双环醇对奥沙利铂联合5-氟尿嘧啶方案引起肝损伤保护作用的实验研究

Protection of Bicyclol on Hepatic Injury Induced by the Combination Therapy of Oxaliplatin and 5-Fluorouracil in Tumor-bearing Mice

目的研究治疗肝炎药物双环醇在荷瘤小鼠对抗肿瘤药物奥沙利铂(oxaliplatin,L-OHP)与5-氟尿嘧啶(5-fluo-rouracil,5-FU)合用引起肝损伤的保护作用,并考察对抑瘤活性的影响。方法 C57/BL小鼠接种Lewis肺癌后6天腹腔注射L-OHP(6mg.kg-1×1)及5-FU(25mg.kg-1×5),建立大剂量L-OHP/5-FU合用引起荷瘤小鼠肝损伤模型,同时给予双环醇(150,300mg.kg-1×7)。于开始给药后的第8天处理动物,取瘤称重,全自动生化分析仪分析血清ALT,AST水平,H.E.染色考察肝脏病理状态。结果 L-OHP与5-FU合用,对Lewis肺癌具显著抑制活性,抑瘤率达72.7%,同时出现明显毒副反应,26.7%的动物死亡,肝脏受到损伤,肝细胞出现变性、坏死,血清ALT,AST水平升高。双环醇150、300mg.kg-1与L-OHP/5-FU合用,能够明显改善肝脏病理状态,降低血清转氨酶水平,减少动物死亡率,对抑瘤率亦有小的升高作用。双环醇300mg.kg-1单独给药对Lewis肺癌的抑瘤率为25.6%,肝脏无损伤且整个实验过程中小鼠无死亡。结论双环醇在不影响L-OHP/5-FU抑瘤率的情况下,对后者引起的肝脏损伤有明显保护作用,能降低荷瘤小鼠死亡率,临床应用值得参考。

Objective To determine the effect of bicyclol against oxaliplatin/5-fluorouracil-induced hepatotoxicity and the influence on the antitumor capacity of oxaliplatin/5-fluorouracil in tumour-bearing mice. Methods C57/ BL mice implanted with Lewis lung tumors for 6 days were treated with oxaliplatin（6mg·kg^-1×） and 5-fluorouracil （25mg·kg^-1×1） to establish the liver damage model. Bicyclol（150,300mg·kg^-1） was pretreated 2hr before the injection of oxaliplatin/5-fluorouracil. All animals were killed on the eighth day after oxaliplatin/5-fluorouracil treatment and tumor weight of each animal was measured. The activities of ALT and AST were meseared by automatic chemistry analyzer（TBA-40FR）. Liver histopathological changes were examined by H.E. and light microscopy. Results The combination therapy of oxaliplatin and 5-fluorouracil significantly inhibited the growth of Lewis lung tumor and the inhibiton rate is 72.7%. At the same time, the obvious toxic reaction emerged expressed as 26.7% mice were death, the pathology of liver tissue was damaged and the serum aminotransferases were elevated. Bicyclol showed a significant protection as evidenced by the improvement of histotpathological injury and the decrease of elevated serum amino- transferases induced by oxaliplatin/5-fluorouracil. The administration of bicyclol could also reduce the mortality and increase slightly the anti-tumor activity of oxaliplatin/5-fluorouracil. Gonclusion Bicyclol showed potent protective activity against oxaliplatin/5-fluorouracil-induced liver damage and decreased the death by the high-dose chemotherapy without affecting the associated inhibition of tumor growth. This maybe provide a new approach for preventing the hepatotoxicity induced by oxaliplatin/5-fluorouracil in the clinic.