Prevention of Heart Failure induced by Doxorubicin with Early Administration of Dexrazoxane

阿霉素是一种脱氧核糖核酸拓扑异构酶2a(Top2a)的抑制剂，是乳腺癌的常规治疗药物 癌症、肉瘤和儿童白血病。在拓扑异构酶2的两种同工酶中，Top2a在 癌细胞，是细胞分裂所必需的。然而，成年心肌细胞只表达拓扑异构酶2b (Top2b)，它参与DNA转录，但不参与DNA复制。长期癌症幸存者 曾接受阿霉素和其他蒽环类药物治疗的患者往往会出现剂量依赖性心脏毒性。 实验室数据显示，Top2a介导阿霉素的杀瘤活性，而Top2b 介导阿霉素的心脏毒性作用。目前，Dexrazoxane是FDA批准的唯一用于治疗 心脏保护。右旋氮杂环己烷的心脏保护作用是由于其与ATPase结合的能力 Top2b结构域抑制Top2b的催化循环。目前，Dexrazoxane是同时服用的 阿霉素。因为Dexrazoxane也与Top2a结合，所以它有可能干扰阿霉素的 杀瘤作用。然而，已知阿霉素引起的亚临床心脏毒性发生得更早， 也许是在阿霉素治疗开始的时候。因此，Dexrazoxane的临床应用有限，具体如下 FDA批准的适应症。在初步研究中，Dexrazoxane诱导泛素/蛋白酶体- 介导Top2b的降解，而不是Top2a的降解。在8小时前注射右旋氮杂环己烷 阿霉素，Top2b将被降解，以避免心脏毒性，而Top2a将保持完整，以 保持杀瘤效果。因为右旋糖苷的半衰期为两小时，93.75%的右旋氮杂环己烷 将在服药后8小时(四个半衰期)被消除。事实上，右旋氮杂环己烷预治疗8次 阿霉素对阿霉素诱导的动物心脏毒性提供完全保护前几小时 模特。在这项提案中，这一新策略将在开阿霉素处方的乳腺癌患者身上进行测试。 包含养生法。我们将研究两个具体目标。目标1：确定右旋氮杂环己烷是否在 低于FDA批准的剂量对Top2b的降解有效，且Top2b的降解时程 在人类志愿者中。目标2：检验一种基于机制的假说，早期给药 右氧唑烷预防阿霉素对HER2阴性的非转移性女性患者的心脏毒性作用 乳腺癌患者。HER2阴性、I-III期女性乳腺癌患者将参加本次活动 前瞻性随机、安慰剂对照、双盲研究。患者将通过心脏核磁共振进行监测， Dexrazoxane/阿霉素治疗前后TOP2a、Top2b和生物标记物。肿瘤消退将是 接下来是临床上的肿瘤学家。总体存活率、无事件存活率和总体反应(使用反应 将收集实体肿瘤的评估标准(RECIST)，以比较癌症治疗的结果与或 不加右旋氮杂环己烷的前处理。这些试验的成功实施将提供一种新颖和 预防阿霉素心脏毒性的成本效益策略。

Doxorubicin, an inhibitor of DNA topoisomerase 2a (Top2a), is routinely used in the treatment of breast cancer, sarcoma, and pediatric leukemia. Of the two topoisomerase 2 isozymes, Top2a is highly expressed in cancer cells and is required for cell division. However, adult cardiomyocytes express only topoisomerase 2b (Top2b), which is involved in DNA transcription, but not DNA replication. Long-term cancer survivors who were treated with doxorubicin and other anthracyclines often suffer from dose-dependent cardiotoxicity. Laboratory data showed that Top2a mediates doxorubicin’s tumoricidal activity, whereas Top2b mediates doxorubicin’s cardiotoxic effect. At present, dexrazoxane is the only FDA approved drug for cardio-protection. The cardio-protective effect of dexrazoxane is due to its ability to bind to the ATPase domain of Top2b to inhibit Top2b’s catalytic cycle. Currently, dexrazoxane is given concurrently with doxorubicin. Because dexrazoxane also binds to Top2a, it has the potential to interfere with doxorubicin’s tumoricidal effect. However, subclinical doxorubicin-induced cardiotoxicity is known to occur much earlier, perhaps at the initiation of doxorubicin therapy. Thus, dexrazoxane has limited clinical utility as specified by FDA’s approved indication. In preliminary studies, dexrazoxane induced an ubiquitin/ proteasome- mediated degradation of Top2b, but not Top2a. By administering dexrazoxane eight hours before doxorubicin, Top2b will be degraded to avoid cardiotoxicity, whereas Top2a will remain intact to preserve tumoricidal efficacy. Because the half-life of dexrazoxane is two hours, 93.75% of dexrazoxane will be eliminated eight hours (four half-lives) after administration. Indeed, dexrazoxane pre-treatment eight hours before doxorubicin provided complete protection against doxorubicin-induced cardiotoxicity in an animal model. In this proposal, this novel strategy will be tested in breast cancer patients prescribed doxorubicin- containing regimens. Two specific aims will be studied. Aim 1: To determine whether dexrazoxane given at a lower than FDA-approved dose is effective in degrading Top2b and the time-course of Top2b degradation in human volunteers. Aim 2: To test a mechanism-based hypothesis that early administration of dexrazoxane prevents doxorubicin-induced cardiotoxicity in non-metastatic, HER2- negative female breast cancer patients. HER2-negative, stage I-III female breast cancer patients will be enrolled in this prospective randomized, placebo-controlled, double-blind study. Patients will be monitored by cardiac MRI, Top2a, Top2b, and biomarkers before and after dexrazoxane/doxorubicin therapy. Tumor regression will be followed by oncologists clinically. Overall survival, event-free survival, and overall response (using response evaluation criteria in solid tumors -RECIST) will be collected to compare outcomes of cancer therapy with or without pre-treatment of dexrazoxane. Successful implementation of these trials will provide a novel and cost-effective strategy to prevent doxorubicin-induced cardiotoxicity.