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BASIC STUDIES OF EXPERIMENTAL TUMOR MODELS

实验肿瘤模型的基础研究

基本信息

批准号：
3175405
负责人：
ROBERT M SUTHERLAND
金额：
$ 28.56万
依托单位：
SRI INTERNATIONAL
依托单位国家：
美国
项目类别：
财政年份：
1984
资助国家：
美国
起止时间：
1984-08-01 至 1994-05-31
项目状态：
已结题

项目摘要

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，细胞的内在特性和外在特性微环境条件在人类肿瘤中起着重要的直接作用，在确定基本肿瘤细胞特征中的间接作用，影响对治疗方式敏感性，辐射关于这些异质的内在和人肿瘤细胞对辐射的外在特性敏感性，因为在大多数情况下，这些研究等待发展合适的实验模型和技术。方法和需要开发实验模型来表征这一点异质性，以评估影响生物学行为的机制，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。研究这里提出的方案包括旨在比较多细胞球状体放射治疗的有用性和相关性，克隆生成干细胞测定和异种移植。的具体目标实验是（1）优化和表征这3种生长方式来自选定的人类癌症（主要是鳞状细胞癌）的细胞分离物的模型系统（2）直接确定某些细胞癌的影响特定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拟系统，以确定对整体辐射响应的重要性在不同的内在细胞生长阶段，敏感性，细胞间接触，修复，分化，缺氧，改变生长动力学，例如静止细胞的发育人口。我们要问的主要问题是：（a） 3种模型系统的相对优势和局限性，和人类癌细胞的特征 (b)人类肿瘤细胞在体外实验条件反映了体内的重要特性？ (c)哪些检测试剂盒和终点对表征信息最丰富临床相关的生物学行为和用于预测治疗响应？ (d)患者之间的肿瘤差异有哪些负责敏感和耐药的疾病？ (e)什么治疗单独使用放射或与药物结合使用的策略将是有效的治疗耐药肿瘤拟议的研究代表了最初阶段一个集中的，合作的努力，更直接地研究人类癌症，在适当的模型系统，可以评估的意义，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。