HIGH ENERGY IONS AND GENOMIC INSTABILITY

描述：（申请人的描述） 致癌作用被广泛认为是一个多阶段的过程， 在时间上分开的不同事件。 很难想象一个 一次短时间暴露在低剂量的辐射下可能会导致多个 突变，但它是公认的，适度的辐射剂量可以 导致一系列恶性肿瘤 这种可能性看起来 很可能是辐射导致了一个单一的初始突变， 基因组的不稳定性，随后是一系列事件， 恶性肿瘤 有许多关于基因组不稳定性的报道，但 研究的终点是染色体畸变或突变。 申请人 成功地将永生化的人类支气管上皮细胞 用单个低剂量的高能（1 GeV/核子）铁离子或用 因此，在体外培养多代之后， 在裸鼠体内致瘤。 在辐射和表达 在致瘤性方面，发生一系列顺序变化： 饱和密度，终末分化刺激的丧失， 锚定依赖性和染色体变化的积累。 这将 似乎是一个理想的模型，基因组不稳定性与肿瘤的发生， 终点。 他提出：（a）研究基因组不稳定性是否 低剂量高能铁离子诱导的细胞 对后续剂量的低能中子的转化敏感， 高能质子或γ射线;（B）从许多（25） 暴露于高能铁离子导致的肿瘤， 染色体畸变和/或染色体丢失的可重复模式;（c） 使用一种新的可选择的报告系统来确定肿瘤细胞系是否 铁离子诱导的支气管上皮细胞功能不匹配 修复基因 这一应用对太空旅行具有实际意义 由于宇航员的体细胞可能偶尔会被一种高浓度的 能量铁离子并随后暴露于低能中子和/或低能 LET辐射，如伽马射线或高能质子。

DESCRIPTION: (Applicant's Description) Carcinogenesis is widely held to be a multi-stage process involving a number of distinct events separated in time. It is difficult to visualize how a single brief exposure to a low dose of radiation could result in multiple mutations, and yet it is well established that a modest radiation dose can result in a whole spectrum of malignancies. A possibility that seems more likely is that radiation causes a single initial mutation resulting in genomic instability, followed by a cascade of events leading to a malignancy. There are many reports of genomic instability, but the endpoints studied are chromosomal aberrations or mutations. The applicant has succeeded in transforming immortalized human bronchial epithelial cells with a single low dose of high energy (1 GeV/nucleon) iron ions or with alpha particles so that, after in vitro culture for many generations, they become tumorigenic in nude mice. Between irradiation and the expression of tumorigenicity, a series of sequential changes take place: increased saturation density, loss of stimulus to terminal differentiation, loss of anchorage dependence, and accumulation of chromosomal changes. This would appear to be an ideal model of genomic instability with tumorigenesis as the endpoint. He proposes: (a) To investigate whether genomic instability induced by a low dose of high energy iron ions renders the cells more sensitive to transformation by a subsequent dose of low energy neutrons, high energy protons, or gamma-rays; (b) Establish cell lines from many (25) tumors resulting from exposure to high energy iron ions and look for repeatable patterns of chromosomal aberrations and/or chromosome loss; (c) Use a novel selectable reporter system to determine whether tumor cell lines induced by iron ions in bronchial epithelial cells have functional mismatch repair genes. This application has practical implications to space travel since somatic cells in astronauts may be occasionally traversed by a high energy iron ion and subsequently exposed to low energy neutrons and/or low LET radiations, such as gamma-rays or high energy protons.