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）有选择地增强 通过调节糖酵解/高能来调节肿瘤热敏感性 磷酸循环，(2) 开发代谢基础并评估 非侵入性预测肿瘤热敏感性的可能性（基于 肿瘤能量状态和pH指数），以及（3）评估可能性 耐热性衰减动力学是可变的且具有组织特异性。 耐受性衰减动力学的组织特异性变异可能有助于 作为构建热疗分割方案的基础，以最大限度地减少 损害正常组织并最大限度地损害肿瘤组织。 为了实现这些目标，进行了一系列正常和 转化细胞将在规定的体外条件下进行 (1)确定细胞与代谢之间的耦合程度 控制 pH 值和细胞能量状态，以及 (2) 确定独立的 pH（细胞内和细胞外）和能量的相互作用 细胞热敏感性的状态（例如 ATP/Pi）。 这些的选择 用于研究的代谢物基于体外研究表明 细胞 ATP 水平或细胞外 pH 值突然发生显着变化 影响细胞热敏感性以及途径的差异 正常和正常之间这些代谢物的产生和净产生 癌细胞。 肿瘤细胞与正常组织的不同之处不仅在于 他们调节这些代谢物的能力，而且还在于他们对 底物可用性和酸转运抑制剂。 使用的肿瘤细胞 用于体外研究也将用于体内肿瘤 研究。 在这些体内研究中，自然发生的和选择性的 能量状态和 pH 值的诱导变化将针对肿瘤进行评估 热敏化特性。 组织代谢物浓度为 使用 31p-NMR 进行侵入性和非侵入性测定。 组织特异性和可变耐受性衰减动力学的存在将 在各种缓慢或非增殖的小鼠正常组织中进行评估 以及增殖更快的肿瘤。 明确的评估 增殖率和耐受性衰减动力学之间的关系将 由在以下条件下表达完全接触抑制的模型细胞系制成 中等密度，但在低细胞密度下迅速增殖。