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Optimizing dose selection for doxorubicin-induced cardiotoxicity in mice: A comprehensive analysis of single and
Min Li1, Yiyin Zhang1, Bohan Wu1
1Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China.
Objective:
To provide evidence-based dosing recommendations for doxorubicin (DOX)-induced acute and chronic cardiotoxicity models in mice.
Methods:
A systematic literature search was conducted in PubMed, Web of Science, CNKI, Wanfang, and VIP databases (January 2015-October 2024) for studies on DOX-induced cardiotoxicity in mice.
Results:
Analysis of 808 studies from 736 articles revealed 182 unique mouse models, including 21 single-dose and 161 multiple-dose regimens. For single-dose protocols, the most common administered doses were 10, 15, and 20 mg/kg. Cardiotoxicity was effectively induced at a single dose of 15-20 mg/kg, with higher mortality observed at 20 mg/kg compared with 15 mg/kg. For multiple-dose regimens, the most prevalent protocol is 5 mg/kg administered weekly for 4 weeks, accounting for 21.23 % of relevant studies. Besides, across different dosing intervals, the median single dose ranged from 2.5 to 5.5 mg/kg, given 3-6 times, with a median cumulative dose of 15-20 mg/kg. Notably, cumulative doses of 15-24 mg/kg reliably induced cardiac injury, but survival rates declined at doses ≥20 mg/kg.
Conclusion:
For acute cardiotoxicity, a single dose of 15 mg/kg is recommended. For chronic cardiotoxicity, two regimens are proposed: (a) the widely used 5 mg/kg weekly for 4 weeks, or (b) a flexible regimen of 2.5-5.5 mg/kg per dose, administered 3-6 times, with a cumulative dose of 15-20 mg/kg, adjustable based on experimental requirements.
Insights
This study provides evidence-based dosing guidelines for doxorubicin (DOX)-induced cardiotoxicity in mice. Recommended doses are 15 mg/kg for acute models and specific regimens for chronic models to ensure reliable induction and survival.
Area of Science:
- Pharmacology and Toxicology
- Cardiovascular Research
- Preclinical Models
Background:
- Doxorubicin (DOX) is a widely used chemotherapy agent with known cardiotoxic side effects.
- Establishing reliable mouse models of DOX-induced cardiotoxicity is crucial for preclinical research.
- Standardized dosing protocols are needed to ensure reproducibility and comparability across studies.
Purpose of the Study:
- To systematically review and synthesize evidence for optimal doxorubicin (DOX) dosing in mouse models of acute and chronic cardiotoxicity.
- To provide evidence-based recommendations for inducing reproducible cardiotoxicity in preclinical research.
- To identify dosing regimens that balance cardiotoxicity induction with acceptable survival rates.
Main Methods:
- Systematic literature search of multiple databases (PubMed, Web of Science, CNKI, Wanfang, VIP) from January 2015 to October 2024.
- Analysis of 808 studies from 736 articles to identify unique mouse models and dosing regimens.
- Evaluation of single-dose and multiple-dose protocols, including administered doses, frequency, cumulative doses, and observed outcomes (cardiotoxicity, mortality).
Main Results:
- 182 unique mouse models of DOX-induced cardiotoxicity were identified.
- For acute models, single doses of 15-20 mg/kg effectively induced cardiotoxicity, with 15 mg/kg showing lower mortality.
- For chronic models, a common regimen is 5 mg/kg weekly for 4 weeks, or flexible dosing (2.5-5.5 mg/kg per dose, 3-6 times) with a cumulative dose of 15-20 mg/kg.
Conclusions:
- A single dose of 15 mg/kg is recommended for acute doxorubicin (DOX)-induced cardiotoxicity in mice.
- For chronic cardiotoxicity, two regimens are proposed: a standard weekly protocol or a flexible cumulative dosing strategy.
- These recommendations aim to optimize the induction of cardiotoxicity while managing animal survival in preclinical studies.
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