Department of Biochemistry and Molecular & Cell Biology, Georgetown University Medical Center, Research Building, Room E518, 3970 Reservoir Rd., NW, Washington, DC 20057-1468, USA.
Radiat Oncol. 2012 Jan 20;7:6. doi: 10.1186/1748-717X-7-6.
Ionizing radiation-induced hematopoietic injury could occur either due to accidental exposure or due to diagnostic and therapeutic interventions. Currently there is no approved drug to mitigate radiation toxicity in hematopoietic cells. This study investigates the potential of ON 01210.Na, a chlorobenzylsulfone derivative, in ameliorating radiation-induced hematopoietic toxicity when administered after exposure to radiation. We also investigate the molecular mechanisms underlying this activity.
Male C3H/HeN mice (n = 5 mice per group; 6-8 weeks old) were exposed to a sub-lethal dose (5 Gy) of γ radiation using a ¹³⁷Cs source at a dose rate of 0.77 Gy/min. Two doses of ON 01210.Na (500 mg/kg body weight) were administered subcutaneously at 24 h and 36 h after radiation exposure. Mitigation of hematopoietic toxicity by ON 01210.Na was investigated by peripheral white blood cell (WBC) and platelet counts at 3, 7, 21, and 28 d after radiation exposure. Granulocyte macrophage colony forming unit (GM-CFU) assay was done using isolated bone marrow cells, and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) was performed on bone marrow sections at 7 d post-exposure. The DNA damage response pathway involving ataxia telangiectasia mutated (ATM) and p53 was investigated by Western blot in bone marrow cells at 7 d post-exposure.
Compared to the vehicle, ON 01210.Na treated mice showed accelerated recovery of peripheral WBC and platelet counts. Post-irradiation treatment of mice with ON 01210.Na also resulted in higher GM-CFU counts. The mitigation effects were accompanied by attenuation of ATM-p53-dependent DNA damage response in the bone marrow cells of ON 01210.Na treated mice. Both phospho-ATM and phospho-p53 were significantly lower in the bone marrow cells of ON 01210.Na treated than in vehicle treated mice. Furthermore, the Bcl2:Bax ratio was higher in the drug treated mice than the vehicle treated groups.
ON 01210.Na treatment significantly mitigated the hematopoietic toxicity induced by a sub-lethal radiation dose. Mechanistically, attenuation of ATM-p53 mediated DNA damage response by ON 01210.Na is contributing to the mitigation of radiation-induced hematopoietic toxicity.
电离辐射诱导的造血损伤可能是由于意外暴露或诊断和治疗干预引起的。目前没有批准的药物可以减轻造血细胞的辐射毒性。本研究探讨了 ON 01210.Na（一种氯苯甲砜衍生物）在辐射暴露后给药时减轻辐射诱导的造血毒性的潜力。我们还研究了这种活性的分子机制。
雄性 C3H/HeN 小鼠（每组 5 只小鼠；6-8 周龄）使用¹³⁷Cs 源以 0.77 Gy/min 的剂量率接受亚致死剂量（5 Gy）γ 射线照射。在辐射暴露后 24 小时和 36 小时，皮下给予两种剂量的 ON 01210.Na（500 mg/kg 体重）。通过外周白细胞（WBC）和血小板计数在辐射暴露后 3、7、21 和 28 天来研究 ON 01210.Na 对造血毒性的缓解作用。使用分离的骨髓细胞进行粒细胞巨噬细胞集落形成单位（GM-CFU）测定，在暴露后 7 天对骨髓切片进行末端脱氧核苷酸转移酶 dUTP 缺口末端标记（TUNEL）。在辐射暴露后 7 天，通过 Western blot 研究涉及共济失调毛细血管扩张突变（ATM）和 p53 的 DNA 损伤反应途径。
与载体相比，ON 01210.Na 处理的小鼠外周血白细胞和血小板计数恢复更快。用 ON 01210.Na 处理照射后的小鼠也导致 GM-CFU 计数增加。在骨髓细胞中，ON 01210.Na 处理减轻了 ATM-p53 依赖性 DNA 损伤反应，这与缓解作用有关。ON 01210.Na 处理组骨髓细胞中的磷酸化 ATM 和磷酸化 p53 明显低于载体处理组。此外，药物处理组的 Bcl2:Bax 比值高于载体处理组。
ON 01210.Na 治疗显著减轻了亚致死剂量辐射引起的造血毒性。从机制上讲，ON 01210.Na 减弱 ATM-p53 介导的 DNA 损伤反应有助于减轻辐射引起的造血毒性。
