5-氟尿嘧啶与白消安合用诱导建立大鼠急性再生障碍性贫血模型

A novel rat aplastic anemia model induced by 5-fluorouracil combined with busulfan

目的 根据 5 氟尿嘧啶 (5 FU)富集干细胞和白消安损伤干细胞的作用 ,采用两者联合用药的方案 ,成功地建立了大鼠造血干细胞衰竭型急性再生障碍性贫血 (再障 )模型。方法 Wistar大鼠于腹腔 1次注射 5 FU后第 5天 ,口服白消安每周 1次 ,连续 3周 ;以单纯 5 FU组和单纯白消安组为对照 ,观察患病率和死亡率、血象、骨髓有核细胞数、脾脏指数、骨髓CFU GM数和造血器官的病理形态。结果 5 FU与白消安合用组 ,急性再障的患病率为 82 .0 % (49只中 40只 ) ,平均存活时间为 (30 .0±6 5 )d ,其余 9只为慢性再障 (占 18.0 % ) ,总患病率为 10 0 % ;再障死亡率 98%。再障动物各项血液学指标均呈持续性减低 ,停药后 2～ 3周血常规各项指标降到最低 ,约为实验前的二分之一 ;濒死时BMNC数为实验前的 7% ,脾脏指数约为实验前一半。骨髓CFU GM未能检出。病理形态学观察 :骨髓脂肪化 ,脾脏、淋巴结和胸腺等淋巴器官组织明显萎缩 ,凋亡细胞多见 ,肝、脾无髓外造血灶。单纯 5 FU组血常规有一过性减低 ,停药后 10天很快恢复至正常 ,无一死亡。单纯白消安组 ,12只大鼠中仅 3只发生再障而死亡 ,其余大鼠于停药后血常规恢复。结论 5 FU与白消安合用可较彻底地杀灭造血干细胞 ,使骨髓 淋巴细胞萎缩 。

Objective To develop an aplastic anemia model with hematopoietic stem cell failure in rats. Methods Normal Wistar rats were injected i.p. with 5 fluorouracil and 5 days later p.o. by busulfan once a week for 3 times. A 5 FU alone group and a busulfan alone group were as control. The parameters tested indices were as following: incidence and mortality of aplastic anemia rats, blood picture, bone marrow nucleated cell count, CFU GM of bone marrow cells and histology of hematopoietic organs. Results In the 5 FU plus busulfan group, the incidence of acute aplastic anemia was 82.0%(40/49 rats), the average survival time was (30.0±6.5) days. The remained 9 rats developed chronic aplastic anemia (18.0%). The total incidence of aplastic anemia was 100%, and the mortality was 98%. The blood cells count of the aplastic anemia rats was gradually reduced to a level of half the premedications and no CFU GM was detected, and the patho morphological examination showed that the bone marrow was replaced by fat cells, and the lymphoid tissue of spleen, thymus and lymph nodes were remarkably atrophied without extra medullary hematopoiesis. The control group (5 FU treated) developed a transient hematopoiesis suppression, and recovered rapidly to normal. Three of 12 rats in the busulfan treated group developed aplastic anemia. Conclusion 5 FU combined with busulfan could impair the hematopoietic stem cells and resulted in an irreversible aplastic anemia in rats, making a rat aplastic anemia model with hematopoietic stem cell failure.