Optimizing dose selection for doxorubicin-induced cardiotoxicity in mice: A comprehensive analysis of single and multiple-dose regimens

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.