DNA DAMAGE IN RADIATION RESPONSE OF TISSUES AND TUMORS

尽管人们普遍认为基因组DNA代表着主要的。 电离辐射的细胞靶标、DNA与 肿瘤和正常组织的损伤和修复过程与放射敏感性 组织的定义仍然很模糊。这在很大程度上是由于缺乏良好的 体内DNA或染色体损伤的检测，以及这样一个事实 靶细胞群体在组织或肿瘤中的行为可能是 被很少或根本不起作用的细胞的反应所掩盖 对辐射的生物反应。这项建议的目的是 量化DNA损伤和修复之间的关系 组织和肿瘤内的细胞亚群及其生物学特性 以克隆形成为主的方法测量这些组织的反应 干细胞存活的关键。我们将研究DNA与 通过使用对正常组织如骨髓的损伤和修复 用来控制辐射反应的放射调节剂。我们还将 检查几种具有不同固有放射敏感性的小鼠肿瘤 使用放射调整剂进一步调节这些 肿瘤。我们将研究的另一个测试系统是一系列 DNA某些方面存在缺陷的辐射敏感啮齿动物细胞系 修复；这些株系将在体内生长在免疫抑制的小鼠和 评估它们的辐射敏感性以及DNA损伤和修复 特点。一个特别的目标将是扩大DNA的范围 可在活体内测量的损伤和染色体畸变 生物相关剂量的辐射。我们还将评估使用 流式细胞术检测个体DNA或染色体损伤 肿瘤和正常组织中特定细胞类型的细胞基础。 通过这些信息，我们希望能更好地了解 DNA损伤与体内和BE细胞死亡的关系 确定这些因素(如氧分压或谷胱甘肽)的位置 级别)负责先前描述的单元格之间的差异 培养系统和组织或肿瘤。

Despite the general belief that genomic DNA represents the primary. cellular target for ionizing radiation, the relationships between DNA damage and repair processes and the radiosensitivity of tumors and normal tissues remain poorly defined. This is due largely to the lack of good assays for DNA or chromosome damage in vivo and to the fact that the behavior of the target cell population in a tissue or tumor may be obscured by the response of cells that play little or no part in the biological response to radiation. The objective of this proposal is to quantitate the relationships between DNA damage and repair in various cellular subpopulations within tissues and tumors and the biological response of these tissues as measured by predominantly clonogenic assays of stem cell survival. We will investigate the relationships between DNA damage and repair in normal tissues such as bone marrow through the use of radiomodifying agents to manipulate radiation response. We will also examine several mouse tumors of varying intrinsic radiosensitivity and use radiomodifying agents to further modulate the response of these tumors. A further test system that we will study is a series of radiosensitive rodent cell lines that have a defect in some aspect of DNA repair; these lines will be grown in vivo in immune suppressed mice and assessed for their radiosensitivity and for their DNA damage and repair characteristics. A particular goal will be to expand the range of DNA lesions and chromosomal aberrations that can be measured in vivo after biologically relevant doses of radiation. We will also assess the use of flow cytometry in evaluating DNA or chromosome damage on an individual cell basis in specific cell types within tumors and normal tissues. Through this information, we hope to develop a better understanding of the relationships between DNA damage and cell death in vivo and be in a position to identify those factors (such as oxygen tension or glutathione levels) responsible for the previously described differences between cell culture systems and tissues or tumors.