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目的:研究荷瘤裸鼠按时辰给予吉非替尼的药效学。方法:取BALB/c-nu裸鼠复制非小细胞肺癌模型后,随机分为不同时间给药的吉非替尼(4:00、8:00、12:00、16:00、20:00、24:00)组和模型组,每组10只。吉非替尼组裸鼠分别按相应时间ig给药1 mg/kg,模型组裸鼠ig给予等量的1%聚山梨酯80溶液,连续给药21 d。检测20 d内各组裸鼠的瘤体积及第21天时的瘤质量,计算抑瘤率;检测各组裸鼠肿瘤组织中表皮生长因子受体(EGFR)和细胞外调节蛋白激酶(ERK1/2)的m RNA及蛋白表达情况。结果:与模型组比较,各吉非替尼组裸鼠第18天时肿瘤体积均增加缓慢,除20:00组外其余各吉非替尼组裸鼠瘤质量降低、抑瘤率增加,其中4:00、8:00组裸鼠肿瘤组织中EGFR m RNA表达减弱,4:00、8:00、12:00组裸鼠肿瘤组织中ERK1/2 m RNA表达减弱,4:00、8:00、12:00、24:00组裸鼠肿瘤组织中p-EGFR蛋白表达减弱,4:00、8:00、24:00组裸鼠肿瘤组织中p-ERK1/2蛋白表达减弱,以上差异均具有统计学意义(P<0.05)。与20:00组比较,4:00、8:00、12:00组裸鼠瘤质量降低,4:00、8:00组裸鼠肿瘤组织中p-EGFR蛋白表达减弱,8:00组裸鼠肿瘤组织中p-ERK1/2蛋白表达减弱,以上差异均具有统计学意义(P<0.05)。结论:吉非替尼对荷瘤裸鼠具有瘤抑制作用,并呈现时辰节律性,其中8:00给药肿瘤抑制效果最好,20:00给药抑制效果最差;其机制可能与EGFR、ERK1/2介导的传导通路有关。
Objective: To study the pharmacodynamics of gefitinib in tumor-bearing nude mice on time. Methods: BALB / c-nu nude mice were injected with non-small cell lung cancer model and then randomly divided into gefitinib (4: 00,8: 00,12: 00,16: 00,20: 00 , 24:00) group and model group, 10 rats in each group. Gefitinib group nude mice were given ig 1mg / kg corresponding time, the model group nude mice given equal amount of 1% polysorbate 80 solution, continuous administration of 21 d. The tumor volume of the nude mice in each group was detected within 20 days and the tumor mass on the 21st day. The tumor inhibition rate was calculated. The expressions of epidermal growth factor receptor (EGFR) and extracellular regulated protein kinase (ERK1 / 2) ) Of m RNA and protein expression. Results: Compared with the model group, the tumor volume increased slowly in each gefitinib group on the 18th day. The tumor mass of the rest gefitinib group was decreased and the tumor inhibition rate increased except for the group of 20:00, of which 4 : The expression of EGFR m RNA in the nude mice tumor tissues decreased at 00 and 8:00, and the expression of ERK1 / 2 m RNA decreased in the tumor tissues at 4:00, 8:00 and 12:00 in the nude mice group. At 4:00 and 8:00 , The expression of p-EGFR protein in the tumor tissue of nude mice was weakened at 12: 00,24: 00, and the expression of p-ERK1 / 2 decreased in the tumor tissues of 4: 00,8: 00,24: 00 group Statistically significant (P <0.05). Compared with the 20:00 group, the tumor mass of the nude mice at 4: 00,8: 00,12: 00 decreased, the expression of p-EGFR decreased in the tumor tissue of the 4: 00,8: 00 group, and the naked group at 8:00 The expression of p-ERK1 / 2 protein in murine tumor tissue decreased, the above differences were statistically significant (P <0.05). Conclusion: Gefitinib has tumor inhibitory effect on tumor-bearing nude mice and presents the rhythms of the hour. The tumor inhibition effect is the best at 8:00, and the suppressive effect at 20:00 is the worst. The mechanism may be related to EGFR, ERK1 / 2-mediated conduction pathway.