吉非替尼时辰给药Lewis肺癌荷瘤小鼠的药效学研究

Chronopharmacology of gefitinib in the mouse model of Lewis lung carcinoma

目的探讨吉非替尼按时辰给药荷瘤小鼠的药效学特点。方法利用C57BL/6小鼠建立Lewis肺癌小鼠模型,将荷瘤小鼠随机分成7组,每组8只,分别为对照组,8:00、12:00、16:00、20:00、24:00和次日4:00时给药的实验组(A、B、C、D、E、F组)。ig给药50 mg/kg,对照组给予相同剂量含有羧甲基纤维素钠的蒸馏水。每天观察小鼠的生存质量和肛周红肿的数量;每3天测定小鼠肿瘤的直径,计算小鼠的肿瘤体积。经过3周的给药,小鼠进行眼眶取血,处死小鼠并剥离肿瘤,称定质量,计算抑瘤率。取部分肿瘤组织做病理切片,观察肿瘤组织坏死情况;同时取小鼠皮肤组织进行扫描电镜观察。运用ELISA技术检测血液中IL-6的水平。结果吉非替尼可以明显地抑制荷瘤小鼠肿瘤的生长。与其他实验组比较,A组(8:00时给药)小鼠肿瘤体积增长最缓慢,其抑瘤率最高,F组(次日4:00给药)次之。病理学分析显示A组(8:00时给药)的肿瘤组织坏死情况最严重。通过扫描电镜观察上皮细胞发现,A组(8:00时给药)和F组(次日4:00时给药)的上皮细胞损伤较轻,其肛周红肿发生率和IL-6水平较其他实验组低。结论吉非替尼对荷瘤小鼠的抗肿瘤作用和毒副作用存在一定的时辰节律性,8:00和4:00时疗效较好。

Objective To compare the efficacy and adverse effects of gefitinib administration at different time points during a day on Lewis lung carcinoma in tumor-bearing mice. Methods The Lewis lung carcinoma model was built in C57BL/6 mice. The animals were randomly divided into seven groups （n=8）, including control and A -- F six experimental groups which were treated at 8：00, 12：00, 16：00, 20：00, 24：00, and the next day 4：00. Mice in the six experimental groups were ig given a single dose of gefitinib （50 mg/kg）, and those in the control group were provided with distilled water containing sodium carboxymethylcellulose daily. The quality of life and perianal swelling was recorded every day, and the tumor volume was determined every three days. After three weeks of the administration of gefitinib to the mice, the tumor inhibition rate was calculated and some tumors were used for pathological analysis. And some skin tissues were sent to inspect by scanning electron microscope （SEM）. The blood samples were collected for ELISA. Results Gefitinib could significantly inhibit the growth of tumor in C57BL/6 mice. The tumor volume of group A （administrated at 8：00） increased more slowly （P 〈 0.01）, with the maximum tumor inhibition rate. Group F （administrated at the next day 4：00） took the second place. Histological analysis showed that tumor tissue necrosis in A group （administered at 8：00） was the severest. And SEM analysis showed less injury to the skin tissue when gefitinib was administered at 8：00 and the next day 4：00. The perianal smelling rate and IL-6 levels in A and F groups were lower than others. Conclusion Both the anti-tumor effect and toxicities of gefitinib display circadian rhythm. Administration at 8：00 and 4：00 can impove its efficacy.