MECHANISMS OF CELLULAR RADIOSENSITIVITY

细胞辐射敏感性的机制

• 批准号: 6584603
• 负责人: JERRY R WILLIAMS
• 金额: $ 29.41万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6584603
• 关键词: apoptosis; cell line; cell type; colorectal neoplasms; gene targeting; glioblastoma multiforme; laboratory mouse; neoplasm /cancer radiation therapy; neoplastic cell; p53 gene /protein; phenotype; radiation sensitivity; radiation therapy dosage; tissue /cell culture; xenotransplantation

This project will determine whether novel patterns of dose and dose-rate can improve radiation therapy of human cancer when based on mechanisms that determine radiosensitivity in human tumor cells. We have made three novel observations in a system of genetically-defined human colorectal tumor cells: 1) two distinctly different patterns of response to acute and protracted irradiation (radioresponse phenotypes) are observed and p53 predicts the pattern of response observed in a specific cell line; 2) protracted irradiation alters the radiosensitivity in tumor cells through two distinct mechanisms, with some cells becoming more resistant and some more sensitive depending on the specific cell type; 3) p21- modulated apoptosis has no effect on in vitro radio-sensitivity but modifies tumor response. Importantly, other radio-resistant tumor cells such as glioblastomas can be dramatically sensitized by protracted irradiation and if this sensitizing process can be translated into the clinic it might have significant impact. These data taken together suggest that radiotherapy of tumors, to be optimally effective, should exploit the particular radio-response phenotype of the constituent tumor cells. We have used these several observations to construct a new model that we term the alpha-omega model. This model presents a new analytical structure for planning radiation therapy protocols that use combinations of dose and dose-rate to achieve optimal effects. We now propose to use the alpha omega model to suggest patterns of acute and protracted irradiation hypothesized to produce maximum cell kill in vitro and test these predictions experimentally. Project 2 will provide data that describe the effects of tumor microenvironment on mechanisms of radiosensitivity including radio-sensitization by protracted irradiation. These data when combined with results from this project will be used to propose radiotherapy protocols that will maximize response in experimental tumors. The several cores and projects will together test these hypotheses and if successful, translate these into the clinic. This project will test the hypothesis: Radiotherapy protocols of combined acute and protracted irradiation will improve response in cells and tumors in such protocols are based on the radio- response phenotype of the constituent cells.

该项目将根据确定人类肿瘤细胞的放射敏感性的机制，确定新型剂量和剂量率的新模式是否可以改善人类癌症的放射治疗。我们已经在遗传定义的人结直肠肿瘤细胞系统中进行了三个新的观察：1）观察到了对急性和旷日持久的辐射的两个明显不同的反应模式（放射性响应表型），并且p53预测了在特定细胞系中观察到的反应模式； 2）长期的辐照通过两种不同的机制改变了肿瘤细胞中的放射敏感性，其中一些细胞变得更具耐药性，并且根据特定的细胞类型更敏感。 3）P21-调制凋亡对体外无线电敏感性没有影响，但会改变肿瘤反应。重要的是，可以通过旷日持久的辐照来显着敏感其他耐胶质细胞瘤等耐胶质细胞的肿瘤细胞，如果可以将这种敏化过程转化为诊所，则可能会产生重大影响。这些数据一起表明，最佳有效的肿瘤放射疗法应利用组成肿瘤细胞的特定放射反应表型。我们已经使用了这些几个观察结果来构建一个新的模型，我们将其称为alpha-Omega模型。该模型为计划放射治疗方案提供了一种新的分析结构，该结构使用剂量和剂量率的组合来实现最佳效果。现在，我们建议使用alpha欧米茄模型来提出假设的急性和长期辐照模式，以在体外产生最大的细胞杀伤，并通过实验测试这些预测。项目2将提供描述肿瘤微环境对放射敏性机制的影响，包括通过旷日持久的辐射射线敏化。这些数据与该项目的结果结合使用，将用于提出放射疗法方案，以最大程度地提高实验肿瘤的反应。几个核心和项目将共同检验这些假设，如果成功，将其转化为诊所。该项目将检验假设：急性和持久照射的放疗方案将改善此类方案中细胞和肿瘤的反应，基于组成细胞的射击反应表型。