ROLE OF PROGRAMMED CELL DEATH IN RADIATION RESPONSE

该研究项目的目标是了解 抗辐射，使肿瘤细胞逃脱的模式， 细胞死亡称为凋亡。 它是基于实验 在上一次供资期间在研究者实验室进行 这表明相对容易治愈的肿瘤 显示大量的凋亡，而肿瘤， 耐药细胞无凋亡反应。 这些结果是一致 前提是细胞凋亡可能在肿瘤中起重要作用， 对辐射的反应。 然而，由于许多肿瘤似乎是 抵抗这种细胞死亡模式， 描绘了生物化学和分子机制， 决定了细胞凋亡倾向。 有两种分子途径 这可能是由于辐射抵抗， 抑制细胞凋亡，这些都是由bcl-2控制的， 癌基因和p53肿瘤抑制基因。 的具体目标 本建议旨在了解这些机制， 更多细节，探索策略，以克服他们的能力， 细胞凋亡，anc评估其可能的作用， 放疗患者。 具体而言，研究人员建议：（1） 确定bcl-2癌基因 调节凋亡倾向。 (2)评估战略， 调节p53功能以增强细胞凋亡， 耐药肿瘤 (3)研究细胞凋亡的可能作用， 通过回顾性分析患者对放疗的反应， 预处理活检标本。 抵抗细胞的存在， 肿瘤可能是决定最终治愈的关键因素。 患者放疗。 尽管许多因素 以前检查过测量和预测肿瘤细胞对 在辐射中，细胞凋亡的倾向是一个相对较新的终点。 该项目的具体目标是解决以下问题： 放射反应中的细胞凋亡，并可能最终影响患者 通过验证预处理凋亡指数预测治疗 制定战略，以克服 抑制凋亡倾向。

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.