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.

该研究项目的目标是了解 允许肿瘤细胞逃避辐射模式的抗辐射性 细胞死亡称为细胞凋亡。 它是基于实验的 上次资助期间在研究人员实验室进行 表明肿瘤相对容易治愈的时期 表现出大量的细胞凋亡，而相对较弱的肿瘤 耐药者无凋亡反应。 这些结果是一致的 前提是细胞凋亡可能在肿瘤中发挥重要作用 对辐射的反应。 然而，由于许多肿瘤似乎 研究人员重点关注的是对这种细胞死亡模式的抵抗力 描述生物化学和分子机制 决定细胞凋亡倾向。 两条分子途径已被 发现这可能是通过辐射抗性的原因 抑制细胞凋亡，这些是由 bcl-2 控制的 癌基因和p53抑癌基因。 具体目标 该提案旨在理解这些机制 更详细地探讨克服其阻止能力的策略 细胞凋亡，并评估它们在响应中可能的作用 放射治疗患者。 具体而言，研究人员建议：（1） 确定 bcl-2 癌基因的生化机制 调节细胞凋亡倾向。 (2) 评估策略 调节 p53 功能以增强细胞凋亡 耐药肿瘤。 (3) 考察细胞凋亡的可能作用 回顾性分析患者对放疗的反应 治疗前活检标本。 耐药细胞的存在 肿瘤可能是决定最终治愈的关键因素 接受放射治疗的患者。 尽管许多因素已经 先前检查以测量和预测肿瘤细胞对 辐射中，细胞凋亡的倾向是一个相对较新的终点。 该项目的具体目标旨在解决 放射反应中的细胞凋亡并可能最终影响患者 通过验证治疗前细胞凋亡指数预测来进行治疗 应对措施并制定克服阻力的策略 抑制细胞凋亡倾向。