吉非替尼不同给药时间对肺癌模型小鼠不良反应及表皮生长因子受体、基质金属蛋白酶-9表达的影响

Effects of gefitinib administration time on toxic and side effects and epidermal growth factor receptor and matrix metallopeptidase 9 expression in lung cancer model mice

目的探讨吉非替尼不同时间用药对肺癌模型小鼠不良反应及表皮生长因子受体(EGFR)和基质金属蛋白酶-9(MMP-9)表达的影响。方法70只肺癌模型小鼠简单随机抽样法分为对照组、4 h组、8 h组、12 h组、16 h组、20 h组、24 h组,对照组给予等量含羧甲基纤维素钠的蒸馏水,其余均给予50 mg/kg吉非替尼悬浮液灌喂,连续给药21 d。比较各组抑瘤效果、血清白细胞介素-6(IL-6)及肿瘤坏死因子-α(TNF-α)含量、肿瘤组织EGFR与MMP-9基因相对表达量。采用单因素方差进行统计学分析。结果8 h组抑瘤效果[(59.42±7.54)%]高于4 h组[(50.54±7.12)%]、12 h组[(44.20±6.45)%]、16 h组[(35.87±5.36)%]、20 h组[(31.52±5.24)%]、24 h组[(40.94±5.32)%,P<0.05,F=81.64]。对照组血清IL-6、TNF-α含量[(30.12±4.34)、(15.43±2.78)ng/L]低于4 h组[(41.20±5.24)、(22.45±3.12)ng/L]、8 h组[(37.45±5.41)、(18.36±2.45)ng/L]、12 h组[(62.32±7.43)、(38.45±5.12)ng/L]、16 h组[(92.45±12.14)、(45.36±5.34)ng/L]、20 h组[(131.21±7.65)、(51.14±6.20)ng/L]、24 h组[(68.12±8.24)、(40.12±4.54)ng/L,F=114.29、98.38,P<0.05]。对照组EGFR、MMP-9基因相对表达量[(1.32±0.56)、(1.23±0.02)ng/L]高于4 h组[(0.48±0.09)、(0.54±0.04)ng/L]、8 h组[(0.29±0.04)、(0.32±0.07)ng/L]、12 h组[(0.56±0.07)、(0.78±0.12)ng/L]、16 h组[(0.78±0.10)、(0.83±0.05)ng/L]、20 h组[(0.89±0.08)、(0.86±0.08)ng/L]、24 h组[(0.96±0.12)、(0.98±0.06)ng/L,F=105.45、92.72,P<0.05]。结论吉非替尼4、8 h给药抑瘤效果最好,不良反应较轻。

Objective To study the effect of gefitinib administration time on adverse reactions and epidermal growth factor receptor(EGFR),matrix metallopeptidase 9(MMP-9)expression in lung cancer model mice.Methods A total of 70 lung cancer model mice were randomly divided into control group,gefitinib 4 h group,gefitinib 8 h group,gefitinib 12 h group,gefitinib 16 h group,gefitinib 20 h group,gefitinib 24 h group.The control group was given an equal amount of distilled water containing sodium carboxymethylcellulose,and the rest group were given 50 mg/kg gefitinib suspension at different time points.After 21 days of continuous administration,the anti-tumor effect,interleukin(IL)-6 and tumor necrosis factor-α(TNF-α),EGFR and MMP-9 expression were compared.Results(1)Antitumor effect:the gefitinib 8 h group[(59.42±7.54)%]showed a higher antitumor effect than the gefitinib 4 h group[(50.54±7.12)%],gefitinib 12 h group[(44.20±6.45)%],gefitinib 16 h group[(35.87±5.36)%],gefitinib 20 h group[(31.52±5.24)%],and gefitinib 24 h group[(40.94±5.32)%,F=81.64,P<0.05].(2)Serum IL-6 and TNF-αlevels:the control group[(30.12±4.34),(15.43±2.78)ng/L]had lower levels of IL-6 and TNF-αthan the gefitinib 4 h group[(41.20±5.24),(22.45±3.12)ng/L],gefitinib 8 h group[(37.45±5.41),(18.36±2.45)ng/L],gefitinib 12 h group[(62.32±7.43),(38.45±5.12)ng/L],gefitinib 16 h group[(92.45±12.14),(45.36±5.34)ng/L],gefitinib 20 h group[(131.21±7.65),(51.14±6.20)ng/L],and gefitinib 24 h group[(68.12±8.24),(40.12±4.54)ng/L,F=114.29,98.38,P<0.05].(3)Relative gene expression of EGFR and MMP-9:the control group[(1.32±0.56),(1.23±0.02 ng/L)had higher EGFR and MMP-9 gene expression than gefitinib 4 h group[(0.48±0.09),(0.54±0.04)ng/L],gefitinib 8 h group[(0.29±0.04),(0.32±0.07)ng/L],gefitinib 12 h group[(0.56±0.07),(0.78±0.12)ng/L],gefitinib 16 h group[(0.78±0.10),(0.83±0.05)ng/L],gefitinib 20 h group[(0.89±0.08),(0.86±0.08)ng/L],and gefitinib 24 h group[(0.96±0.12),(0.98±0.06)ng/L,F=105.45,92.72,P<0.05].Conclusion Gefitinib administration has the best antitumor effect at 4 h and 8 h,and the side effects are milder.