Hui-Ming Chang, Jinn-Yuan Hsu, Chul Ahn, Edward T H Yeh
{"title":"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。","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":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>Twenty-five healthy female volunteers received an intravenous infusion of dexrazoxane at doses ranging from 100 mg/m<sup>2</sup> to 500 mg/m<sup>2</sup>. 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.</p><p><strong>Results: </strong>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<sup>2</sup> and 500 mg/m<sup>2</sup> groups (p = 0.005). However, topoisomerase 2a (Top2a), the molecular target of doxorubicin's tumor-killing effect, remained unchanged following dexrazoxane infusion.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Trial registration: </strong>(Funded by the National Institute of Health, RO1HL151993; PHOENIX trials, ClinicalTrials.gov number, NCT03930680.).</p>","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":"{\"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\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>Twenty-five healthy female volunteers received an intravenous infusion of dexrazoxane at doses ranging from 100 mg/m<sup>2</sup> to 500 mg/m<sup>2</sup>. 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.</p><p><strong>Results: </strong>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<sup>2</sup> and 500 mg/m<sup>2</sup> groups (p = 0.005). However, topoisomerase 2a (Top2a), the molecular target of doxorubicin's tumor-killing effect, remained unchanged following dexrazoxane infusion.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Trial registration: </strong>(Funded by the National Institute of Health, RO1HL151993; PHOENIX trials, ClinicalTrials.gov number, NCT03930680.).</p>\",\"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}","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}
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/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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