Department of Radiation Oncology, Saarland University, Kirrbergerstr. Geb. 49/ 51, 66421 Homburg/Saar, Germany.
Int J Radiat Oncol Biol Phys. 2010 Mar 15;76(4):1206-13. doi: 10.1016/j.ijrobp.2009.10.009.
There is increasing evidence that genetic factors regulating the recognition and/or repair of DNA double-strand breaks (DSBs) are responsible for differences in radiosensitivity among patients. Genetically defined DSB repair capacities are supposed to determine patients' individual susceptibility to develop adverse normal tissue reactions after radiotherapy. In a preclinical murine model, we analyzed the impact of different DSB repair capacities on the cumulative DNA damage in normal tissues during the course of fractionated irradiation.
Different strains of mice with defined genetic backgrounds (SCID(-/-) homozygous, ATM(-/-) homozygous, ATM(+/-)heterozygous, and ATM(+/+)wild-type mice) were subjected to single (2 Gy) or fractionated irradiation (5 x 2 Gy). By enumerating gammaH2AX foci, the formation and rejoining of DSBs were analyzed in organs representative of both early-responding (small intestine) and late-responding tissues (lung, kidney, and heart).
In repair-deficient SCID(-/-) and ATM(-/-)homozygous mice, large proportions of radiation-induced DSBs remained unrepaired after each fraction, leading to the pronounced accumulation of residual DNA damage after fractionated irradiation, similarly visible in early- and late-responding tissues. The slight DSB repair impairment of ATM(+/-)heterozygous mice was not detectable after single-dose irradiation but resulted in a significant increase in unrepaired DSBs during the fractionated irradiation scheme.
Radiation-induced DSBs accumulate similarly in acute- and late-responding tissues during fractionated irradiation, whereas the whole extent of residual DNA damage depends decisively on the underlying genetically defined DSB repair capacity. Moreover, our data indicate that even minor impairments in DSB repair lead to exceeding DNA damage accumulation during fractionated irradiation and thus may have a significant impact on normal tissue responses in clinical radiotherapy.
越来越多的证据表明，调节 DNA 双链断裂（DSB）识别和/或修复的遗传因素是导致患者放射敏感性差异的原因。遗传定义的 DSB 修复能力应决定患者在接受放射治疗后发生不良反应正常组织反应的个体易感性。在临床前的小鼠模型中，我们分析了不同 DSB 修复能力对分次照射过程中正常组织累积 DNA 损伤的影响。
不同遗传背景的小鼠（SCID(-/-)纯合子、ATM(-/-)纯合子、ATM(+/-)杂合子和 ATM(+/+)野生型小鼠）分别接受单次（2 Gy）或分次照射（5 x 2 Gy）。通过计数γH2AX 焦点，分析了器官中 DSB 的形成和重接，这些器官代表了早期反应（小肠）和晚期反应组织（肺、肾和心脏）。
在修复缺陷的 SCID(-/-)和 ATM(-/-)纯合子小鼠中，每次分割后仍有大量辐射诱导的 DSB 未修复，导致在分次照射后明显累积残留的 DNA 损伤，在早期和晚期反应组织中均可见到。ATM(+/-)杂合子小鼠的 DSB 修复轻微受损在单次剂量照射时无法检测到，但在分次照射方案中导致未修复的 DSB 显著增加。
在分次照射期间，DSB 在急性和晚期反应组织中累积相似，而残留 DNA 损伤的整体程度取决于潜在的遗传定义的 DSB 修复能力。此外，我们的数据表明，即使 DSB 修复存在轻微受损，也会导致在分次照射过程中 DNA 损伤累积超过，从而对临床放射治疗中的正常组织反应产生重大影响。
