| Ovarian cancer is the third most common pelvic cancer and the leading cause of death from gynecologic malignancies, which is threatening the female health severely. Approximately 70%~80% of patients have been diagnosed as advanced stages with wide dissemination and implantation of abdominal cavity and massive ascites, which made it difficult to cure by means of just surgery, so chemotherapy is one of the most important therapeutic ways. Nowadays, the first-line treatment of epithelial ovarian cancer patients with platinum-based combination chemotherapy in our country hasn't improved the long-term survival but usually results in severe adverse effects and chemotherapeutic resistance. Therefore, new effective and subtoxic therapeutic modalities are needed.Arsenic is an ancient agent. Arsenic trioxide has been used successfully in the treatment of patients with acute promyelocytic leukemia(APL) who relapsed after initial therapy with chemotherapy and all-trans retinoic acid and symbolizes the new milestone of malignant tumor therapy and stirs up the hot spot for antitumor effect of As2O3 in the world. Although the mechanism of antileukemia effect of As2O3 is well understood, there has been few reports regarding the effect of As2O3 on solid tumors, especially on ovarian cancer. The combined anti-ovarian-carcinoma effect of As2O3 and cisplatin(DDP) has no reports in the world. In this study, three parts were divided to explore the antitumor effect of As2O3 in combination with DDP and the molecular mechanisms of them on the effect of cell adhesion,metastasis and angiogenesis of human ovarian cancer cell line. The aim was to provide experimental data for therapy of ovarian cancer and clinical application of As2O3.Part I:Objective:To study the combined effect of arsenic trioxide(As2O3) and cisplatin(DDP) on the cell proliferation,cell cycle and apoptosis in human ovarian carcinoma cell line SKOV3 cells. Methods:MTT assay was used to analyze the effect of As2O3 and DDP administered alone or in combination on the growth of SKOV3 cells.Inverted phase-contrast microscopy,transmission electron microscopy and flow cytometry were used to observe the cells changes in morphology,cell cycle and apoptosis. Results:alone or in combination As2O3 and DDP could inhibit the growth of SKOV3 cells in a time- and dose-dependent fashion.There were synergistic effects of As2O3 and DDP while the inhibitory rates were less 85 percent.SKOV3 cells could be induced arrest in G2/M phase by As2O3 ,S and G2/M phase by DDP and the similar arrest to DDP but more significant by As2O3 and DDP combination. SKOV3 cells presented some typical morphologic features of apoptosis after 36 hours exposure to alone or in combination As2O3 and DDP.Conclusion: As2O3 and DDP combination could increase the effects of proliferation inhibition and cycle arrest induction, and manifestate a synergistic effect in a wide concentration range.Part II:Objective:To explore the effect and the related mechanism of As2O3 and DDP alone or in combination on the SKOV3 cells adhesion and metastasis. Methods:Cells adhesive capacity was determined after 48 hours exposure to As2O3 and DDP alone or in combination. Immunocytochemical staining was used to examine the expression of CD44v6,E-cadherin and Matrix metalloproteinase-2(MMP2) of these cells. Results: As2O3 and DDP alone or in combination could inhibit SKOV3 cells adhesion in a dose-dependent fashion, and the inhibitory effect was more significant in the combined group. As2O3 could slightly upgrade the expression of E-cadherin and significantly downregulate the expression of CD44v6. The combined group was more striking in changing the expression of CD44v6. MMP2 could be decreased by As2O3 and DDP with no relation to concentration. Conclusion: As2O3 could decrease the cell adhesion capacity and inhibit tumor metastasis through downregulating expression of CD44v6 and MMP2, even upgrading E-cadherin expression. As2O3 and DDP combination could manifestate a better anti... |
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