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[目的]研究c-Met抑制剂PHA665752联合5氟尿嘧啶(5-fluorouracil,5-Fu)对人结肠癌细胞SW620生长的抑制作用及机制。[方法]选取48只4周龄的雄性裸鼠皮下接种人结肠癌细胞SW620,建立裸鼠移植瘤模型,随机分为对照组(2.5%二甲亚砜稀释液隔日用药)、5-Fu组(40mg/kg 5-Fu每隔3日给药)、PHA组(25mg/kg PHA665752隔日给药)、5-Fu+PHA组(40mg/kg 5-Fu每隔3日给药+25mg/kg PHA665752隔日给药)各12只。免疫组织化学SP法检测瘤体组织内的E-cadherin和Ki-67蛋白表达情况,TUNEL法检测细胞凋亡情况。[结果]治疗结束时,5-Fu组、PHA组、5-Fu+PHA组3组裸鼠的体重和瘤体体积均明显低于对照组(P<0.05),且5-Fu+PHA组裸鼠的瘤体体积显著低于5-Fu组、PHA组(P<0.05)。5-Fu组、PHA组、5-Fu+PHA组3组裸鼠的E-cadherin蛋白OD值显著高于对照组(P<0.05);5-Fu+PHA组裸鼠的E-cadherin蛋白OD值显著高于5-Fu组、PHA组(P<0.05);5-Fu组、PHA组、5-Fu+PHA组3组裸鼠的Ki-67蛋白OD值显著低于对照组(P<0.05);5-Fu+PHA组裸鼠的Ki-67蛋白OD值显著低于5-Fu组、PHA组(P<0.05);5-Fu组、PHA组、5-Fu+PHA组3组裸鼠的凋亡指数(apoptotic index,AI)显著高于对照组(P<0.05);5-Fu+PHA组裸鼠的AI值显著高于5-Fu组、PHA组(P<0.05)。[结论]c-Met抑制剂PHA665752联合5-Fu对人结肠癌细胞SW620生长的抑制有协同作用,其机制可能与上调E-cadherin、下调Ki-67表达有关。
[Objective] To investigate the inhibitory effect of c-Met inhibitor PHA665752 combined with 5-fluorouracil (5-Fu) on the growth of human colon carcinoma cell line SW620 and its mechanism. [Methods] Forty-eight 4-week-old male nude mice were inoculated subcutaneously with human colon cancer cell line SW620 to establish a nude mouse xenograft model and were randomly divided into control group (2.5% dimethyl sulfoxide dilution every other day), 5-Fu group (40 mg / kg 5-Fu every 3 days), PHA group (25 mg / kg PHA665752 every other day), 5-Fu + PHA group PHA665752 administered on alternate days) 12 each. Immunohistochemistry was used to detect the expression of E-cadherin and Ki-67 in tumor tissues. The apoptosis was detected by TUNEL. [Results] At the end of treatment, body weight and tumor volume of 5-Fu group, PHA group and 5-Fu + PHA group were significantly lower than those of control group (P <0.05) The tumor volume of nude mice was significantly lower than that of 5-Fu group and PHA group (P <0.05). The OD value of E-cadherin protein in nude mice in 5-Fu group, PHA group and 5-Fu + PHA group was significantly higher than that in control group (P <0.05). The E-cadherin protein OD (P <0.05). The OD values of Ki-67 in nude mice in 5-Fu group, PHA group and 5-Fu + PHA group were significantly lower than those in control group (P < 0.05). The OD value of Ki-67 in 5-Fu + PHA group was significantly lower than that in 5-Fu group and PHA group (P <0.05) The apoptotic index (AI) of nude mice was significantly higher than that of the control group (P <0.05). The AI of 5-Fu + PHA group was significantly higher than that of 5-Fu group and PHA group (P <0.05). [Conclusion] The inhibitory effect of c-Met inhibitor PHA665752 combined with 5-Fu on the growth of human colon cancer cell line SW620 is synergistic. The mechanism may be related to the up-regulation of E-cadherin and the down-regulation of Ki-67 expression.