ROLE OF PROGRAMMED CELL DEATH IN RADIATION RESPONSE

程序性细胞死亡在辐射响应中的作用

• 批准号: 6235903
• 负责人: RAYMOND E MEYN
• 金额: $ 19.85万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-30 至 1998-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6235903
• 关键词: DNA damage; apoptosis; biopsy; cell free system; gene expression; laboratory mouse; neoplasm /cancer genetics; neoplasm /cancer radiation therapy; neoplastic cell; oncogenes; radiation genetics; radiation sensitivity; tissue /cell culture; tumor suppressor genes; western blottings

The goal of this research project is to understand the mechanisms of radiation-resistance that allow tumor cells to escape the mode of cell death known as apoptosis. It is based on experiments conducted in the investigators' laboratory during the last funding period that indicated that tumors that are relatively easy to cure display substantial apoptosis whereas tumors that are relatively resistant have no apoptotic response. These results are consistent with the premise that apoptosis may play a significant role in tumor response to radiation. However, since many tumors appear to be resistant to this mode of cell death the researchers have focused on delineating the biochemical and molecular mechanisms which dictate apoptosis propensity. Two molecular pathways have been uncovered which may account for radiation-resistance through inhibition of apoptosis and these are controlled by the bcl-2 oncogene and the p53 tumor suppressor gene. The specific aims of this proposal are directed to understanding these mechanisms in more detail, exploring strategies to overcome their ability to block apoptosis, anc evaluate their possible role in the response of radiotherapy patients. Specifically the investigators propose to: (1) Determine the biochemical mechanism by which the bcl-2 oncogene regulates apoptosis propensity. (2) Evaluate strategies for modulating p53 function in an effort to enhance apoptosis in resistant tumors. (3) Examine the possible role of apoptosis in patient response to radiotherapy by retrospective analysis of pretreatment biopsy specimens. The presence of resistant cells in tumors may be a critical factor in determining the ultimate cure of patients by radiotherapy. Whereas many factors have been examined previously to measure and predict tumor cell sensitivity to radiation, the propensity for apoptosis is a relatively new endpoint. The specific aims of this project are designed to address the role of apoptosis in radiation response and may ultimately impact patient treatment by verifying that the pretreatment apoptotic index predicts response and by developing strategies for overcoming resistance due to suppressed apoptosis propensity.

该研究项目的目的是了解 允许肿瘤细胞逃脱的辐射抗性 细胞死亡称为凋亡。 它基于实验 在上次资金中在调查人员实验室进行 表明相对容易治愈的肿瘤 表现出大量凋亡，而肿瘤相对 抗性没有凋亡反应。 这些结果是一致的 凋亡可能在肿瘤中起重要作用的前提 对辐射的反应。 但是，由于许多肿瘤似乎是 对这种细胞死亡方式的抗药性研究人员专注于 描述生化和分子机制 决定凋亡倾向。 两个分子途径已经 发现可以通过 抑制细胞凋亡，这些受到Bcl-2的控制 癌基因和p53肿瘤抑制基因。 具体目的 该提议旨在理解这些机制 更多细节，探索策略克服其阻止能力 凋亡，ANC评估了它们在反应中的作用 放疗患者。 特别是研究人员建议：（1） 确定Bcl-2癌基因的生化机制 调节凋亡倾向。 （2）评估策略 调节p53功能以增强凋亡 抗性肿瘤。 （3）检查凋亡在 通过回顾性分析对患者对放疗的反应 预处理活检标本。 抗性细胞中的存在 肿瘤可能是确定最终治愈的关键因素 通过放射疗法患者。 而许多因素已经 先前检查以测量和预测肿瘤细胞对 辐射，凋亡的倾向是一个相对较新的终点。 该项目的具体目的旨在解决 辐射反应的凋亡，最终可能影响患者 通过验证预处理凋亡指数预测的处理 回应并通过制定克服抵抗的策略 抑制凋亡倾向。