Prevention of Heart Failure Induced by Doxorubicin with Early Administration of Dexrazoxane (PHOENIX Study): dose response and time course of dexrazoxane-induced degradation of topoisomerase 2b
Abstract Background Dexrazoxane, a putative iron chelator, is effective in preventing doxorubicin-induced cardiotoxicity. However, dexrazoxane is also a catalytic inhibitor of topoisomerase 2b (Top2b), a key mediator of doxorubicin toxicity. Preclinical studies have shown that dexrazoxane induces To...
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| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-05-01
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| Series: | Cardio-Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40959-025-00339-0 |
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| Summary: | Abstract Background Dexrazoxane, a putative iron chelator, is effective in preventing doxorubicin-induced cardiotoxicity. However, dexrazoxane is also a catalytic inhibitor of topoisomerase 2b (Top2b), a key mediator of doxorubicin toxicity. Preclinical studies have shown that dexrazoxane induces Top2b degradation, and early administration (8 h before doxorubicin) can prevent doxorubicin-induced cardiotoxicity. In this study, we investigated the dose–response relationship and time course of dexrazoxane-induced Top2b degradation in human volunteers. Methods Twenty-five healthy female volunteers received an intravenous infusion of dexrazoxane at doses ranging from 100 mg/m2 to 500 mg/m2. Blood samples were collected hourly from time zero to 12 h, as well as at 24- and 48-h post-infusion. Peripheral blood mononuclear cells (PBMCs) were isolated, nuclear fractions were extracted, and Top2b expression was analyzed by western blot using Lamin B1 as a control. A linear mixed-effects model was used to assess differences among the five dose groups. Results Dexrazoxane infusion led to a rapid and sustained reduction of Top2b in PBMCs, lasting up to 12 h. Statistical analysis revealed a significant difference in Top2b levels among the five dose groups (p = 0.0002). Subgroup analysis identified a significant difference between the 100 mg/m2 and 500 mg/m2 groups (p = 0.005). However, topoisomerase 2a (Top2a), the molecular target of doxorubicin’s tumor-killing effect, remained unchanged following dexrazoxane infusion. Conclusions Findings from this dose–response and time-course study can inform the design of future clinical trials investigating the efficacy of early dexrazoxane administration in preventing doxorubicin-induced cardiotoxicity while minimizing the risk of tumor protection. Trial registration (Funded by the National Institute of Health, RO1HL151993; PHOENIX trials, ClinicalTrials.gov number, NCT03930680.) |
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| ISSN: | 2057-3804 |