Mucinous adenocarcinoma of the ovary (MAC), the third most common type of epithelial ovarian cancers (EOC) comprising 10-12% of EOC, appears to have a distinctly different clinical behavior from that of other EOC. MAC has a very poor prognosis (median survival, 14.8 months in advanced disease), in part because of its resistance to conventional platinum- or taxane-based chemotherapy. Hence, a novel treatment strategy for advanced MAC is urgently necessary. We conducted the present study to identify an effective chemotherapy for MAC. Five human MAC cell lines (MN-1, OMC-1, RMUG-L, RMUG-S, and TU-OM-1) were used in this study. The sensitivity of the cells to cisplatin (CDDP), 5-fluorouracil (5FU), oxaliplatin (L-OHP), paclitaxel (PTX), etoposide (VP-16), or 7-ethyl-10-hydroxycamptothecin (SN-38), which is an active metabolite of camptothecin was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and we assessed drug sensitivity by calculating the assay area under the curve (AUC) for each agent. Median-effect plot analyses and calculation of the combination index (CI) were analyzed by the method of Chou and Talalay. The protein expression was confirmed by western blot analysis, and apoptosis was assessed by annexin V staining. We also examined the efficacy of combination chemotherapy on survival in a xenograft model of nude mice. The IC50s ranged from 3.78 to 49.78 \#956;M for CDDP, from 0.68 to 29.27 \#956;M for 5FU, from 2.21 to 39.58 \#956;M for L-OHP, from 0.29 to 0.83 \#956;M for PTX, from 0.02 to 4.18 \#956;M for SN-38, and from 0.31 to 0.65 \#956;M for VP-16 indicating that these cell lines showed various sensitivities to anticancer agents. When the assay AUC was compared with clinically achievable AUC with a standard dose of each drug, 2 of 5 cell lines (MN-1 and TU-OM-1) were defined as sensitive to L-OHP, 5FU, or VP-16 and only one (TU-OM-1) was sensitive to SN-38. All cell lines were resistant to CDDP and PTX. The combination of L-OHP and 5FU resulted in additive or synergistic effects on all cell lines. The number of apoptotic cells also increased additively after treating with L-OHP and 5FU in all cell lines. Furthermore, the combination of L-OHP and 5FU significantly prolonged survival in a MAC xenograft model of nude mice (median survival, 188 days for L-OHP with 5FU treatment, 83days for PBS treatment, 96 days for 5FU treatment, and 124 days for L-OHP treatment). Among DNA repair proteins, the expression levels of the excision repair cross-complementation group 1 (ERCC1) were lower in L-OHP sensitive cells. Moreover, exposure to 5FU downregulated ERCC1 expression in MAC cells.These results indicate thatcombination chemotherapy consisting of L-OHP and 5FU was an effective treatment and may be a pivotal candidate for a novel treatment strategy for MAC.
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4580.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO