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Toxicity of the mitochondrial poison dequalinium chloride in a murine model system
G Gamboa-Vujicic1, D A Emma, S Y Liao
1Department of Obstetrics and Gynecology, University of California, Irvine 92668.
Abstract:
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)
Insights
Dequalinium chloride (DECA) exhibits toxicity in mice, with a maximum tolerated dose of 15 mg/kg and an LD50 of 18.3 mg/kg after single administration. Cumulative dosing showed varying tolerance levels, with higher doses causing severe effects.
Area of Science:
- Pharmacology
- Toxicology
- Oncology
Background:
- Dequalinium chloride (DECA) is a cationic, lipophilic mitochondrial poison targeting epithelial carcinoma cells.
- DECA inhibits cellular energy production and shows potential as a cytotoxic agent for cancer therapy.
Purpose of the Study:
- To determine the acute and subchronic toxicity of DECA in a murine model (BALB/c mice).
Main Methods:
- Mice were divided into three groups receiving single, every-other-day (QOD), or weekly intraperitoneal (ip) doses of DECA.
- Toxicity was evaluated over 30–60 days based on respiratory distress, weight loss, and mortality.
- Histologic examination assessed liver, kidney, and lung tissues.
Main Results:
- Single ip administration: Maximum tolerated dose (MTD) was 15 mg/kg; LD50 was 18.3 mg/kg. Doses of 20 and 25 mg/kg caused >50% mortality.
- Cumulative dosing: 60% tolerated 15 QOD doses of 6-7 mg/kg; 100% tolerated 5 weekly doses of 11-12 mg/kg.
- Histology revealed significant liver and kidney damage, with pulmonary congestion secondary to renal-hepatic failure.
Conclusions:
- DECA exhibits dose-dependent toxicity in mice, affecting liver, kidneys, and lungs.
- Specific dosing schedules and cumulative exposure influence DECA's toxic effects and tolerance.
- Further research is needed to establish safe and effective therapeutic windows for DECA in cancer treatment.