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 l ipophilic, cationic antimicrobial agent dequalinium chloride (DECA) di splays potent in vitro and in vivo antitumor activity against carcinom a cells. The primary mechanism of DECA activity is directed against th e mitochondria where it disrupts cellular energy production. One of th e direct antitumor effects of tumor necrosis factor (TNF) is also targ eted against the mitochondria. The ability of DECA to synergize this e ffect was examined in vitro against a panel of human ovarian cancer ce ll lines. The data from single agent and combined drug exposure were a nalyzed by the isobologram methods of Tsai et al (Cancer Res 49: 2390- 2397, 1989). We demonstrate that TNF and DECA strongly synergize in vi tro 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 dis playing the greatest synergistic effect. DECA treatment also prolonged animal survival in mice bearing the PA-1 intraperitoneal ovarian carc inoma xenograft. Single agent DECA (5 mg/kg; qod) increased animal sur vival by 37% (p=0.002) whereas recombinant human TNF (0.5 mug/mouse; q od) 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 necro sis factor against ovarian cancer cell lines.