| Objective:To investigate whether apatinib has anti-tumor effect on the cne-2 nasopharyngeal carcinoma,and Whether there was a synergistic antitumor effect and possible mechanism for the tumor of the CNE2nasopharyngeal carcinoma in the combination of apatinib combined with radiotherapy.Methods:Nude mice's right thigh were injected subcutaneously with CNE-2 nasopharyngeal carcinoma cells.When the volume of transplanted tumor in nude mice increased to about 150-200 mm~3,nude mice were randomly divided into 6 groups(Each experimental group had eight nude mice):1).control group(NS 0.1ml/d,ig,d1-7),2).Apatinib group(Apatinib 200mg/kg/day,ig,d1-7),3).12gy group(12gy radiotherapy,d1),4).18gy group(18gy radiotherapy,d1),5).Apatinib+12gy group(Apatinib 200 mg/kg/day,ig,d1-7+12gy radiotherapy,d8)and 6).Apatinib+18gy group(Apatinib200 mg/kg/day,ig,d1-7+18gy radiotherapy,d8).After grouping the experimental nude mice,the general condition of the nude mice was observed every day.The size of the transplanted tumor was measured every 3 days,and the tumor tissue volume was observed in each group,and the tumor growth curve was plotted.In the 18th day after the treatment,each group of nude mice was executed by dislocation of the cervical vertebra.The tumor was stripped and the tumor inhibition rate and the combined effect Q were calculated.VEGFR-2 antibody was used to detect the expression of VEGFR-2 in tumor tissues by immunohistochemistry.The microvascular density(MVD)of tumor tissue was detected by immunohistochemistry using CD31 antibody,and the tumor angiogenesis was determined.Immunohistochemical method was used to test the ratio of?-h2ax positive cells to evaluate the degree of DNA damage of tumor cells.Unisense oxygen microelectrodes were used to measure the partial oxygen pressure of tumor tissues directly,and compare the hypoxic status of tumor tissues in each experimental group.PET/CT of small animals evaluated tumor metabolism by detecting 18 FDG uptake(T/M).Results:At the end of the treatment,the growth of tumor in each treatment group was inhibited.In the control group,the group of apatinib group,the single radiotherapy 12gy group,and the single radiotherapy 18gy group were generally healthy,and the diet,drinking water and defecate were normal,and there was no obvious weight loss and decreased subcutaneous fat.Apatinib+12gy radiotherapy group,apatinib+18gy radiotherapy group nude mice showed a transient emaciation and poor mental health,but during the experiment,the mice were able to tolerate the death of nude mice without the occurrence of nude mice.The tumor growth was the fastest in the blank control group,and the tumor volume of the 18th day was about 2042 mm~3,and its growth rate was significantly faster than that of the other groups.The difference was statistically significant(P<0.05).The inhibition effect of single radiotherapy 18gy on the tumor was stronger than that of single radiotherapy12gy,and the difference was statistically significant(P<0.05).The inhibitory effect of apatinib+12gy radiotherapy group on tumor growth was stronger than that of single apatinib and single radiotherapy in 12gy group,and the difference was statistically significant(P<0.05).The inhibitory effect of apatinib+18gy radiotherapy group on tumor growth was stronger than that of single apatinib and single radiotherapy in 18gy group,and the difference was statistically significant(P<0.05).The tumor inhibition rate of apatinib group,12gy group,18gy group,apatinib+12gy group and apatinib+18gy group was 33.3%,61.5%,79.3%,85.9%and 92.8%respectively.The inhibition rate of apatinib+radiotherapy for tumor was higher than that of single apatinib or alone radiotherapy group,and the difference was statistically significant(P<0.05).The combined effect of apatinib+12gy was 1.156,and its Q value was>1.15,indicating the synergistic effect of apatinib combined with single 12gy radiotherapy.The combined effect of apatinib+18gy was 1.077,and its Q value was between 0.85 and 1.15,indicating that the therapeutic effect of apatinib combined with single 18gy radiotherapy was the addition of two therapeutic methods.Both of the combined treatment group Q values were>0.85,indicating the synergistic effect of apatinib combined with radiotherapy in the treatment of nasopharyngeal carcinoma.The tumor metabolism of tumor tissues in the blank control group was significantly higher than that in the other treatment groups,and the difference was statistically significant(P<0.05).The tumor metabolism of tumor tissues in 18gy group was lower than that in the single radiotherapy 12gy group,and the difference was statistically significant(P<0.05).The tumor metabolism in the apatinib+12gy group was lower than that of the single apatinib and the single 12gy radiotherapy group,and the difference was statistically significant(P<0.05).The tumor metabolism in the apatinib+18gy group was lower than that of the individual apatinib and the single 18gy radiotherapy group,and the difference was statistically significant(P<0.05).The partial oxygen pressure of the blank control group was significantly higher than that of the other groups,and the difference was statistically significant(P<0.05).The partial oxygen pressure of the tumor tissues in the single radiotherapy 18gy group was lower than that in the single radiotherapy group of 12gy group,and the difference was statistically significant(P<0.05).The partial oxygen pressure of the tumor tissues of the apatinib+12gy group was lower than that of the single apatinib and the single12gy radiotherapy group,and the difference was statistically significant(P<0.05).The partial oxygen pressure of the tumor tissue of apatinib+18gy group was lower than that of the single apatinib and the single 18gy radiotherapy group,and the difference was statistically significant(P<0.05).The proportion of VEGFR-2 positive cells was the highest in the blank control group,and the difference was statistically significant compared with other groups(P<0.05).The proportion of VEGFR-2 positive cells in the apatinib+12gy group were lower than the single apatinib and the single 12gy radiotherapy group,and the difference was statistically significant(P<0.05).The proportion of VEGFR-2positive cells in the apatinib+18gy group were lower than the single apatinib and the single 18gy radiotherapy group,and the difference was statistically significant(P<0.05).The microvascular density of tumor tissue was the highest in the blank control group,and the difference was statistically significant(P<0.05)compared with other groups.The microvascular density of the tumor tissue in the apatinib+12gy group was lower than that of the single apatinib and the single 12gy radiotherapy group,and the difference was statistically significant(P<0.05).The microvascular density of the tumor tissue in the apatinib+18gy group was lower than that of the individual apatinib and the single 18gy radiotherapy group,and the difference was statistically significant(P<0.05).The proportion of?-h2ax positive cells in the tumor tissues in the blank control group was the lowest,which was statistically significant compared with the other groups(P<0.05).The proportion of positive cells in the single 18gy radiotherapy group was higher than that in the single 12gy radiotherapy group,and the difference was statistically significant(P<0.05).The proportion of?-h2ax positive cells in the apatinib+12gy group was higher than that of the single apatinib and the single 12gy radiotherapy group,and the difference was statistically significant(P<0.05).The proportion of?-h2ax positive cells in apatinib+18gy group was higher than that of the single apatinib group and the single 18gy radiotherapy group,and the difference was statistically significant(P<0.05).Conclusion:1.Apatinib has anti-tumor effect on the model of xenograft tumor of CNE-2 nasopharyngeal carcinoma,and has synergistic anti-tumor effect when combined with radiotherapy.2.The anti-tumor effect of apatinib is mainly achieved by reducing the effective expression of VEGFR-2,reducing tumor tissue microvascular density,causing tumor tissue DNA damage,reducing tumor tissue partial oxygen pressure,and reducing tumor metabolism.3.Apatinib combined with radiotherapy can significantly reduce the effective expression of VEGFR-2,reduce tumor tissue microvascular density,promote tumor tissue DNA damage,reduce tumor tissue partial oxygen pressure,and reduce tumor metabolism.4.When apatinib combined with radiotherapy for CNE-2 nasopharyngeal carcinoma of the nude mouse model,either alone or combined treatment,the adverse reactions were tolerable. |
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