BASIC STUDIES OF EXPERIMENTAL TUMOR MODELS

实验肿瘤模型的基础研究

• 批准号: 3175401
• 负责人: ROBERT M SUTHERLAND
• 金额: $ 23.05万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-08-01 至 1987-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3175401
• 关键词: cell differentiation; cell growth regulation; cellular oncology; clone cells; disease /disorder model; hypoxia; radiation sensitivity; respiratory oxygenation; tissue /cell culture; xenotransplantation

It is hypothesized that both intrinsic cellular properties and extrinsic microenvironmental conditions in human tumors play significant direct and indirect roles in determining basic tumor cellular characteristics which influence sensitivity to therapeutic modalities such as ionizing radiation. Little is known about these heterogeneous intrinsic and extrinsic properties of human tumor cells with respect to radiation sensitivity because, for the most part, such studies await the development of appropriate experimental models and techniques. Methods and experimental models need to be developed to characterize this heterogeneity, to evaluate mechanisms affecting biological behavior and responsiveness to therapy, to develop and evaluate new therapeutic strategies, and to predict for therapeutic responsiveness. The research program proposed here includes experiments designed to compare the usefulness and relevance for radiation therapy of multicell spheroids, clonogenic stem cell assays, and xenografts. The specific aims of the experiments are (1) to optimize and characterize the growth in these 3 model systems of cell isolates from selected human cancer (mainly squamous cell carcinoma), (2) to directly determine the influence of certain specific external environmental conditions on intra-spheroid oxygenation and on cellular heterogeneities, and (3) to use these in vitro and in vivo model systems to determine the importance to the overall radiation response of human tumors at different stages of growth of intrinsic cell sensitivity, intercellular contact, repair, differentiation, hypoxia, and altered growth kinetics such as the development of quiescent cell populations. The central general questions we are asking are (a) What are the relative strengths and limitations of the 3 model systems for growing and characterizing human cancer cells? (b) Do human tumor cells under experimental conditions in vitro reflect the important in vivo properties? (c) What assays and endpoints are most informative for characterizing clinically relevant biological behavior and for predicting therapeutic responsiveness? (d) What are some of the inter-patient tumor differences responsible for sensitive and resistant disease? (e) What therapeutic strategies using radiation alone or combined with drugs would be effective for resistant tumors? The research proposed represents the initial phases of a concentrated, collaborative effort to more directly study human cancer in appropriate model systems which can evaluate the significance of the dynamic nature of cellular and environmental diversity that occurs at different stages of tumor growth.

据推测，内在的细胞特性和外在的细胞特性 微环境条件在人类肿瘤中发挥着重要的直接和 在确定基本肿瘤细胞特征中的间接作用 影响对治疗方式（例如电离）的敏感性 辐射。 人们对这些异质的内在和 人类肿瘤细胞关于辐射的外在特性 敏感性，因为在大多数情况下，此类研究等待开发 适当的实验模型和技术。 方法和 需要开发实验模型来表征这一点 异质性，评估影响生物行为的机制和 对治疗的反应，开发和评估新的治疗方法 策略，并预测治疗反应。 研究 这里提出的计划包括旨在比较的实验 多细胞球体放射治疗的有用性和相关性， 克隆干细胞测定和异种移植。 该计划的具体目标 实验是 (1) 优化和表征这 3 个方面的增长 从选定的人类癌症（主要是鳞状细胞癌）中分离出的细胞模型系统 细胞癌），（2）直接确定某些因素的影响 特定的外部环境条件对球体内氧合的影响 和细胞异质性，以及（3）在体外和体内使用这些 模型系统以确定总体辐射响应的重要性 人类肿瘤内在细胞生长不同阶段的研究 敏感性、细胞间接触、修复、分化、缺氧和 改变生长动力学，例如静止细胞的发育 人口。 我们要问的核心一般性问题是 (a) 什么是 3种增长模型系统的相对优势和局限性 并表征人类癌细胞？ (b) 人类肿瘤细胞是否处于 体外实验条件反映了重要的体内特性吗？ (c) 哪些测定和终点对表征最有信息性 临床相关的生物学行为和预测治疗 反应能力？ (d) 患者之间的肿瘤差异有哪些 负责敏感和耐药疾病？ (e) 什么治疗方法 单独使用放射或与药物联合使用的策略将是有效的 对于耐药肿瘤？ 拟议的研究代表了初始阶段 集中、协作努力更直接地研究人类癌症 在适当的模型系统中，可以评估 细胞和环境多样性的动态性质发生在 肿瘤生长的不同阶段。