Effect of low-dose metronomic chemotherapy with cisplatin on nude mice bearing human epithelial ovarian cancer and the xenograft tumors / 肿瘤

ABSTRACT

Objective: To investigate the impact of low-dose metronomic chemotherapy (LDM) and maximum tolerated dose chemotherapy (MTD) with cisplatin on BALB/c nude mice bearing human ovarian cancer and the xenograft tumors of SKOV3 cells, and to explore the influence of these two chemotherapeutic protocols on expression levels of breast cancer resistant protein (BCRP), lung resistance protein (LRP) and tumor stem cell marker CD133. Methods: The human ovarian cancer SKOV3 cells were used to establish BALB/c nude mice model bearing subcutaneous tumor xenografts. Thirty-six mice were randomly divided into three groups: control group (n = 12), LDM group (n = 12) and MTD group (n = 12). The general situation of nude mice and the growth of tumor xenografts were observed during chemotherapy, and the tumor inhibition rate was calculated. The expression levels of BCRP, LRP and CD133 proteins in tumor xenografts in nude mice were detected by Western blotting. The small metastatic lesions in internal organs and the pathological feature of tumor xenografts were observed by hematoxylin-eosin (HE) staining. Results: The volume of tumor xenografts of MTD and LDM groups were significantly smaller than that of the control group (P < 0.05), while the tumor volume of LDM group was significantly smaller than that of MTD group. The tumor inhibition rates of MTD group and LDM group were 27.00% and 54.29%, respectively. The body weight and food-intake of mice in MTD group and LDM group were both significantly lower than those in the control group (all P < 0.05). As compared to LDM group and the control group, white blood cell (WBC) count in MTD group was lower (P < 0.05). Hepatocellular fatty degeneration was observed in two mice in MTD group. The expression levels of BCRP, LRP and CD133 proteins in tumor xenografts in MTD group and LDM group were significantly higher than those in the control group (all P < 0.05), while the BCRP and CD133 protein expression levels in LDM group were lower than those in MTD group. Conclusion: LDM can lead to greater tumor growth inhibition and less bone marrow suppression as compared with MTD, at the same total cumulative dose. Tumor cells with partial tumor stem cell properties and high expression levels of drug resistance-related proteins were easier to be enriched in MTD model. LDM is a new potential therapeutic mode which may reduce tumor recurrence and increase the sensitivity to chemotherapy.