Toxicity of the mitochondrial poison dequalinium chloride in a murine model system.
Dequalinium chloride (DECA), a cationic, lipophilic mitochondrial poison, selectively targets the mitochondrial membrane of certain epithelial carcinoma cells, in which it inhibits cellular energy production. It has demonstrated potency as a cytotoxic agent specific for carcinomas and may provide a novel approach for cancer therapy, either as a single agent or as an adjunct to conventional chemotherapy. The purpose of this study was to determine the toxicity of DECA in the murine model. One hundred female BALB/c mice were divided into three schedule groups. Group one received a single intraperitoneal (ip) dose of DECA at 10, 15, 20, or 25 mg/kg of body weight. Group two received DECA at 6, 7, 8, 9, or 10 mg/kg ip every other day (QOD), and group three received DECA at 10, 11, 12, 13, or 14 mg/kg ip every 7 days. Over a 30- to 60-day period, acute and subchronic toxicities were evaluated on the basis of the following clinical parameters: respiratory distress, weight loss, and mortality. After a single ip administration, we found a maximum tolerated dose of 15 mg/kg and a lethal dose (LD50) of 18.3 mg/kg. Single ip doses of 20 and 25 mg/kg produced > 50% mortality. Histologic examination of the tissues revealed significant damage to the liver and kidneys, with pulmonary congestion occurring secondary to renal-hepatic failure. A cumulative assessment revealed that 60% of the animals tolerated 15 doses of 6 and 7 mg/kg QOD and that 100% tolerated 5 doses of 11 and 12 mg/kg (every 7 days). Higher DECA doses under either regimen induced severe toxic effects and mortality.(ABSTRACT TRUNCATED AT 250 WORDS)
Gamboa-Vujicic
G
G
Department of Obstetrics and Gynecology, University of California, Irvine 92668.
Emma
D A
DA
Liao
S Y
SY
Fuchtner
C
C
Manetta
A
A
D000818:Animals; D003868:Dequalinium / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007928:Lethal Dose 50; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects; D008954:Models, Biological; D020112:Rhodamine 123; D012235:Rhodamines / Q000633:toxicity; D013997:Time Factors
D012235:Rhodamines; D020112:Rhodamine 123; D003868:Dequalinium