METABOLIC FACTORS IN RADIATION BIOLOGY AND ONCOLOGY

放射生物学和肿瘤学中的代谢因素

• 批准号: 3481949
• 负责人: LEO E GERWECK
• 金额: $ 37.88万
• 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 1996-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3481949
• 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指标， 辐射（氧增强比）和生物学 激活药物，丝裂霉素C.了解这些指数的知识 代谢状态不仅应用于预测响应 到特定的治疗剂，也可以选择治疗 方法，用于各种人类肿瘤。 能量和氧化还原 状态将通过测量ATP，ADP的内容来确定 放大器，CRP和NAD+，NADH，NADP+，NADPH，单个 通过高压液相色谱提取细胞或组织提取物。 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是继发于 缺氧或低血糖或碳源不足 氧化磷酸化。 在拟议的研究中，关系 在可变氧，葡萄糖和氨基酸浓度之间 将评估细胞能量和氧化还原状态。 同时，辐射氧增强比和细胞 对固定剂量的热量和丝裂霉素C的敏感性将是 评估。 具体而言，辐射氧增强比（OER）和 代谢状态的参数将在6-8的氧气中确定 浓度。 随后，延长氧气的影响 脱离，100 ppm 02，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 将评估热，辐射和丝裂霉素C 受限的葡萄糖和氨基酸条件。 关系 在能量和氧化还原状态以及细胞对这些细胞的敏感性之间 代理将被确定。 预计特定的更改 在能量和氧化还原状态下，将对每个唯一的 营养状况，这些代谢指数将是 预测热，辐射和药物敏感性。 除了在两种细胞系上进行的这些体外分析，鼠 FSA-II和人类胶质母细胞瘤U87，这两条线将被用作 氧化不良的FSA-II和充氧的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，低氧细胞分数和肿瘤 灵敏度将作为肿瘤体积的函数评估。 这些研究将确定这些参数的实用性 预测热，辐射（肿瘤缺氧）和对 生物学激活药物。