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Acute toxicity of maytansine in F344 rats
Abstract:
The toxicity of maytansine given by sc administration was studied in 5-week-old mald F344 rats. The LD50 (14-day) was 0.48 mg/kg. A dose response to drug administration was indicated by body weight changes and diarrhea. A single, acutely toxic dose of maytansine was shown to possess marked activity against dividing cells which was regarded as an important factor in the pathogenesis of acute lesions in tissues with a normal high rate of cell division. Histologically, mitotic figues were observed in many tissues from 6 to 24 hours after drug administration. Subsequently, necrotizing lesions led to atrophic changes in gastrointestinal tract mucosa, thymus, spleen, bone marrow, and testis. Maytansine also induced hemorrhagic lesions in parenchymatous organs and brain and perivascular monomuclear infiltration in the meninges, and chromatolysis and vacuolation of dorsal root ganglion cells, accompanied by clinical signs of ataxia. Ulcerative skin lesions were observed at the sc site of drug administration.
Insights
Maytansine is toxic to rats, with a 14-day LD50 of 0.48 mg/kg. This potent anti-mitotic agent causes cell damage in rapidly dividing tissues, leading to organ damage and neurological signs.
Area of Science:
- Pharmacology
- Toxicology
- Cell Biology
Background:
- Maytansine is a potent antimitotic agent.
- Understanding its toxicity is crucial for potential therapeutic applications and safety assessments.
Purpose of the Study:
- To determine the toxicity profile of maytansine following subcutaneous administration in rats.
- To investigate the dose-response relationship and identify target organs.
Main Methods:
- Subcutaneous administration of maytansine to 5-week-old male F344 rats.
- Determination of the 14-day lethal dose 50 (LD50).
- Histopathological examination of tissues and clinical observation.
Main Results:
- The 14-day LD50 was determined to be 0.48 mg/kg.
- Dose-dependent effects included body weight loss and diarrhea.
- Maytansine induced mitotic arrest and subsequent necrotizing and atrophic lesions in the gastrointestinal tract, thymus, spleen, bone marrow, and testes.
- Hemorrhagic lesions, neurotoxicity (ataxia, chromatolysis, vacuolation), and local skin reactions were observed.
Conclusions:
- Maytansine exhibits significant toxicity in rats, primarily targeting rapidly dividing cells.
- The observed pathological changes highlight the potential for severe systemic toxicity and localized effects at the administration site.