METABOLIC FACTORS IN HEAT & RADIATION LETHALITY

热量中的代谢因素

• 批准号: 3481951
• 负责人: LEO E GERWECK
• 金额: $ 29.44万
• 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 1993-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3481951
• 关键词: NAD(H) phosphate; NAD(P) transhydrogenase; acidity /alkalinity; adenosine diphosphate; adenosine monophosphate; adenosine triphosphate; aminoacid; athymic mouse; biopsy; colon neoplasms; creatine phosphate; drug hypersensitivity; glioblastoma multiforme; glucose; glycogenolysis; head /neck neoplasm; high performance liquid chromatography; hypoglycemia; hypoxia; metabolism disorder; mitomycin C; molecular genetics; molecular oncology; neoplasm /cancer radiation therapy; neoplasm /cancer thermotherapy; neoplastic cell culture for noncancer research; nicotinamide adenine dinucleotide; oxidation reduction reaction; oxidative phosphorylation; oxygen tension; radiation genetics; radiation sensitivity; relative biological effectiveness; respiratory oxygenation; stress proteins; tissue /cell culture

The objective of this research is to evaluate cell energy status and redox status, as predictors of cellular response to heat, radiation (oxygen enhancement ratio), and the bioreductively activated drug, mitomycin C. Knowledge of these indices of metabolic status should be of use not only for predicting response to a particular therapeutic agent, but also for choosing treatment approaches, for a variety of human neoplasms. Energy and redox status will be determined by measuring the content of ATP, ADP, AMP, CrP, and NAD+, NADH, NADP+, NADPH, on a single extract of cells or tissue by high pressure liquid chromatography. Biochemical considerations and experimental evidence suggest that changes in tumor energy and redox status occur secondary to hypoxia, or hypoglycemia, or inadequate carbon sources for oxidative phosphorylation. In the proposed study, the relationship between variable oxygen, glucose, and amino acid concentration, and cell energy and redox status, will be evaluated. Simultaneously, the radiation oxygen enhancement ratio and cell sensitivity to fixed doses of heat, and mitomycin C will be evaluated. Specifically, the radiation oxygen enhancement ratio (OER) and parameters of metabolic status will be determined at 6-8 oxygen concentrations. Subsequently, the effect of prolonged oxygen depreviation, 100 PPM 02, on the OER, energy status, and redox status, will be determined. Cellular response to fixed doses of heat, radiation, and mitomycin C will be evaluated under restricted glucose and amino acid conditions. The relationship between energy and redox status and sensitivity of cells to these agents will be determined. It is anticipated that specific changes in energy and redox status will occur in response to each unique nutrient condition, and that these metabolic indices will be predictors of heat, radiation and drug sensitivity. In addition to these in vitro analyses on two cell lines, the murine FSa-II and human glioblastoma U87, both lines will be employed as poorly oxygenated FSa-II and well oxygenated U87 tumor models in C3H/Sed and NCr/Sed (nu/nu) mice. In these in vivo studies, redox status, energy status, hypoxic cell fraction and tumor sensitivity will be evaluated as a function of tumor volume. These studies will establish the utility of these parameters as predictors of heat, radiation (tumor hypoxia), and sensitivity to bioreductively activated drugs.

这项研究的目的是评估细胞能量状态 和氧化还原状态，作为细胞对热反应的预测因子， 辐射（氧增强比）和生物还原 激活药物，丝裂霉素C。这些指标的知识 代谢状态不仅可以用于预测反应 针对特定的治疗药物，也用于选择治疗 方法，用于多种人类肿瘤。 能量和氧化还原 通过测量 ATP、ADP 的含量来确定状态 AMP、CrP 和 NAD+、NADH、NADP+、NADPH，在单个 通过高压液相色谱法提取细胞或组织。 生化考虑和实验证据表明 肿瘤能量和氧化还原状态的变化继发于 缺氧、低血糖或碳源不足 氧化磷酸化。 在拟议的研究中，关系 在不同的氧气、葡萄糖和氨基酸浓度之间， 以及电池能量和氧化还原状态将被评估。 同时，辐射氧增强比和细胞 对固定剂量热的敏感性，丝裂霉素 C 将 评价。 具体而言，辐射氧增强比（OER）和 代谢状态参数将在 6-8 氧时确定 浓度。 随后，长时间吸氧的效果 depreviation，100 PPM 02，关于 OER、能量状态和氧化还原 状态，将被确定。 细胞对固定剂量的反应 热、辐射和丝裂霉素 C 将在以下条件下进行评估 限制葡萄糖和氨基酸条件。 关系 能量和氧化还原状态以及细胞对这些状态的敏感性之间 将确定代理。 预计具体变化 能量和氧化还原状态将响应每个独特的 营养状况，这些代谢指标将 热、辐射和药物敏感性的预测因子。 除了对两种细胞系的体外分析外，小鼠 FSa-II 和人胶质母细胞瘤 U87，这两个系都将用作 氧合不良的 FSa-II 和氧合良好的 U87 肿瘤模型 在 C3H/Sed 和 NCr/Sed (nu/nu) 小鼠中。 在这些体内研究中， 氧化还原状态、能量状态、缺氧细胞分数和肿瘤 将根据肿瘤体积的函数来评估敏感性。 这些研究将确定这些参数的效用： 热、辐射（肿瘤缺氧）和敏感性的预测因素 生物还原活性药物。