The Effect Of Tamoxifen And Medroxyprogesterone On The Growth Of Cisplatin-resistant Human Epithelial Ovarian Cancer Cell Line SKOV-3/DDP

Ovarian carcinoma is one of the most common fatal gynecologic malignancies in the world. It is diagnosed in an advanced state and is high in mortality. Ovarian carcinoma is current treated with cytoreductive surgery and cisplatin-basted combination chemotherapy. But patients whose tumor was resistant to cisplatin-basted chemotherapy have a poor 5-year survival and only approximate 30% 5-year survival.In recent years, the fact that ovarian carcinoma is a hormones-dependent tumor has been proved with epidemiology and experiment research. Hormones are important to etiologic factor and adjuvant therapy of ovarian tumor. The research found that estradiol and medroxyprogesterone at high concentrations could inhibit the growth of OVACAR-3 cell line and could reverse the doxorubin resistance of OVACAR-3 cell line. But which effect is it that hormones inhibit the growth of cisplatin-resistant human epithelial ovarian cancer cell line? This article is rare. Tamoxifen which is an estrogen receptor antagonist could inhibit the growth of tumor cell by competition to receptor with estrogen. Medroxyprogesterone could inhibit the growth of ovarian tumor cell including ER and PR by PR. The article's objective are 1. to study the effects of tamoxifen and medroxyprogesterone on the growth of cisplatin-resistant human epithelial ovarian cancer cell line SKOV-3/DDP and to discuss their mechanisms. 2. to study the effects of tamoxifen and medroxyprogesterone on the growth of human epithelial ovarian cancer cell line SKOV-3/DDP involving a novel mutation of ER transcripts.Methods SKOV-3/DDP cells were treated with different concentrations tamoxifen and medroxyprogesterone. 1. The inhibition of SKOV-3/DDP cell growth was measured by methyl thiazolyl tetrazolium(MTT) rapid photocolorimetric assay. 2.The morphological change of cell was observed by electron microscopy. 3. Cell cycle and apoptotic percentage were accounted by flow cytometry.Results 1. SKOV-3/DDP cell growth was inhibited by tamoxifen at high concentration (1 × 10-6-1 × 10-4mol/L) in a dose-dependent manner (P<0.01) .Low concentration (1× 10-10~1 × 10-7mol/L) of tamoxifen had no effect on SKOV-3/DDP cell growth. With the high concentration (1×10-6-1×10-4mol/L) of tamoxifen, G0/G1 arrest of SKOV-3/DDP cell was enhanced. With the higher concentration of tamoxifen (1×10-5, 1×10-4mol/L) ,the apoptotic peak and percentage was enhanced. 2. Every concentration (1×10-10~1 ×10-4mol/L) of medroxyprogesterone had no effect on SKOV-3/DDP cell growth (P>0.05) . 3. SKOV-3/DDP cell growth was inhibited by tamoxifen combined with medroxyprogesterone at high concentration (1×10-6~1× 10-4mol/L) (P<0.01) .Low concentration (1×10-10-1X 10-7mol/L) of them had no effect on SKOV-3/DDP cell growth (P>0.05 ) . The effect of tamoxifen combined with medroxyprogesterone was more obvious than tamoxifen used separately (P<0.05 ) . 4. After SKOV-3/DDP cells were treated with tamoxifen at 1×10-7mol/L concentration in 24h, high concentration (1×10-5~1×10-4mol/L) of medroxyprogesterone inhibited the growth of SKOV-3/DDP cells. The inhibitory effect of medroxyprogesterone was significantly blocked by mifepristone which is an progesterone receptor antagonist. Conclusions1. Tamoxifen inhibits the growth of SKOV-3/DDP cells involving a novel mutation of ER transcripts by a receptor-independent mechanism.2. The inhibitory effect of medroxyprogesterone on the growth of SKOV-3/DDP cells requires association ER with PR fuctionally.3. The present study suggests that a potential interaction between the anti-E/ER and P/PR systems could be important in the growth regulation of SKOV-3/DDP cells by tamoxifen and medroxyprogesterone.4. Tamoxifen and medroxyprogesterone with the inhibitory effect on the growth of cisplatin-resistant ovarian cancer cells and the minor ill effect could be used to ovarian cancer patients as an adjuvant therapy.