酸化提供了一种黑色素瘤发生的机制 通过化学手段敏化pH依赖的治疗剂，如 体温过高。我们已经证明，仅有高血糖不太可能 对体温过高有显著的敏感度。战略一直是 通过急性肿瘤将黑色素瘤增强为热疗 酸化。这项研究计划将提供新的机械论见解。 单独酸化或与热疗联合作用对 在确定的分子系统中复制DNA(项目1)；调节 PHI和抑制黑色素瘤细胞质子转运的方法 在低Phe条件下生长(项目2)；细胞骨架阻力和 伴随黑色素瘤生长的HSP27、HSP60和HSP72的上调 低PHE的细胞(项目3)；化学方法增强 高血糖诱导的人黑色素瘤移植瘤的酸化(项目 4)和通过急性酸化对以下反应的敏化 黑色素瘤异种移植到相对于正常组织的高温(项目 4)。宾夕法尼亚大学的一个分包合同将测量异种移植 PHI等代谢参数的无创性磁共振检测 技巧。这项研究计划是以下进展的结果 之前NCI的支持。四个互动项目和两个核心是 建议。项目1和3提供了分子和细胞机制 酸化对高温反应的影响。项目2寻求 了解phi的调节，寻找抑制质子的新药 诱导细胞内酸化的泵送机制。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和比较 异种移植和正常组织进行热疗。此外，项目4 提供黑色素瘤细胞以及异种移植和正常组织对 体温过高。此外，项目4提供黑色素瘤细胞和组织 TO项目1、2和3，以在体外验证所提出的假设。这个 行政核心提供行政支持、统计和数据 对所有项目进行管理和外部审查。爱护动物核心 为提供黑色素瘤的异种移植动物购买和提供护理 所有项目的细胞和肿瘤。

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.