MODIFICATION OF HYPERTHEMIA RESPONSE

通过急性降低细胞外pH值（pHi） pH（pHe）导致高温致敏和热耐受性降低 发展 然而，细胞通过以下方式适应长期暴露于低pH He 重新建立接近正常的pHi，并且不再体温过高 敏感 我们和其他人已经证明，大部分肿瘤患者都是 低于正常pHe（平均值为7.2 vs. 7.4），高血糖可急性 并在两种细胞中特异性地将肿瘤pHe降低另外0.2个pH单位， 美国和中国患者。 该计划的总体目标 是为了检验肿瘤对 可以通过降低pHi来增强热疗。 如果pH值的操作是 通过三联疗法提高治疗率 治疗，必须根据基本原则制定策略 这可以为临床试验的设计提供合理的依据。 提出了五个互动项目。项目#1测试假设 细胞质子排出能力的增强 可以通过两个质子中的一个或两个的活性增加来解释 被认为是主要系统的移位机制 在哺乳动物细胞中有活性：a）阿米洛利敏感的钠质子 (Na+/H+）交换，和B）钠敏感的氯化物-碳酸氢盐 （HCO 3-/Cl-）交换。 项目#2测试了抑制的假设 Na+/H+反向转运系统，抑制H+/乳酸盐同向转运或 在适应低pH He细胞中抑制HCO 3-/Cl-交换将降低 并且会对体温过高敏感。 无论是体温过高 主要通过致敏或主要通过 评价耐热性发展的抑制。 在 此外，假设合成某些热休克 蛋白质与耐热性的发展密切相关， 测试. 项目#3测试了降低pHi将 增强对细胞结构的热诱导的潜在致命损伤 系统，从而导致更多的杀戮。 项目#4测试 假设慢性酸中毒区域由底物引起 正常骨髓中存在局限性，因此骨髓干细胞 和承诺的前体也可能是敏感的热化疗， 抑制Na+/H+反向转运或抑制乳酸转运。 热疗对肿瘤血流的影响 以及血流量与间质pH之间的相关性 记录在项目#5中。 肿瘤血流的改变导致 代谢物可及性的伴随改变， 乳酸和其他代谢副产物的积累， 通过对流过程的温度消散。 有一个核心 提供行政、统计和技术 支持物（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.