ROLE OF PROGRAMMED CELL DEATH IN RADIATION RESPONSE

本研究项目的目的是了解心绞痛的发病机制。 抗辐射，使肿瘤细胞能够逃脱 细胞死亡称为细胞凋亡。它是以实验为基础的 在最后一次资助期间在调查人员的实验室进行 这一时期表明相对容易治愈的肿瘤 显示出大量的细胞凋亡，而肿瘤相对 耐药细胞无细胞凋亡反应。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，由于许多肿瘤似乎是 对这种细胞死亡模式的抵抗是研究人员关注的 描述了生物化学和分子机制 决定了细胞的凋亡倾向。有两条分子途径是 发现了可能解释辐射抗性的 抑制细胞凋亡，这些都是由bcl2控制的 癌基因和P53抑癌基因。的具体目标 本提案旨在理解 更多细节，探索克服其阻挡能力的策略 细胞凋亡，ANC评估它们在反应中的可能作用 放射治疗患者。具体地说，调查人员建议：(1) 确定bcl2癌基因的生化机制 调节细胞凋亡倾向。(2)评估战略 调控P53功能以促进细胞凋亡 耐药肿瘤。(3)研究细胞凋亡在以下方面的可能作用 患者对放射治疗反应的回顾性分析 前处理活组织标本。耐药细胞的存在 肿瘤可能是决定最终治愈的关键因素 患者接受放射治疗。鉴于许多因素已经被 先前检查以测量和预测肿瘤细胞对 辐射后，细胞凋亡倾向是一个相对较新的终点。 该项目的具体目标旨在解决以下角色 细胞凋亡在放射反应中的作用并可能最终影响患者 通过验证预处理的凋亡指数预测治疗 应采取的应对措施和克服抗药性的策略 抑制细胞凋亡倾向。

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.