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.

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/m(2) to 500 mg/m(2). 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/m(2) and 500 mg/m(2) 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.).