FRACTIONATED HYPERTHERMIA: CELL AND METABOLIC FACTORS

分段热疗：细胞和代谢因素

• 批准号: 3165968
• 负责人: LEO E GERWECK
• 金额: $ 21.57万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-02-01 至 1988-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3165968
• 关键词: X ray; acidity /alkalinity; deficient growth media; glucose; glycogenolysis; hypoxia; metabolism disorder; molecular oncology; neoplasm /cancer radiation therapy; neoplasm /cancer thermotherapy; oxygen tension; radiation dosage; radiation sensitivity; radiobiology; relative biological effectiveness; tissue /cell culture

The long-term objectives of this proposal are to (1) selectively enhance tumor thermal sensitivity by modulating the glycolysis/high-energy phosphate cycle, (2) develop the metabolic basis for and evaluate the possibility of non-invasively predicting tumor thermal sensitivity (based on indices of tumor energy status and pH), and (3) evaluate the possibility that thermotolerance decay kinetics are variable and tissue specific. Tissue specific variability in the kinetics of tolerance decay could serve as a basis for structuring hyperthermia fractionation protocols to minimize damage to normal tissue and maximize damage to tumor tissue. To accomplish these objectives, a series of experiments with normal and transformed cells will be performed under defined in-vitro conditions to (1) determine the degree of cellular coupling between, and metabolic control of, pH and cell energy status, and (2) determine the independent and interactive effect of pH (intracellular and extracellular) and energy status (e.g. ATP/Pi) on cell thermal sensitivity. The choice of these metabolites for investigation is based on in-vitro studies showing that abrupt changes in cellular ATP levels or extracellular pH markedly influence cell thermal sensitivity, and on differences in the pathways of generation and the net production of these metabolites between normal and cancer cells. Tumor cells likely differ from normal tissues not only in their capacity to regulate these metabolites, but also in their response to substrate availability and acid transport inhibitors. The tumor cells used for the in-vitro studies will also be employed for the in-vivo tumor studies. In these in-vivo studies, naturally occurring and selectively induced changes in energy status and pH will be evaluated for their tumor thermal sensitizing properties. Tissue metabolite concentrations will be determined invasively, as well as non-invasively using 31p-NMR. The existence of tissue specific and variable tolerance decay kinetics will be evaluated in various slowly or non-proliferating murine normal tissues and in more rapidly proliferating tumors. An explicit evaluation of the relationship between proliferative rate and tolerance decay kinetics will be made with model cell lines which express full contact inhibition at moderate densities, but proliferate rapidly at low cell densities.

该提案的长期目标是（1）选择性增强 通过调节糖酵解/高能量来通过调节肿瘤热敏感性 磷酸盐周期，（2）为并评估代谢基础 非侵入性预测肿瘤热敏感性的可能性（基于 关于肿瘤能量状态和pH的指标），以及（3）评估可能性 这种热耐腐烂动力学是可变的，并且特定于组织。 耐受性衰减动力学的组织特异性变异性可以使用 作为构建高温分馏协议以最小化的基础 对正常组织的损害，并最大程度地损害肿瘤组织。 为了实现这些目标，一系列具有正常和的实验 转化的细胞将在定义的体外条件下进行 （1）确定与代谢之间的细胞耦合程度 控制pH和细胞能量状态，以及（2）确定独立 pH（细胞内和细胞外）和能量的互动效应 细胞热敏感性的状态（例如ATP/PI）。 这些选择 用于研究的代谢产物基于体外研究表明 细胞ATP水平或细胞外pH的突然变化明显变化 影响细胞的热灵敏度，并影响途径的差异 正常和 癌细胞。 肿瘤细胞不仅与正常组织不同 他们调节这些代谢产物的能力，但也在回应 底物的可用性和酸转运抑制剂。 肿瘤细胞使用 对于体外研究，还将用于体内肿瘤 研究。 在这些体内研究中，自然发生和有选择性地发生 诱导的能量状态变化和pH值将评估其肿瘤 热敏化特性。 组织代谢物浓度将是 使用31P-NMR侵入性地确定和非侵入性。 组织特异性和可变的耐受性衰减动力学的存在将会 在各种缓慢或不扩散的鼠正常组织中进行评估 并在更快速的肿瘤中。 对 增殖率和公差衰减动力学之间的关系将 用模型细胞系制成，以表达完全接触的抑制 中等密度，但在低细胞密度下迅速增殖。