Study On The Antitumor Activity Of Sheloveplatin In Vivo And In Vitro And Evaluation Of The Related Toxicity

Objective:To study the anti-tumor activity of Sheloveplatin in vivo and in vitro and evaluate the toxicity of liver and kidney in vivo,compared with lobaplatin.Methods:Using human breast cancer(MCF-7)cells,human non-small cell lung cancer(A549)cells,human gastric cancer(MKN74)cells and human colon cancer(HCT116)cells as model,MTT assay explained the effects of Sheloveplatin on the proliferation of MCF-7,A549,MKN74 and HCT116 cells;using flow cytometry(FCM)to detect the apoptosis rate of MCF-7 cells and A549 cells induced by compound Sheloveplatin and cell cycle arrest in MCF-7 and A549 cells.Using mouse transplantable tumor sarcoma S180 as model,the tumor inhibition rate(%)was used as an indicator to evaluate the inhibitory effect of the compound Sheloveplatin on tumor growth in vivo;using body weight,thymus index,spleen index,liver index,and kidney index as index,compared with kidney tissue and liver tissue sections of tumor-bearing mice dealt with Hematoxylin-eosin stain,to evaluate the toxicity of Sheloveplatin,especially kidney and liver toxicity.Results:1.The results of MTT assay showed that the median inhibitory concentration IC50 of the compound Sheloveplatin on MCF-7 cells at 48h and 72h was 10.3±1.3 pM and 7.2±1.2 μM,the median inhibitory concentration IC50 on A549 cells at 48h and 72h was 16.2±1.2pM and 12.9±1.9pM,the median inhibitory concentration IC50 on MKN74 cells at 48h and 72h was 36.3±5.3μM and 20.3±5.5μM,the median inhibitory concentration IC50 on HCT116 cells at 48h and 72h was 10.9±13.0μM and 8.3±2.6pM.2.The results of FCM showed that the compound Sheloveplatin could obviously affect the cell cycle distribution of MCF-7 and A549 cells and arrest cells in S phase.For MCF-7 cells,the negative control group cells in S phase were 21.9%,G0/G1 phase were 70.7%and G2/M phase were 7.4%.MCF-7 were treated by Sheloveplatin at the concentration of 1.25,2.5,5μM for 24h,S phase cells increased to 39.2%,52%,64.5%,G0/G1 phase cells were 44.8%,36.8%,31.1%and the G2/M phase cells were 16.0%,11.2%,4.4%,the changes show a clear dose-effect relationship.For A549 cells,the negative control group cells in S phase were 30.7%,G0/G1 phase were 55.5%and G2/M phase were 13.8%.A549 were treated by Sheloveplatin at the concentration of 1.25,2.5,5μM in 24h,S phase cells were 43.4%,57.4%,69.8%.G0/G1 phase cells were 39.0%,30.4%,24.7%and the G2/M phase cells were 17.6%,12.2%,5.5%,the changes also show a clear dose-effect relationship.3.The compound Sheloveplatin obviously induced apoptosis in MCF-7 and A549 cells.For MCF-7 cells,the negative control group were mainly live cells,apoptosis rate was 1.7%.MCF-7 were treated by Sheloveplatin at the concentration of 2.5,5,10μM for 48h,the apoptosis rate was 14.1%,36.5%,53.9%,necrosis and apoptosis rates were 15.7%,38.1%,62.2%,showed a good dose-effect relationship.For A549 cells,the negative control group were mainly live cells,apoptosis rate was 1.9%.A549 were treated by Sheloveplatin at the concentration of 2.5,5,10μM for 48h,the apoptosis rate was 11.4%,15.5%,29.3%,necrosis and apoptosis rates were 114.2%,18.5%,34.8%,showed a good dose-effect relationship,too.4.Anti-tumor experiment results in vivo showed that intraperitoneal injection of the compound Sheloveplatin had a significant inhibitory effect on the growth of transplanted sarcoma S180 in mice.The tumor inhibition rates of Sheloveplatin whose doses were 0.33,1 and 3 μM/kg were 45.23%,52.79%and 63.68%,showed a good dose-effect relationship.5. Sheloveplatin had almost no effect on body weight of tumor-bearing mice compared with negative controls.However,the weight of mice in the same dose groups of cisplatin and lobaplatin was significantly reduced.Sheloveplatin had no significant effect on the immune organs,such as spleen and thymus,lobaplatin and cisplatin showed significant inhibitory effects.Judging from the liver index and kidney index,the effects of Sheloveplatin and lobaplatin were not obvious,but cisplatin had a significant effect,showing that the liver and kidney indexes were reduced significantly.Conclusions:The compound Sheloveplatin has obvious anti-tumor effect in vitro and in vivo,and the effect is closely related to the arrest of tumor cell cycle and apoptosis induction of tumor cells.Sheloveplatin has increased the stability on the basis of loloplatin.While maintaining the activity of platinum antitumor drugs,Sheloveplatin has not increased its toxicity in the body weight,spleen,thymus,liver and kidney of mice.