EFFECT OF RECOMBINANT HUMAN TUMOR-NECROSIS-FACTOR-ALPHA AND DEQUALINIUM CHLORIDE ON HUMAN OVARIAN-CANCER CELL-LINES IN-VITRO

Due to preferential uptake and retention, the small molecular weight lipophilic, cationic antimicrobial agent dequalinium chloride (DECA) displays potent in vitro and in vivo antitumor activity against carcinoma cells. The primary mechanism of DECA activity is directed against the mitochondria where it disrupts cellular energy production. One of the direct antitumor effects of tumor necrosis factor (TNF) is also targeted against the mitochondria. The ability of DECA to synergize this effect was examined in vitro against a panel of human ovarian cancer cell lines. The data from single agent and combined drug exposure were analyzed by the isobologram methods of Tsai et al (Cancer Res 49: 2390-2397, 1989). We demonstrate that TNF and DECA strongly synergize in vitro at clinically achievable doses for TNF and potentially clinically achievable doses for DECA. The degree of synergy varied with the cell line tested with UCI-101 being the least responsive and PA-1 cells displaying the greatest synergistic effect. DECA treatment also prolonged animal survival in mice bearing the PA-1 intraperitoneal ovarian carcinoma xenograft. Single agent DECA (5 mg/kg; qod) increased animal survival by 37% (p=0.002) whereas recombinant human TNF (0.5 mug/mouse; qod) increased survival by 12% (p=0.27) in those animals treated 3 days post tumor injection. Sequential DECA/TNF enhanced animal survival by 45% (p=0.0002) in similarly treated animals. DECA, as a mitochondrial poison is an agent capable of potentiating the effects of tumor necrosis factor against ovarian cancer cell lines.