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首页> 美国卫生研究院文献>Frontiers in Oncology >Differential Superiority of Heavy Charged-Particle Irradiation to X-Rays: Studies on Biological Effectiveness and Side Effect Mechanisms in Multicellular Tumor and Normal Tissue Models
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Differential Superiority of Heavy Charged-Particle Irradiation to X-Rays: Studies on Biological Effectiveness and Side Effect Mechanisms in Multicellular Tumor and Normal Tissue Models

机译：重电荷粒子辐照对X射线的差异优势：在多细胞肿瘤和正常组织模型中的生物学有效性和副作用机制的研究

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This review is focused on the radiobiology of carbon ions compared to X-rays using multicellular models of tumors and normal mucosa. The first part summarizes basic radiobiological effects, as observed in cancer cells. The second, more clinically oriented part of the review, deals with radiation-induced cell migration and mucositis. Multicellular spheroids from V79 hamster cells were irradiated with X-rays or carbon ions under ambient or restricted oxygen supply conditions. Reliable oxygen enhancement ratios could be derived to be 2.9, 2.8, and 1.4 for irradiation with photons, 12C+6 in the plateau region, and 12C+6 in the Bragg peak, respectively. Similarly, a relative biological effectiveness of 4.3 and 2.1 for ambient pO2 and hypoxia was obtained, respectively. The high effectiveness of carbon ions was reflected by an enhanced accumulation of cells in G2/M and a dose-dependent massive induction of apoptosis. These data clearly show that heavy charged particles are more efficient in sterilizing tumor cells than conventional irradiation even under hypoxic conditions. Clinically relevant doses (3 Gy) of X-rays induced an increase in migratory activity of U87 but not of LN229 or HCT116 tumor cells. Such an increase in cell motility following irradiation in situ could be the source of recurrence. In contrast, carbon ion treatment was associated with a dose-dependent decrease in migration with all cell lines and under all conditions investigated. The radiation-induced loss of cell motility was correlated, in most cases, with corresponding changes in β1 integrin expression. The photon-induced increase in cell migration was paralleled by an elevated phosphorylation status of the epidermal growth factor receptor and AKT-ERK1/2 pathway. Such a hyperphosphorylation did not occur during 12C+6 irradiation under all conditions registered. Comparing the gene toxicity of X-rays with that of particles using the γH2AX technique in organotypic cultures of the oral mucosa, the superior effectiveness of heavy ions was confirmed by a twofold higher number of foci per nucleus. However, proinflammatory signs were similar for both treatment modalities, e.g., the activation of NFκB and the release of IL6 and IL8. The presence of peripheral blood mononuclear cell increased the radiation-induced release of the proinflammatory cytokines by factors of 2–3. Carbon ions are part of the cosmic radiation. Long-term exposure to such particles during extended space flights, as planned by international space agencies, may thus impose a medical and safety risk on the astronauts by a potential induction of mucositis. In summary, particle irradiation is superior to gamma-rays due to a higher radiobiological effectiveness, a reduced hypoxia-induced radioresistance, a multicellular radiosensitization, and the absence of a radiation-induced cell motility. However, the potential of inducing mucositis is similar for both radiation types.
机译：这篇综述的重点是使用肿瘤和正常黏膜的多细胞模型与X射线相比，碳离子的放射生物学。第一部分概述了在癌细胞中观察到的基本放射生物学作用。该评价的第二个更注重临床的部分涉及辐射诱导的细胞迁移和粘膜炎。在环境或有限的氧气供应条件下，用X射线或碳离子辐照来自V79仓鼠细胞的多细胞球体。对于光子，高原区域的 12 C +6 和 12 ，光子辐照的可靠增氧比分别为2.9、2.8和1.4。布拉格峰中的sup> C +6 。同样，对于环境中的pO2和缺氧，相对生物学有效性分别为4.3和2.1。碳离子的高效率通过G2 / M中细胞积累的增强和细胞凋亡的剂量依赖性大规模诱导来反映。这些数据清楚地表明，即使在低氧条件下，重荷电的颗粒对肿瘤细胞的灭菌也比常规照射更有效。临床相关剂量的X射线（3 ofGy）诱导U87迁移活性增加，但LN229或HCT116肿瘤细胞没有迁移。原位照射后细胞运动的这种增加可能是复发的来源。相反，在所研究的所有条件下，碳离子处理与所有细胞系迁移的剂量依赖性降低相关。在大多数情况下，辐射引起的细胞运动性丧失与β1整联蛋白表达的相应变化有关。光子诱导的细胞迁移增加与表皮生长因子受体和AKT-ERK1 / 2途径的磷酸化状态升高相关。在所有记录的条件下，在 12 C +6 照射过程中都没有发生这种过度磷酸化。比较在口腔粘膜器官型培养中使用γH2AX技术的X射线和颗粒的基因毒性，重离子的优越功效被每个核的焦点数量提高了两倍。然而，两种治疗方式的促炎迹象相似，例如，NFκB的活化以及IL6和IL8的释放。外周血单个核细胞的存在使辐射诱导的促炎细胞因子释放增加了2-3倍。碳离子是宇宙辐射的一部分。按照国际空间机构的计划，在长时间的太空飞行中长期暴露于此类颗粒中，可能通过诱发粘膜炎而对宇航员造成医疗和安全风险。总而言之，由于较高的放射生物学效力，降低的低氧诱导的放射抵抗，多细胞放射敏化和不存在放射诱导的细胞运动性，粒子辐照优于伽马射线。然而，两种辐射类型诱发粘膜炎的潜力相似。

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