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Comparison of the Biological Effectiveness of 45 MeV C-Ions and γ-Rays in Inducing Early and Late Effects in Normal Human Primary Fibroblasts

机译:45meV c-离子和γ射线在正常人母原发性成纤维细胞早期和晚期效应中的生物效果比较

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Investigation of the mechanisms underlying the biological effects induced by densely ionizing radiation has relevant implications in both radiation protection and therapy. In particular, the possible advantages of hadrontherapy with respect to conventional radiotherapy in terms of high conformal tumor treatment and sparing of healthy tissues are well known. Further improvements are limited by lack of radiobiological knowledge, particularly about the specific cellular response to the damage induced by particles of potential interest for tumor treatment. This study compares early and late effects induced in AG01522 normal human primary fibroblasts by γ-rays and C-ions having E ~ 45 MeV/u at the cell entrance, corresponding to LET (in Water)~49 keV/μm. Different end points have been investigated, namely: cell killing and lethal mutation, evaluated as early and delayed reproductive cell death, respectively; chromosome damage, as measured by micronuclei induction (MN); DNA damage, in terms of DSB induction and repair, as measured by the H2AX phosphorylation/dephosphorylation kinetics. Linear dose-response relationships were found for cell killing and induction of lethal mutations, with RBEs of about 1.3 and 1.6 respectively, indicating that the presence of genomic instability is greater in the progeny of C-ions irradiated cells. H2AX phosphorylation/dephosphorylation kinetics have shown a maximum foci number at 30 min after irradiation, higher for γ-rays than for C-ions. However, in the first 12 h the fraction of residual γ-H2AX foci was higher for C-ions irradiated cells, indicating a lower removal rate, possibly related to multiple/more complex damage along the particle track, with respect to hte sparse lesions produced by γ-rays. MN induction, observed after 72 h from irradiation, was also greater for C-ions. Overall, these data indicate a more severe DNA damage induced by 45 MeV/u C-ions with respect to γ-rays, likely responsible of an increased cellular misrepair, leading to the greater observed levels of chromosome damage and, eventually, of genomic instability. They give strong support to the idea that higher damage severity at molecular level, determined by the typical deposition pattern of densely ionizing radiation, is the earliest relevant factor for the more severe late effects at cellular level.
机译:通过密集电离辐射诱导的生物学效应的机制研究对辐射保护和治疗具有相关的影响。特别是,在高共形肿瘤处理和健康组织的备受术语方面,HATRONTHEACAPACY对常规放射治疗的可能优势是众所周知的。通过缺乏放射生物学知识的进一步改善是有限的,特别是关于对肿瘤治疗潜在兴趣颗粒诱导的损伤的特异性细胞反应。该研究将Ag01522正常人母原发生成纤维细胞的早期和晚期效应与在细胞入口处的γ射线和C-ICEγ射线和C-离子进行了比较,对应于(在水中)〜49keV /μm。已经研究了不同的终点,即:细胞杀伤和致命突变,分别评估为早期和延迟的生殖细胞死亡;通过微核感应(Mn)测量的染色体损伤;根据DSB诱导和修复,DNA损伤,如H2AX磷酸化/去磷酸化动力学所测量的。发现线性剂量 - 响应关系对于细胞杀伤和致命突变的诱导,rBE分别为约1.3和1.6,表明基因组不稳定性的存在在C-离子辐照细胞的后代更大。 H2AX磷酸化/去磷酸化动力学在照射后30分钟显示最大焦点数,比C-离子更高。然而,在第一12 H中,对于C-ICE照射的细胞,残留γ-H2AX焦点的级分较高,表明较低的去除率,可能与沿粒子轨道的多/更复杂的损坏有关,相对于所产生的HTE稀疏病变通过γ射线。 Mn诱导,在72小时内观察到辐射后,对于C离子也更大。总体而言,这些数据表明,相对于γ射线的45meV / U C-离子诱导的更严重的DNA损伤,可能是增加的细胞误导性,导致染色体损伤的较大水平较大,最终是基因组不稳定性。它们对典型沉积图案的分子水平造成更高的损伤严重程度的理念,对典型电离辐射的沉积模式确定的敏感性,是在细胞水平下更严重的后期效应的最早相关因素。

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