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.

IF 3.2 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS

Cardio-oncology Pub Date : 2025-05-02 DOI:10.1186/s40959-025-00339-0

Hui-Ming Chang, Jinn-Yuan Hsu, Chul Ahn, Edward T H Yeh

{"title":"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.","authors":"Hui-Ming Chang, Jinn-Yuan Hsu, Chul Ahn, Edward T H Yeh","doi":"10.1186/s40959-025-00339-0","DOIUrl":null,"url":null,"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.).","PeriodicalId":9804,"journal":{"name":"Cardio-oncology","volume":"11 1","pages":"42"},"PeriodicalIF":3.2000,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12046681/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cardio-oncology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1186/s40959-025-00339-0","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}

引用次数: 0

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.).

查看原文本刊更多论文

早期给予右拉唑烷预防阿霉素诱导的心力衰竭（PHOENIX研究）：右拉唑烷诱导的拓扑异构酶2b降解的剂量反应和时间过程。

背景：Dexrazoxane是一种公认的铁螯合剂，可有效预防阿霉素引起的心脏毒性。然而，dexrazoxane也是拓扑异构酶2b （Top2b）的催化抑制剂，Top2b是阿霉素毒性的关键介质。临床前研究表明，dexrazoxane可诱导Top2b降解，早期给药（比阿霉素早8小时）可预防阿霉素引起的心脏毒性。在本研究中，我们研究了右唑嗪诱导人体志愿者降解Top2b的量效关系和时间过程。方法：25名健康女性志愿者静脉输注右旋razoxane，剂量范围为100mg /m2 ~ 500mg /m2。从时间0到12小时，以及在输注后24和48小时，每小时采集一次血液样本。分离外周血单个核细胞（PBMCs），提取核组分，以Lamin B1为对照，western blot检测Top2b的表达。采用线性混合效应模型评估五个剂量组之间的差异。结果：Dexrazoxane输注导致PBMCs中Top2b快速持续下降，持续时间长达12 h。统计学分析显示，5个剂量组间Top2b水平差异有统计学意义（p = 0.0002）。亚组分析发现100 mg/m2组和500 mg/m2组之间存在显著差异（p = 0.005）。然而，拓扑异构酶2a (Top2a)，阿霉素杀伤肿瘤作用的分子靶点，在输注dexrazoxane后保持不变。结论：这项剂量反应和时间过程研究的结果可以为未来临床试验的设计提供信息，研究早期给药dexrazoxane在预防阿霉素诱导的心脏毒性方面的功效，同时将肿瘤保护的风险降至最低。试验注册：(由国家卫生研究所资助，RO1HL151993；PHOENIX试验，ClinicalTrials.gov号码，NCT03930680)。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊