吉非替尼按時辰給藥的藥理作用特點及其機制研究
發(fā)布時間：2018-09-03 14:08
【摘要】：目的初步探討吉非替尼按時辰給藥荷瘤小鼠的藥理作用特點及其作用機制。 方法 1.建立肺癌小鼠模型并分組：利用C57BL/6小鼠建立lewis肺癌小鼠模型,將荷瘤小鼠隨機分成13組(n=10),即A-F六個實驗組、a-f六個空白組和對照組；A-F實驗組分別在8：00、12：00、16：00、20：00、24：00、次日4：00以灌胃方式給藥(100m·kg-1),空白組和對照組給予相同劑量的含有5%羧甲基纖維素鈉的蒸餾水。 2.日常指標的測定：連續(xù)給藥時間21天,每天觀察并記錄各組小鼠生存狀態(tài)及出現肛周紅腫的小鼠數量,每三天測定一次小鼠腫瘤體積,三周后在相應的時間進行眼眶取血并脫臼處死小鼠,剝離腫瘤并稱量瘤重,計算抑瘤率。 3.血常規(guī)檢測：各組每只荷瘤小鼠取50μl血液進行血常規(guī)檢測。 4.腫瘤組織和皮膚組織的觀察：對剝離的腫瘤同時進行病理學分析以及掃描電鏡分析,同時對部分皮膚組織進行掃描電鏡觀察。 5.細胞因子的測定：應用ELISA技術(按照美國Biolegend公司試劑盒說明書的要求)測定不同組的小鼠血液中細胞因子IL-6. IL-2和TNF-a水平。 6.基因表達的測定：應用RT-PCR技術測定腫瘤組織中EGFR、MMP-9、ABCG2和P35基因表達。 結果 1.吉非替尼對小鼠的生存質量有一定的影響,A、B、F組的小鼠精神狀態(tài)和身體狀況比C、D、E組好,A組和F組荷瘤小鼠的肛周紅腫率較其它實驗組低。 2.吉非替尼可以明顯抑制腫瘤的增長,在所有的實驗組中,A組荷瘤小鼠的腫瘤體積增長最緩慢(P0.05),A組的抑瘤率最高,C組最低(44.12%vs14.15%,x2=36.00,P=0.000),F組次之；病理學分析和掃描電鏡分析顯示A組和F組腫瘤組織壞死最嚴重,該組的上皮細胞損傷程度較其它實驗組輕。 3.血常規(guī)分析各組白細胞、紅細胞、血紅蛋白、中性粒細胞差異沒有統(tǒng)計學意義(P0.05)；實驗組小鼠血清中的IL-6、IL-2和TNF-a含量升高。A組和F組血清中的IL-6、IL-2和TNF-α水平最接近對照組的水平,C組和D組含量最高,差異顯著(P0.05)。 4.時辰給藥荷瘤小鼠對EGFR基因表達影響不同,A組EGFR表達最低,C、D組EGFR基因表達相對較高,差異有統(tǒng)計學意義(P0.05)�？瞻捉M間EGFR基因表達呈節(jié)律性變化,12:00左右時表達最高,20：00左右時EGFR表達最低。各實驗組中MMP-9、ABCG2和P53基因表達有顯著性差異,C組和D組表達最高,A組表達最低(P0.05)。結論 1.吉非替尼在荷瘤小鼠上的抗腫瘤活性和毒副作用存在時辰節(jié)律性,明期早期(8：00)和暗期晚期(4：00)的抗腫瘤活性較強,對小鼠的毒副作用相對較低。 2.吉非替尼藥理學作用特點呈時辰節(jié)律性變化,其機制可能與荷瘤小鼠體內的EGFR呈節(jié)律性變化有關；應用吉非替尼時,應考慮時間因素的影響。
[Abstract]:Objective to investigate the pharmacological characteristics and mechanism of gifitinib in mice with tumor-bearing drugs. Method 1. To establish lung cancer mice model and group: the lewis lung cancer mice model was established by C57BL/6 mice. The tumor bearing mice were randomly divided into 13 groups, namely A-F six experimental groups, a-f six blank group and control group. A-F experimental group was given orally at 8: 00 at 12: 00 to 16: 00 at 20: 00: 24: 00, by gavage at 4:00 the next day (100m kg-1). The blank group and the control group were given the same dose of distilled water containing 5% carboxymethyl cellulose sodium. 2. Measurement of daily indexes: continuous administration for 21 days, observed and recorded the survival status and the number of mice with perianal redness and swelling in each group, and measured the tumor volume of mice every three days. Three weeks later, blood was taken from orbit and dislocated mice were killed at the corresponding time, tumor was stripped and weighed, and tumor inhibition rate was calculated. Blood routine examination: 50 渭 l blood samples were taken from each tumor-bearing mouse in each group. 4. 4. Observation of tumor tissue and skin tissue: pathological analysis and scanning electron microscope analysis of exfoliated tumor were carried out simultaneously, and some skin tissues were observed by scanning electron microscope at the same time. Determination of cytokines: determination of cytokine IL-6. in blood of different groups of mice by ELISA technique (as required by Biolegend kit specification) IL-2 and TNF-a levels. Detection of gene expression: RT-PCR technique was used to detect the expression of EGFR,MMP-9,ABCG2 and P35 genes in tumor tissues. Result 1. Gefitinib had a certain effect on the quality of life of mice. The mental state and physical condition of the BF group were lower than those of the other experimental groups. 2. The rate of perianal red swelling in group A and group F was lower than that in group A and F. Gefitinib could significantly inhibit tumor growth. In all the experimental groups, the tumor volume of group A was the slowest (P0.05), the inhibition rate of group C was the highest (44.12 vs 14.15x36.00 P0. 000) and that of group F was the lowest. Pathological analysis and scanning electron microscope analysis showed that tumor tissue necrosis was the most serious in group A and group F, and the degree of epithelial cell injury in group A was less than that in other experimental groups (3.3%). There was no significant difference in white blood cell, erythrocyte, hemoglobin, neutrophil in each group by blood routine analysis (P0.05). The levels of IL-6,IL-2 and TNF- 偽 in serum of group A and F were the highest in group C and group D (P0.05). Effect of time administration on the expression of EGFR gene in tumor-bearing mice the expression of EGFR gene in the lowest EGFR expression group (P 0.05) was significantly higher than that in the control group (P 0.05). There was a rhythmic change of EGFR gene expression in the blank group. The highest expression of EGFR gene was observed at about 12: 00 and the lowest at about 20: 00. There was significant difference in the expression of MMP-9,ABCG2 and p53 gene in each experimental group. The expression of MMP-9,ABCG2 and p53 gene was the lowest in group C and group D (P0.05). Conclusion 1. The antitumor activity and side effects of Gifitinib in tumor-bearing mice were rhythmic, and the antitumor activity in early stage (8:00) and late stage (4:00) was stronger, and the toxicity and side effect of gifitinib on mice was relatively low. 2. The pharmacological characteristics of gefitinib were time-rhythmic, and its mechanism might be related to the rhythmic change of EGFR in tumor-bearing mice, and the effect of time should be taken into account when gifetini was used.
【學位授予單位】：青島大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R965
本文編號：2220197
[Abstract]:Objective to investigate the pharmacological characteristics and mechanism of gifitinib in mice with tumor-bearing drugs. Method 1. To establish lung cancer mice model and group: the lewis lung cancer mice model was established by C57BL/6 mice. The tumor bearing mice were randomly divided into 13 groups, namely A-F six experimental groups, a-f six blank group and control group. A-F experimental group was given orally at 8: 00 at 12: 00 to 16: 00 at 20: 00: 24: 00, by gavage at 4:00 the next day (100m kg-1). The blank group and the control group were given the same dose of distilled water containing 5% carboxymethyl cellulose sodium. 2. Measurement of daily indexes: continuous administration for 21 days, observed and recorded the survival status and the number of mice with perianal redness and swelling in each group, and measured the tumor volume of mice every three days. Three weeks later, blood was taken from orbit and dislocated mice were killed at the corresponding time, tumor was stripped and weighed, and tumor inhibition rate was calculated. Blood routine examination: 50 渭 l blood samples were taken from each tumor-bearing mouse in each group. 4. 4. Observation of tumor tissue and skin tissue: pathological analysis and scanning electron microscope analysis of exfoliated tumor were carried out simultaneously, and some skin tissues were observed by scanning electron microscope at the same time. Determination of cytokines: determination of cytokine IL-6. in blood of different groups of mice by ELISA technique (as required by Biolegend kit specification) IL-2 and TNF-a levels. Detection of gene expression: RT-PCR technique was used to detect the expression of EGFR,MMP-9,ABCG2 and P35 genes in tumor tissues. Result 1. Gefitinib had a certain effect on the quality of life of mice. The mental state and physical condition of the BF group were lower than those of the other experimental groups. 2. The rate of perianal red swelling in group A and group F was lower than that in group A and F. Gefitinib could significantly inhibit tumor growth. In all the experimental groups, the tumor volume of group A was the slowest (P0.05), the inhibition rate of group C was the highest (44.12 vs 14.15x36.00 P0. 000) and that of group F was the lowest. Pathological analysis and scanning electron microscope analysis showed that tumor tissue necrosis was the most serious in group A and group F, and the degree of epithelial cell injury in group A was less than that in other experimental groups (3.3%). There was no significant difference in white blood cell, erythrocyte, hemoglobin, neutrophil in each group by blood routine analysis (P0.05). The levels of IL-6,IL-2 and TNF- 偽 in serum of group A and F were the highest in group C and group D (P0.05). Effect of time administration on the expression of EGFR gene in tumor-bearing mice the expression of EGFR gene in the lowest EGFR expression group (P 0.05) was significantly higher than that in the control group (P 0.05). There was a rhythmic change of EGFR gene expression in the blank group. The highest expression of EGFR gene was observed at about 12: 00 and the lowest at about 20: 00. There was significant difference in the expression of MMP-9,ABCG2 and p53 gene in each experimental group. The expression of MMP-9,ABCG2 and p53 gene was the lowest in group C and group D (P0.05). Conclusion 1. The antitumor activity and side effects of Gifitinib in tumor-bearing mice were rhythmic, and the antitumor activity in early stage (8:00) and late stage (4:00) was stronger, and the toxicity and side effect of gifitinib on mice was relatively low. 2. The pharmacological characteristics of gefitinib were time-rhythmic, and its mechanism might be related to the rhythmic change of EGFR in tumor-bearing mice, and the effect of time should be taken into account when gifetini was used.
【學位授予單位】：青島大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R965
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