| BackgroundMultidrug resistance of gastric cancer cells leads to ineffective internal medicine chemotherapy.The effective rate of verapamil combined with chemotherapeutic drugs through targeted arterial infusion in treating advanced gastric cancer is as high as 70%,but still 30% is not effective.Apoptosis gene BCL-2 was found to be involved in the formation of multidrug resistance in tumor.Based on the previous studies and literature reports,this study further explored the relationship between BCL-2 and verapamil in reversing gastric cancer cells.This study is divided into two parts.ObjectiveThe main purpose of this study is to investigate the clinical effect of targeted arterial infusion of verapamil combined with chemotherapy on patients with advanced gastric cancer.Explore the target artery infusion of verapamil combined with chemotherapy drugs can not cause cardiovascular adverse reactions at the same time,improve tumor cell sensitivity to chemotherapeutic drugs,prolong patient survival.To investigate the chemotherapy resistance reversal in gastric cancer cells with verapamil,screen the target gene Bcl-2 associated with the above reversal process and study its mechanism.Method53 cases of advanced(stage III and above)gastric cancer patients treated with verapamil combined with chemotherapy drug target arterial infusion therapy,each patient intervention once a month,each treatment of 2 to 4 times.Clinical staging was assessed by endoscopy,CT or MRI before and after treatment.And follow-up of patients with survival,evaluation of clinical treatment benefits.The ability of verapamil in reversing the chemotherapy resistance of fluorouracil,doxorubicin and cisplatin in gastric cancer cell lines SGC-7901,BGC-823,AGS and HGC-27 was detected with the CCK-8 method.The effect of verapamil on the apoptosis of doxorubicin-based gastric cancer cell lines(SGC-7901,HGC-27)was also tested with the Annexin V-FITC/PI method.The protein expression levels of Bcl-2 were detected with Western blotting.ResultThe results showed that 40 patients were treated with verapamil plus chemothe-rapy in more than 2 times,with complete remission(CR)in 5 cases,partial remission(PR)in 22 cases and total effective rate(CR + PR)in 67.5% Thirteen patients were treated with chemotherapy alone for more than 2 times.There were 0 complete remission(CR),4 partial remission(PR)and 30% total effective rate(CR + PR).The treatment group was significantly better than the control group.The median PFS for the treatment and control groups was 20 months and 9 months,and the median OS was 25 months and 13 months(Table 4).Treatment group in December,24 disease progression rate,survival rate than the control group increased,median PFS,median OS than the control group extended.Heart function evaluation results showed that 40 patients had no significant changes in cardiac function before and after intervention,ECG showed no significant difference.Interventional treatment of verapamil combined with chemotherapy drugs was not associated with serious side effects and cardiac dysfunction.The IC50 values of SGC-7901 cell lines in ADM(adriamycin)group and ADM-Ver(adriamycin-verapamil)combination group were(1.51±0.12)ug/ml and(0.22±0.01)ug/ml,respectively;there was an obvious difference between the two groups(P< 0.05).The IC50 values of HGC-27 cells were(1.24±0.19)ug/ml and(1.06±0.08)ug/ml;there was no obvious difference between the two groups(P>0.05).The apoptosis experiment showed that apoptosis rates of the SGC-7901 cell line in ADM group and ADM-Ver combination group were 36.76% and 61.10%,respectively.The data were significantly different from that of the blank group(P< 0.05).Apoptosis rates of the HGC-27 cell line in ADM group and ADM-Ver combination group were 19.79% and 21.92%,respectively.The apoptosis index of the SGC-7901 cells promoted by verapamil in ADM group was significantly higher than that of HGC-27 cells,and there was a significant difference between them(P< 0.05).A qRT-PCR experiment was made to screen some apoptosis-related genes.The results showed that Bcl-2 might mediate verapamil in promoting the apoptosis of gastric cancer cells.Western blotting results showed that the Bcl-2 expression in SGC-7901 cells treated with the combination of adriamycin and verapamil was significantly lower than that treated with adriamycin alone.The data had significant differences with the control group while the differences among the four HGC-27 cell groups were not significant.ConclusionIn the treatment of advanced gastric cancer,the target artery infusion of verapamil combined with chemotherapy drugs,not only improve the ability of chemoth-erapy drugs to kill tumor tissue,but also to avoid its toxic side effects on the heart.Verapamil combined with chemotherapy drugs to varying degrees,improve the survival rate of patients with advanced gastric cancer,thereby improving the quality of life of patients.Verapamil by down-regulated the Bcl-2 gene expression enhanced ability of the resistance of verapamil reverse gastric cancer cells to chemotherapy,and promote the gastric cancer cell apoptosis. |
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