雷替曲塞对人胃癌裸鼠移植瘤生长的影响及其机制

Effects and mechanisms of raltitrexed on the growth of human gastric cancer xenograft transplanted in nude mice

目的:初步探索雷替曲塞对人胃癌裸鼠皮下移植瘤生长的影响及其机制。方法:1)建立人胃癌细胞MGC-803裸鼠皮下移植瘤模型;2)药物干预后观察荷瘤鼠一般情况、体重、瘤重并计算抑瘤率;3)流式细胞仪测定瘤细胞的周期分布和凋亡;4)采用RT-PCR、Western blot印迹法检测各组肿瘤p53 mRNA及p53蛋白的表达水平。结果:经雷替曲塞及5-Fu作用后,与对照组相比,两组裸鼠的体重明显下降,瘤体积缩小,抑瘤率分别达到49.02%和45.75%。雷替曲塞组和5-Fu组瘤细胞的G0/G1期比例较对照组比例明显降低(P<0.01),而S期比例较对照组明显升高(P<0.01)。雷替曲塞组和5-Fu组裸鼠肿瘤p53 mRNA与蛋白表达水平均显著升高(P<0.01),但雷替曲塞组和5-Fu组之间并无差异。结论:1)雷替曲塞对人胃癌细胞MGC-803裸鼠移植瘤生长有抑制作用,且与5-Fu抑瘤效果相似;2)雷替曲塞可以诱导人胃癌细胞MGC-803裸鼠移植瘤细胞周期S期的阻滞,并诱导移植瘤细胞凋亡;3)雷替曲塞可通过上调p53mRNA和蛋白的表达水平来发挥抑瘤作用。

Objective：This study was designed to explore the effects and mechanisms of raltitrexed on the growth of the human gastric cancer cell line （MGC-803） transplanted in nude mice. Methods： Models of MGC-803 xenograft transplanted in nude mice were established. Body weight, mental state, food, and stool of the nude mice were closely monitored, and the inhibitory action in the tu-mors was evaluated after drug intervention. Distribution and apoptosis of the tumor cells were examined through flow cytometric assay. P53 mRNA and protein expression levels were determined through reverse transcription-polymerase chain reaction and Western blot analysis. Changes among the three groups were compared. Results：Body weights and tumor volumes of the nude mice were lower in the raltitrexed and 5-fluorouracil （5-Fu） groups than those in the control group. Tumor inhibition ratios were 49.02%and 45.75%in the raltitrexed and 5-Fu groups, respectively. In the G0/G1 stage, the number of cells decreased in the raltitrexed and 5-Fu groups. Signifi-cant differences were found between the experimental and control groups （P〈0.01）. In the S stage, the number of cells increased in the raltitrexed and 5-Fu groups, with significant differences from the control group （P〈0.01）. P53 mRNA and protein expression levels in the raltitrexed and 5-Fu groups were significantly higher than those in the control group （P〈0.01）, but no significant differences were found between the raltitrexed and 5-Fu groups （P〉0.05）. Conclusion：Raltitrexed can inhibit the growth of MGC-803 xenograft trans-planted in nude mice and shows inhibitory effect similar to that of 5-Fu. Raltitrexed can induce the S-phase block of the cell cycle and cell apoptosis in the MGC-803 xenografts in the nude mice. This drug may exhibit an antitumor effect by upregulating the p53 mRNA and protein expression levels.