酒石酸长春瑞滨对大鼠免疫和造血系统的长期毒性作用

Long term toxicity of vinorelbine tartrate on immune and hematopoietic systems in rats

目的从病理学角度研究酒石酸长春瑞滨(NVB)对大鼠免疫和造血系统的长期毒性作用。方法 48只SD大鼠,雌雄各半,随机分为正常对照组和NVB 5.0,10.0和20.0 mg·m-2组。NVB静脉滴注给药,第1和第8天各给药1次,21 d为1个周期,共给药4个周期。末次给药后14 d腹主动脉取血,用ADVIA2120血液分析仪检测白细胞(WBC)、中性粒细胞(Neut)、淋巴细胞(Lym)和红细胞(RBC)数及网织红细胞千分比值(RET‰);剖取胸腺、胸骨骨髓、脾和肠系膜淋巴结进行组织病理学检查;精密称取胸腺和脾质量,计算脏器系数;取出股骨骨髓,进行骨髓涂片分类计数。结果与正常对照组比较,NVB 5.0,10.0和20.0 mg·m-2组雌雄大鼠外周血中WBC,Neut,Lym和RBC数及RET‰均降低(P<0.05,P<0.01),其中雄性大鼠正常对照组Neut为(2.35±0.56)×109L-1,NVB各组分别降低为(1.66±0.44),(0.67±0.22)和(0.20±0.02)×109L-1;雌性大鼠正常对照组Neut为(1.26±0.27)×109L-1,NVB各组分别降低为(1.14±0.56),(0.47±0.13)和(0.21±0.08)×109L-1。骨髓涂片分类计数结果显示,粒系细胞比例降低(P<0.05,P<0.01),其中雄性大鼠正常对照组粒系百分比为(42.7±6.1)%,NVB各组分别降低为(28.8±5.3)%,(22.0±3.2)%和(18.9±3.9)%;雌性大鼠正常对照组粒系百分比为(35.4±3.0)%,NVB各组分别降低为(31.2±4.7)%,(22.9±6.7)%和(20.8±4.2)%。胸腺系数降低(P<0.05,P<0.01),其中雄性大鼠正常对照组为0.36±0.04,NVB各组分别降低为0.31±0.06,0.18±0.03和0.08±0.01;雌性大鼠正常对照组为0.29±0.06,NVB各组分别降低为0.25±0.06,0.19±0.06和0.07±0.01。组织病理学检查结果显示,NVB 5.0,10.0和20.0 mg·m-2可致雌雄大鼠不同程度的胸腺萎缩和骨髓造血抑制,NVB各剂量组亦可见不同程度的脾代偿性髓外造血细胞增多,肠系膜淋巴结均未见明显病理改变。结论 NVB对SD大鼠免疫和造血系统具有毒性作用,表现为胸腺萎缩和骨髓造血抑制。

OBJECTlVE To study the Iong term toxicity of vinoreIbine tartrate（NVB）on rat immune and hematopoietic systems pathologically. METHODS SD Rats were randomly divided into 4 groups：normal control group and NVB 5.0,10.0,and 20.0 mg·m-2 groups,each group containing 6 male and female rats. The rats in NBV groups were administered different concentrations of NVB by intravenous drip on the 1st and 8th days,21 da cycIe,for 4 cycIes. On the 14th day after the Iast administration, white bIood ceIIs（WBC）,neutrophiI（Neut）,Iymphocytes（Lym）,red bIood ceIIs（RBC）and reticuIo-cyte‰（RET‰）were detected by ADVIA2120 hematology analyzer. Thymus,sternum marrow,spIeen and mesenteric Iymph nodes were observed by histopathological examination. The thymus and spIeen were preciseIy weighed to obtain the reIative organ coefficients. Bone marrow smears were made for counting and cIassification. RESULTS Compared with normal control group,WBC,Neut,Lym,RBC and RET% of peripheral bIood of NVB 5,10 and 20 mg·m-2 groups were decreased（P﹤0.05,P﹤0.01）. The Neut value of male rats was（2.35±0.56）×109·L-1 in normal control group,but was reduced to （1.66±0.44）,（0.67±0.22）and（0.20±0.02）×109·L-1（P﹤0.05,P﹤0.01）in NVB 5,10 and 20 mg·m-2 groups. The Neut value of female rats was（1.26± 0.27）× 109 L-1 in normal control group,but was reduced to（1.14±0.56）,（0.47±0.13）and（0.21±0.08）×109 L-1（P﹤0.05,P﹤0.01）in NVB 5,10 and 20 mg·m-2 groups. The resuIts of counting and cIassification of bone marrow smears showed that the myeIoid ceII ratio decreased（P﹤0.05,P﹤0.01）. The myeIoid ceII ratio of male rats was（42.7±6.1）% in normal control group,but was reduced to（28.8±5.3）%,（22.0±3.2）% and（18.9±3.9）% in NVB 5,10 and 20 mg·m-2 groups. The myeIoid ceII ratio of female rats in normal control group was（35.4±3.0）%,＂nbsp;but was reduced to（31.2±4.7）%,（22.9±6.7）% and（20.8±4.2）% in NVB 5,10 and 20 mg·m-2 groups. The thymus coefficient was reduced（P﹤0.05,P﹤0.01）. The thymus coefficient of male rats in normal control group was 0.36±0.04,but was reduced to 0.31±0.06,0.18±0.03 and 0.08±0.01 in NVB 5,10 and 20 mg·m-2 groups. The thymus coefficient of female rats in normal control group was 0.29±0.06,but was reduced to 0.25±0.06,0.19±0.06 and 0.07±0.01 in NVB 5,10 and 20 mg·m-2 groups. Histopatho-Iogical examination showed that thymus was atrophiedand bone marrow was suppressed. SpIeen com-pensatory extrameduIIary hematopoietic ceIIs were increased in NVB 5.0,10.0 and 20.0 mg·m-2 groups （male and female）to different degrees,but the mesenteric Iymph nodes of NVB groups showed no sig-nificant pathological changes. CONCLUSlON NVB has immune and hematopoietic toxicity on SD rats, as is showed by thymic atrophy and bone marrow suppression.