MODIFICATION OF HYPERTHEMIA RESPONSE

急性胞外还原降低胞内pH(Phi) PH(Phe)导致体温过高敏化和耐热性降低 发展。然而，细胞通过以下方式适应低Phe的慢性暴露 重新建立接近正常的phi，不再体温过高 很敏感。我们和其他人已经证明，大部分肿瘤种群是 低于正常Phe(平均值为7.2比7.4)，且高血糖会急性发作 并特异性地将肿瘤Phe再降低0.2pH单位 美国和中国的病人。这项计划的总体目标 是为了检验这样一个普遍假设，即肿瘤对 热疗可以通过降低phi来增强。如果对pH的操纵是 以三联疗法提高治愈率 治疗，策略必须以基本原则为基础 为临床试验的设计提供了合理的依据。 提出了五个互动项目。项目1测试了这个假设 细胞质子排出能力的增强可以在很大程度上 是由两个质子中的一个或两个的活度增加引起的 被认为是主要系统的转移机制 在哺乳动物细胞中的活性：a)阿米洛利敏感的钠质子 (Na+/H+)交换，以及b)钠敏感的氯-碳酸氢盐 (HCO3-/Cl2-)交换。项目2测试了这样一种假设，即抑制 Na~+/H~+逆向转运系统，抑制H~+/乳酸转运蛋白 低Phe对细胞HCO3-/Cl-交换的抑制作用将减弱 Phi和Will对高温敏感。无论是体温过高 主要通过敏化或主要通过以下方式增强反应 将评估对耐热性发育的抑制作用。在……里面 另外，假设合成一定的热休克 蛋白质与耐热性的发展将是紧密耦合的 测试过。项目3测试了PHI的减少将 增强热对细胞结构的潜在致命性损伤 系统，从而导致杀戮增加。项目#4测试 底物引起的慢性酸中毒区域假说 正常骨髓中存在限制，因此骨髓干细胞 而已确定的前体也可以通过以下方式对热化疗敏感 抑制Na+/H+逆向转运或抑制乳酸转运。 体温过高对人体肿瘤血流的影响 体温过高及血流与间质pH值的相关性 在项目5中都有记录。肿瘤血流的改变导致 伴随而来的代谢物可及性变化， 乳酸和其他代谢副产物的积累，以及 由对流过程引起的温度消散。有一个核心 提供管理、统计和技术支持的组件 为所有项目提供支持(例如，细胞内pH测量)。

Reduction of intracellular pH (pHi) by acute reduction of extracellular pH (pHe) leads to hyperthermia sensitization and reduced thermotolerance development. However, cells adapt to chronic exposures to low pHe by re-establishing a near-normal pHi, and are no longer hyperthermia sensitive. We and others have shown that much of the tumor population is below normal pHe (mean of 7.2 vs. 7.4) and that hyperglycemia can acutely and specifically reduce tumor pHe by another 0.2 pH units in both American and Chinese patients. The overall objectives of this program are to test the general hypothesis that the response of tumors to hyperthermia can be enhanced by reducing pHi. If manipulation of pH is to lead to an improvement of the therapeutic ratio by trimodality therapy, strategies must be developed based on fundamental principles which can lead to a rational basis for the design of clinical trials. Five interactive projects are proposed. Project #1 tests the hypothesis that the increased capability for cellular proton expulsion can largely be accounted for by increased activity of one or both of the two proton translocating mechanisms which are thought to be the principal systems active in mammalian cells: a) the amiloride-sensitive sodium-proton (Na+/H+) exchange, and b) the sodium-sensitive chloride-bicarbonate (HCO3-/Cl-) exchange. Project #2 tests the hypothesis that inhibition of the Na+/H+ antiport system, inhibition of the H+/lactate symport or inhibition of HCO3-/Cl- exchange in cells adapted to low pHe will reduce pHi and will sensitize to hyperthermia. Whether the hyperthermia response is enhanced primarily by means of sensitization or primarily by inhibition of thermotolerance development will be evaluated. In addition, the hypothesis that the synthesis of certain heat shock proteins is tightly coupled with thermotolerance development will be tested. Project #3 tests the hypothesis that reduction of pHi will enhance heat-induced potentially lethal damage to cellular structural systems, thereby leading to increased killing. Project #4 tests the hypothesis that regions of chronic acidosis brought about by substrate limitation exist in normal bone marrow, and therefore marrow stem cells and committed precursors may also be sensitized to thermochemotherapy by inhibition of the Na+/H+ antiport or inhibition of lactate transport. The effect of hyperthermia on blood flow in human tumors during hyperthermia, and the correlation between blood flow and interstitial pH are documented in Project #5. Alterations in tumor blood flow result in concomitant alterations in the accessibility of metabolites, the accumulation of lactic acid and other metabolic by-products, and the dissipation of temperature by convective processes. There is a Core component which provides administrative, statistical and technical support (e.g., intracellular pH measurement) for all projects.