BASIC STUDIES OF EXPERIMENTAL TUMOR MODELS

它假设内在的细胞属性和外在的 微环境条件在人类肿瘤中起着重要的直接和 间接确定基本肿瘤细胞特性的作用 影响对电离等治疗方式的敏感性 辐射。对于这些异质的内在和 人体肿瘤细胞对辐射的外在特性 敏感性是因为，在很大程度上，这样的研究等待着发展 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，以评估影响生物行为的机制和 对治疗的反应性，开发和评估新的治疗方法 策略，并预测治疗反应。这项研究 这里提出的计划包括旨在比较 多细胞球体放射治疗的有用性和相关性， 克隆干细胞检测和异种移植。《公约》的具体目标 实验是(1)优化和表征这三种植物的生长。 选定的人类癌症(主要是鳞状细胞癌)的细胞分离模型系统 细胞癌)，(2)直接确定某些影响因素 球体内充氧的特定外部环境条件 和细胞异质性，以及(3)在体外和体内使用这些 确定对整体辐射响应的重要性的模型系统 人类肿瘤不同生长阶段的固有细胞 敏感性、细胞间接触、修复、分化、缺氧和 生长动力学改变，如静止细胞的发育 人口。我们问的主要一般性问题是：(A)什么是 3种增长模式系统的相对优势和局限性 以及人类癌细胞的特征？(B)将人体肿瘤细胞置于 体外实验条件是否反映了体内重要的特性？ (C)哪些分析方法和终点最能反映特征 临床相关的生物学行为和用于预测治疗 响应性？(D)患者之间的肿瘤有哪些不同 对敏感和抵抗疾病负责？(E)什么治疗方法 单独使用辐射或与药物联合使用的策略将是有效的 治疗耐药肿瘤吗？拟议的研究代表了初始阶段 集中合作，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。

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.