Key result
Dexrazoxane infusion dose-dependently cuts PBMC topoisomerase 2b by up to ~97% within one hour.
Why the study?
Preclinical studies showed early dexrazoxane administration prevents doxorubicin-induced cardiotoxicity by degrading Top2b, but the dose-response relationship and time course in humans were unknown.
Does early administration of dexrazoxane reduce Top2b expression in peripheral blood mononuclear cells in healthy female volunteers?
Does early administration of dexrazoxane reduce Top2b expression in peripheral blood mononuclear cells in healthy female volunteers?
Dexrazoxane rapidly and dose-dependently degrades Top2b in human PBMCs for up to 12 hours while sparing Top2a, providing a potential clinical window to prevent doxorubicin-induced cardiotoxicity without compromising its anti-tumor efficacy.
Provides mechanistic support for dexrazoxane cardioprotection; leaves open clinical efficacy in doxorubicin-treated patients.
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. 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. 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. 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. (Funded by the National Institute of Health, RO1HL151993; PHOENIX trials, ClinicalTrials.gov number, NCT03930680.)
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Chang et al. (2025) studied Healthy volunteers (n=25). Dexrazoxane vs. Baseline (pre-infusion) was evaluated on Normalized Top2b/Lamin B1 ratio (Hr/Pre) among five dose groups (p=0.0002). Dexrazoxane infusion led to a rapid, dose-dependent reduction of topoisomerase 2b in peripheral blood mononuclear cells to 3%-21% of baseline within one hour, lasting up to 12 hours.
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