HIGH ENERGY IONS AND GENOMIC INSTABILITY

描述：(申请人描述) 癌症的发生被广泛认为是一个多阶段的过程，涉及许多 在时间上分开的不同事件。很难想象一个 单次短暂暴露在低剂量辐射下可能会导致多次 突变，然而，众所周知，适度的辐射剂量可以 会导致一系列的恶性肿瘤。一种似乎更多的可能性 很可能是辐射导致单一的初始突变，从而导致 基因组不稳定，随之而来的一系列事件导致 恶毒。有很多关于基因组不稳定的报道，但 研究的终点是染色体异常或突变。申请人 成功地将永生化的人支气管上皮细胞转化为 使用单一低剂量的高能(1GeV/核子)铁离子或使用 阿尔法粒子，在体外培养了许多代之后，他们 在裸鼠体内致癌。在辐射和基因表达之间的关系 致瘤性，一系列相继发生的变化：增加 饱和密度，刺激丧失至终末分化，丧失 锚定依赖，染色体堆积改变。这将会 似乎是基因组不稳定的理想模型，肿瘤的发生 终结点。他建议：(A)研究基因组的不稳定性 由低剂量高能铁离子诱导，使细胞 对随后剂量的低能中子的转变很敏感， 高能质子，或伽马射线；(B)从许多(25) 因暴露于高能铁离子而产生的肿瘤 可重复的染色体异常和/或染色体丢失模式；(C) 使用一种新的可选择的报告系统来确定肿瘤细胞系 铁离子诱导的支气管上皮细胞功能错配 修复基因。这一应用对太空旅行具有实际意义。 由于宇航员体内的体细胞有时会被一种高强度的 能量铁离子，随后暴露在低能中子和/或低能中子中 让辐射，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.