阿米福汀对放射性肺损伤保护作用的实验研究

Assessment of the protective effect of amifostine on radiation induced pulmonary injury

目的 用荷瘤和无瘤大鼠的放射性肺损伤模式评价阿米福汀 (Amifostine,WR 2 72 1)的放射性肺损伤保护作用。方法 选 15 0～ 16 0g的Fisher 34 4雌性大鼠 ,在右后胸壁种植R32 30AC人乳腺癌细胞株 ,肿瘤长至直径为 1.0～ 1.5cm时和无肿瘤大鼠随机进入实验组。用 4MVX射线、剂量DT35Gy5分次 5d照射右全肺 ,每次照射前 30min腹腔内注射Amifostine(15 0mg kg)。照射后观测呼吸频率、肿瘤大小和转化生长因子 (TGF β1 )水平。当出现呼吸困难伴体重下降时 ,终止观察 ,否则在 6个月后终止观察。肺组织进行羟脯胺酸和TGF β1 表达等生物学检测。结果 治疗后第 3d体重下降明显 ,照射加Amifostine(15 % )和单用Amifostine(11% )与单纯放射 (7% )间有明显的差别。肿瘤生长延迟和肿瘤生长情况及因肿瘤肺转移死亡贡献生存率 ,用药与未用药者相似。无瘤大鼠单纯照射组的平均呼吸频率增加早 (第 9周开始 )、幅度高 (12 5～ 12 7次 min) ,照射加药组在第 12周开始 ,115～ 118次 min(P <0 .0 0 1)。单纯照射组羟脯胺酸含量明显高于照射加amifostine组 (P =0 .0 42 )、单用药组和对照组 (P <0 .0 1)。血浆TGF β1 含量在照射后 1～ 3个月增加、2个月达高峰 ,单放组的TGF β1 含量[(5 .32± 1.2 1)ng

Objective To assess the radioprotective effect of amifostine on the lung using tumor-bearing and nontumor-bearing rat models for radiation-induced lung injury. Methods Female Fisher-344 rats were transplanted with R3230 AC mammary adenocarcinoma on the back of the right chest wall. As the implanted tumor developed to 1.0～1.5 cm,experiment was started. The rats were group into tumor-bearing and a non tumor-bearing categories, which were subdivided into:1.aminostime + radiation (A+R) group. 2.aminostine(A) group,3.Radiation (R) group and 4. A sham radiation group. Aminostine (50 mg/kg) had been given intra peritonially 30 min before each fraction of radiation. For radiation,4 MV photon,35 Gy/5 f/5 d was given to the right lung under anesthesia. Body weight and breathing rate were recorded weekly or every two weeks. Plasma TGF-β 1 levels were measured monthly after treatment. During the post-treatment period,animals in respiratory distress were sacrificed. Otherwise,they were sacrificed 6 months after irradiation and the lung tissue was processed for biochemical analysis of hydroxyproline content and other biologic analyses. Results There were significantly differences in weight lost within 3 days of treatment between the A+R group (15%),R alone group (7%) and A alone group (11%). Tumor regrowth rate as well as incidence of actuarial death due lung metastasis after radiation were similar in rats given with amifostine or not. In non tumor-bearing rats, breathing rate (BF) increased earlier (from 9th week) and in greater frequency (125～127/min) in the radiation alone rats than those given amifostine prior to radiation (12th week and 115～118/min) (P<0.001). Hydroxyproline content was higher in R alone rats than in A+R (P=0.042). It was higher in A+R than A alone and the S group. Plasma TGF-β 1 level showed an increase from 1 to 3 months after radiation, peaking at 2 months in rats with (2.80±0.23?ng/mL) or without amifostine (5.32±1.21?ng/mL) as compared to sham irradiation. There was significant increase in R alone as compared to radiation added with amifostine (P=0.038). Conclusions Amifostine increases the tolerance of the lung to radiation-induced injury with mild toxicity without protecting the tumor in rat model by fractionated radiation. The change of plasma TGF-β 1 level is correlated with the change of radiation-induced lung injury.