RADIATION, CHROMOSOMAL ABERRATIONS, AND RELATIVE BIOLOGI

描述（改编自申请人摘要） 这项研究的主要目标是更好地了解过程 参与电离诱导染色体畸变 辐射，以帮助确定有前途的途径，为今后的研究， 分子机制也许更重要的是，由于各种特殊的 染色体易位是许多癌症所必需的，该项目应 阐明了诱发癌症的辐射阈值问题 这是辐射防护标准的关键问题。重点是 RBE依赖于能量沉积的微观分布， 这些能量沉积模式可以被操纵， 测试关于畸变形成的性质的特定假设。第一 假设大多数交换畸变是由于受损的 与未受损区域相互作用的DNA区域（例如，重组 误修？），与涉及相互作用的替代假设相反， （不重合）两个损坏的区域非常接近。这将被研究 通过比较将细胞暴露于5 MeV α粒子与~（125）IUdR衰变后损伤粒子的结合 转化成DNA这两种辐射的电离密度相似（~6 KeV 在50纳米直径的球体内），但是密集的 电离层对于两种辐射是不同的。对于α粒子， 球体紧密地堆积在一起以产生密集的电离轨迹50 微米左右的长度;相反，由衰变产生的球体 125I在空间上是分离的。因此，如果两个受损区域必须在 如果发生交换，α粒子会产生 更多的交换比125I衰变，提供相同的剂量， 原子核是阿尔法粒子另一方面，如果只有一个受损区域 如果需要，两种辐射的有效性应该近似为 一样的第二个假设是，对于稀疏的电离辐射， 密集电离径迹末端产生几乎所有的生物效应。 这是基于对Al或C超软X射线的2至3的RBE的观察。 该测试将涉及比较掺入的14CTdR的畸变诱导 相对于掺入DNA的3HTdR。对于3H（范围~0.45微米） 几乎所有的径迹都起源于和终止于核，但对于14C， β粒子（范围~37微米）几乎没有一个轨迹会以 细胞核因此，如果假设是正确的，14C粒子跟踪 应该几乎没有生物学效应，对于给定的核剂量， 掺入的3HTdR应该比掺入的14CTdR有效得多。 由于一些染色体易位是许多癌症的先决条件，因此基本的 了解辐射是如何形成染色体易位的， 更好地了解辐射暴露的危害以及基本的 与肿瘤发生有关的过程。从实际意义上说，这一结果 研究将与辐射阈值问题直接相关 肿瘤发生

DESCRIPTION (adapted from applicant's abstract) The broad objective of this research is to better understand processes involved in the induction of chromosomal aberrations by ionizing radiation to help identify promising avenues of approach for future studies of molecular mechanisms. Perhaps more importantly, since various particular chromosomal translocations are required for many cancers, the project should shed some light on the question of radiation thresholds for cancer induction which is a key issue for radiation protection standards. The focus is on the dependence of RBE on the microscopic distributions of energy deposition in normal human cells where these energy deposition patterns can be manipulated to test specific hypotheses about the nature of aberration formation. The first hypothesis is that most exchange aberrations develop as a result of a damaged region of DNA interacting with an undamaged region (e.g., a recombinational misrepair?), as opposed to an alternative hypothesis involving interaction (misrejoining) of two damaged regions in close proximity. This would be studied by comparing the induction of exchange aberrations after exposing cells to 5 MeV alpha particles with that from damage after decay of 125IUdR incorporated into DNA. The ionization density is similar for these two radiations (~ 6 KeV within a 50 nanometer diameter sphere), but the spacing between the densely ionizing spheres is different for the two radiations. For alpha particles, the spheres are packed closely together to produce densely ionizing tracks 50 microns or so in length; in contrast, the spheres produced by disintegrations of 125I are separated spatially. Therefore, if two damaged regions must be in close proximity for an exchange to occur, the alpha particles would produce more exchanges than 125I disintegrations that deliver the same dose to the nucleus as the alpha particles. On the other hand, if only one damaged region is required, the effectiveness of the two radiations should be approximately the same. The second hypothesis is that for sparsely ionizing radiations, the densely ionizing track ends produce virtually all of the biological effect. This is based on observations of RBEs of 2 to 3 for Al or C ultrasoft x-rays. The test would involve comparing aberration induction by 14CTdR incorporated into DNA relative to 3HTdR incorporated into DNA. For 3H (range ~0.45 microns) virtually all tracks would originate and terminate in the nucleus, but for 14C beta particles (range ~37 microns) almost none of the tracks would end in a cell nucleus. Therefore, if the hypothesis were correct, 14C particle tracks should have almost no biological effect, and for a given dose to the nucleus, incorporated 3HTdR should be much more effective than incorporated 14CTdR. Since some chromosomal translocations are prerequisite for many cancers, basic knowledge of how chromosomal translocations are formed by radiation should help to better understand the hazards of radiation exposure as well as basic processes involved in oncogenesis. In a practical sense, the results of this study would be directly relevant to the question of thresholds for radiation oncogenesis.