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Chronic toxicity of methotrexate in mice
Journal of the National Cancer Institute
|March 1, 1977
Summary
Methotrexate (MTX) is tolerated by young mice at low doses, but higher doses cause severe damage. Older mice tolerate higher MTX doses and develop osteoporosis, offering a new research model.
Area of Science:
- Toxicology
- Pharmacology
- Animal Models
Background:
- Methotrexate (MTX) is a widely used chemotherapy and immunosuppressive drug.
- Long-term toxicity studies in animal models are crucial for understanding MTX side effects in humans.
- Previous studies have not fully elucidated the age-dependent toxicity of MTX.
Purpose of the Study:
- To investigate the long-term toxicity and tolerance of methotrexate in mice of different ages.
- To establish a potential animal model for studying MTX-induced osteoporosis.
Main Methods:
- Administration of varying doses of MTX (0.25-6 mg/kg) daily for 12-18 months to young (5-6 week old) and older (16 week old) mice.
- Clinical observation for survival and adverse effects.
- Histopathological examination of tissues, including lymphoid organs, testes, skin, and bone.
Main Results:
- Young mice tolerated low-dose MTX (0.25-2 mg/kg) with minimal toxicity.
- Higher MTX doses (3-6 mg/kg) in young mice caused acute hematopoietic and gastrointestinal damage, leading to mortality.
- Older mice survived higher MTX doses (3-6 mg/kg) for extended periods, exhibiting pronounced lymphoid tissue, testes, and skin depression.
- Osteoporosis was observed in older mice receiving MTX for ≥10 months.
Conclusions:
- Age significantly influences MTX tolerance and toxicity in mice.
- Long-term, high-dose MTX administration in older mice induces osteoporosis, creating a valuable preclinical model.
- This study highlights the importance of age in MTX treatment protocols and research.