| Objective:Ovarian epithelial cancer is one of the most common genital malignant tumors for female patient. The first-line chemotherapy regimen of epithelial ovarian cancer is paclitaxel combined with platinum. When the first-line chemotherapy failure, there is no accepted and standard chemotherapy regimens in the second-line and above.Vascular-targeted therapies draw more and more attention in the treatment of epithelial ovarian cancer. A successful xenotransplantation model of an human epithelial ovarian cancer cell line (Skov3) was established in nude mice. Apatinib was used to verify the therapeutical effect of epithelial ovarian cancer.Methods:Human epithelial ovarian cancer cell line Skov3 was cultivated. Logarithmic growth Skov3 was injected into the subcutaneous tissue of BALB/c-nu female nude mice (SPF level, 4 to 6 weeks old) . A successful xenotransplantation model of Skov3 was established after 3 weeks. 15 nude mice with similar tumor volume were randomly divided into 3 groups. The blank control group (n=5) was untreated. The Bevacizumab group (n=5) was injected with Bevacizumab (5mg/kg) once every 3 days through intraperitoneal. The Apatinib group (n=5) was treated with Apatinib(100mg/kg) once a day through gavage.To examine inhibitory effects of the growth of transplanted tumor, tumor volume was estimated once every three days, and the rate of relative tumor growth was calculated once every three days too. Treatments continue for 14 days. The transplanted tumors were excised, and the blood were collected at 24 hours after completion of the last treatment. CD31, VEGFR-2 and PDCL3 were marked by immunofluorescent staining in paraffin-embedded tumor tissues. The level of CA125 were detected by ELISA in the serum.Results:Analysis of variance of repeated measures indicated that the differences of tumor volume were significant among different time (F=35.526, P<0.001). There are significant interactive effects for time and therapeutic regimen (F=4.189, P=0.029).The differences of tumor volume were also significant among different therapeutic regimens (F=4.017, P=0.046). When comparing with every point of time, there were significant differences in tumor volumes (P<0.05). The result of one-way analysis of variance indicated that the tumor volumes growth were slowing down in two treatment groups (F=3.005, P=0.088). Tumor volumes showed significant difference at the 9th,12th and 15th day after treatment in three groups (F=4.343,P=0.038; F=4.061,P=0.045; F=4.495, P=0.035). The result of LSD-t test showed that to compare with Bevacizumab group or apatinib group, blank control group had bigger volume at the 9th, 12th and 15th day (P< 0.05). But there was no statistical difference between Bevacizumab group and apatinib group (P > 0.05). In Bevacizumab group,T/C(%) is 93.06, 83.61,72,80, 68.55 and 68.38 at the 3rd,6th,9th,12th and 15th day. In apatinib group,T/C(%) is 93.52, 84.29, 75.16, 73.96 and 72.59 at the 3rd, 6th, 9th, 12th and 15th day.After receiving the specified treatment for 14 days, the MVD counts was less significant in the Bevacizumab group (Z=2.570, P=0.010) and the Apatinib group(Z=2.797,P=0.005) than the blank control group. The total area of wall of micrangium was also less significant in the Bevacizumab group (Z=2.948, P=0.003)and Apatinib group (Z=2.948, P=0.003) than the blank control group. The differences between two treatment groups were not statistical significance.The difference in the value of average optical of VEGFR-2 among the three groups was significant (P<0.05). The value of average optical was higher than Bevacizumab group (63.92±12.40 vs. 53.00±13.39, P=0.008), and was higher than Apatinib group (63.92±12.40 vs. 52.72±12.01, P=0.009). The differences between two treatment groups were not statistical significance (53.00±13.39 vs. 52.72±12.01,P=0.944).In addition, the difference in the value of average optical of PDCL-3 among the three groups was significant (P<0.05). The value of average optical was less than Bevacizumab group (50.48± 12.01 vs. 57.73±10.97,P=0.032),and was less than Apatinib group (50.48±12.01 vs. 57.87±7.69,P=0.031). The differences between Bevacizumab group and Apatinib group were also not statistical significance(57.73±10.97 vs. 57.87±7.69, P=0.967).Compared with blank control group, the concentration of tumor marker CA125 tended to decrease in the serum of nude mice in Bevacizumab group and Apatinib group. But one-way analysis of variance revealed that no significant difference was found among three groups (F=2.610, P=0.085).Conclusions:1. Apatinib could inhibit human epithelial ovarian cancer cell line Skov3 growth in nude mice.2. Apatinib 100mg/kg QD and Bevacizumab 5mg/kg once every 3 days had similar inhibitory effect for transplanted Skov3 ovarian cancer tissue in nude mice.The relative tumor growth rate of above two therapeutic regimen was 72.59% and 68.38%,respectively.3. Apatinib could suppress expression of VEGFR-2, reduce the MVD in ovarian cancer tissue, its anti-angiogenic effect was similar to Bevacizumab in this experiment.4. Apatinib could have as much curative effect as Bevacizumab in nude mice with epithelial ovarian cancer.5. VEGF/VEGFR-2 pathway inhibition may lead to higher expression of PDCL3,which was a molecular chaperone, and could promote VEGFR-2 translation and folding. It may be a novel mechanism of secondary resistance for anti- angiogenesis therapy. But this experiment lacked of evidence, further studies are needed.6. After Apatinib treatment, the concentration of tumor marker CA125 tended to decrease in the serum of nude mice, with no statistical difference. |
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