Antiprogestin mifepristone improves the efficacy of the combination therapy cisplatin/paclitaxel in human ovarian carcinoma cells in vitro.

GAMARRA LUQUES C, HAPON MB, GOYENECHE AA, TELLERIA CM

Orlando, Florida

Congreso; 102nd Annual Meeting of American Association for Cancer Research (AACR); 2011

American Association for Cancer Research (AACR)

Ovarian Cancer (OCa) is the second most common gynecologic malignancy and the leading cause of gynecologic cancer-related deaths in the developed world. The main reason for its poor prognosis is that the majority of cases are diagnosed at advanced stages. Optimal management of advanced OCa involves accurate surgical staging and cytoreductive surgery followed by combination cisplatin (CDDP)/paclitaxel (PTX) therapy. In most patients acute clinical response is reached after this chemotherapeutic strategy, yet the disease eventually recurs with a median survival time of about only 2 yr. Thus, new therapeutic approaches to overcome the limitation of CDDP/PTX therapy for OCa patients are greatly needed. Our laboratory previously demonstrated that antiprogestin mifepristone (MF; RU486) inhibits growth of OCa cells in vitro and in vivo. We also found that MF improves the efficacy of CDDP therapy in OCa cells. In the present study we questioned whether antiprogestin MF was able to improve the efficacy of CDDP when the platinating agent is combined with PTX. We exposed OCa cells of different genetic backgrounds (OV2008, A2780, IGROV-1, and SKOV-3) to clinically relevant, achievable doses and exposure times of 20 ìM CDDP for 1 h, followed by 100 nM PTX for 3 h. Next, the cells were maintained in media with or without 10 ìM MF. The acute lethality of CDDP/PTX was evidenced 4 days after treatment with reduced number of cells, and increased hypodiploid DNA content, morphological features of apoptosis, DNA fragmentation, and cleavage of executer of apoptosis, caspase-3 and of its downstream substrate PARP. Adding MF to the combination CDDP/PTX did not antagonize this acute lethality, but rather slightly potentiated its effect. Seven days after initial chemotherapy, all cultures treated with CDDP/PTX show signs of relapse with escaping colonies that begin to repopulate the culture plate. Such regrow was time-dependent, increasing substantially 14 and 21 days after initial chemotherapy. When cell growth was analyzed by drug-interaction software 7 days following CDDP/PTX, or CDDP/PTX plus MF treatment, isobolograms clearly demonstrate that MF synergizes with the combination CDDP/PTX. Remarkably, all cultures that had been exposed to CDDP/PTX plus MF do not show signs of repopulation neither after 7, 14 or 21 days following initial chemotherapy. Further, the clonogenic capacity of the cells remaining after CDDP/PTX/MF treatment was drastically reduced when compared to that of cells repopulating after CDDP/PTX, suggesting that MF potentiates CCDP/PTX-induced lethality. Altogether, this work supports the concept that antiprogestin MF can be used for chronic non-toxic maintenance therapy following cytotoxic standard CDDP/PTX chemotherapy to improve treatment efficacy and to expand disease-free survival in patients with minimal residual disease.