title: Failure to enhance the in vivo killing of human ovarian carcinoma by sequential treatment with dequalinium chloride and tumor necrosis factor.
abstract: Dequalinium chloride (DECA) is a cationic, lipophilic compound with structure similar to the dye rhodamine 123. DECA is selectively accumulated and retained within the mitochondria of carcinoma cells where it acts as a mitochondrial poison by blocking mitochondrial enzymes which can then disrupt cellular energy production, eventually resulting in cell death. In this manner it is similar to the antimitochondrial effects observed with tumor necrosis factor (TNF). We have previously shown that DECA can synergize the in vitro antitumor effects of TNF against a panel of human ovarian cancer cell lines. Those drug studies have been extended to a xenogenic tumor system with a resultant increase in animal survival. Athymic mice were injected intraperitoneally with 2.0 x 10(7) PA-1 human ovarian cancer cells and DECA +/- TNF treatments begun either on Days 3 or 7 postinjection. Peritoneal tumor implantation was not histologically confirmed by Day 3 postinjection but confirmed by Day 7 following tumor cell injection. Single-agent DECA (5 mg/kg; qod) increased animal survival by 37% (P = 0.002) whereas recombinant human TNF (0.5 micrograms/mouse; qod) only increased survival by 13% (P = 0.27) relative to control animals for those animals treated 3 days post-tumor-injection. Sequential DECA/TNF enhanced animal survival by 45% (P = 0.0002) in similarly treated animals. When drug treatment was initiated 7 days following tumor injection, DECA increased survival by 23% (P = 0.04) while TNF had no effect on prolonging animal survival (3% increase; P = 0.79). Combination DECA/TNF increased survival by 23% (P = 0.04). In the UCI-101 ovarian tumor model, single-agent DECA increased survival by 28% (P = 0.04) while TNF treatment stimulated tumor growth (11% decrease in survival; P = 0.006). Combination DECA + TNF resulted in a 41% increase in survival (P = 0.003). No statistical differences were detected between survival rates for single-agent DECA vs DECA + TNF except for the UCI-101 tumor which showed potentiation due to the in vivo stimulatory effects of TNF.
authors.affiliation: Department of Obstetrics and Gynecology, University of California, Irvine, Orange 92668.
authors.forename: A
authors.initials: A
authors.lastname: Manetta
authors.forename: D
authors.initials: D
authors.lastname: Emma
authors.forename: G
authors.initials: G
authors.lastname: Gamboa
authors.forename: S
authors.initials: S
authors.lastname: Liao
authors.forename: M
authors.initials: M
authors.lastname: Berman
authors.forename: P
authors.initials: P
authors.lastname: DiSaia
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000188:drug therapy* / Q000401:mortality; D003868:Dequalinium / Q000627:therapeutic use*; D004338:Drug Combinations; D004357:Drug Synergism; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000401:mortality; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*
chemical_list: D004338:Drug Combinations; D014409:Tumor Necrosis Factor-alpha; D003868:Dequalinium