REDUCTION OF DOXORUBICIN CARDIOTOXICITY BY ICRF-187

多柔比星是一种对多种肿瘤有活性的化疗药物， 恶性肿瘤。 最重要的剂量限制性副作用的慢性 阿霉素治疗是心肌病。 某些化合物可以改变 阿霉素的心脏毒性。 在早期的研究中，ICRF-159导致 柔红霉素毒性的显著降低。 ICRF-187是水 ICRF-159的可溶性异构体，并降低柔红霉素的心脏毒性 和阿霉素在兔子、仓鼠和狗中的作用。 令人鼓舞的结果， 动物导致了我们实验室对人类对象的初步研究。 给药前30分钟接受静脉推注ICRF-187的组 多柔比星似乎对心脏非侵入性 功能测试比接受安慰剂的组。 的目的 本研究旨在进一步评估ICRF-187改善 阿霉素诱导心脏毒性。 患者将被随机分配至 以双盲方式用ICRF-187或安慰剂预处理。 基线评估将包括病史和体格检查，胸部 X线、心电图、收缩时间间期、超声心动图、核 血管造影、全血细胞计数、肝酶、肿瘤状态和 性能状态。 验血，超声心动图和心脏收缩时间 将在随后给药前立即重复间隔 阿霉素 总评价包括在以下时间进行的所有测试： 当累积阿霉素剂量为300时，将重复基线， 500 mg/m2。 此外，将在以下时间进行肌内膜活检： 在基线和累积剂量为300和500 mg/m2的受试者中， 同意. 将对两组患者进行肿瘤缓解评价 以及两种药物的副作用。 心脏功能研究将 两组各45例，采用双向比较法 方差分析 肌内膜活检将得到一个等级 （比灵厄姆标准），还将通过分析 方差 本研究的成功完成应证明 ICRF-187是否能有效预防阿霉素诱导的心脏 功能和组织学变化。

Doxorubicin is a chemotherapeutic drug active against a variety of malignancies. The most important dose-limiting side effect of chronic doxorubicin treatment is cardiomyopathy. Certain compounds can modify doxorubicin cardiac toxicity in animals. In early studies, ICRF-159 caused a significant reduction of daunorubicin toxicity. ICRF-187 is the water soluble isomer of ICRF-159 and reduces the cardiac toxicity of daunorubicin and doxorubicin in rabbits, hamsters and dogs. The encouraging results in animals led to a preliminary study of human subjects in our laboratory. The group receiving bolus intravenous ICRF-187 30 minutes prior to doxorubicin appears to be having less change of cardiac non-invasive function tests than the group receiving placebo. The purpose of the present study is to further evaluate ICRF-187's ability to ameliorate doxorubicin induced cardiac toxicity. Patients will be randomized to pretreatment with either ICRF-187 or placebo in a double-blinded fashion. Baseline evaluation will include a history and physical examination, chest x-ray, electrocardiogram, systolic time intervals, echocardiograms, nuclear angiogram, complete blood count, liver enzymes, tumor status and performance status. Blood tests, the echocardiogram and systolic time intervals will be repeated immediately prior to subsequent doses of doxorubicin. A total evaluation including all the tests performed at baseline will be repeated when the cumulative doxorubicin dose is 300 and 500 mg/m2. In addition, an endomyocardial biopsy will be performed at baseline and at cumulative doses of 300 and 500 mg/m2 in those subjects who consent. The two groups of patients will be evaluated for tumor response and side effects to the two drug regimens. Cardiac function studies will be compared between the two groups (45 in each group) by the two way analysis of variance. The endomyocardial biopsy will receive a grade (Billingham criteria) and the groups will also be compared by analysis of variance. The successful completion of this study should demonstrate whether ICRF-187 effectively prevents doxorubicin-induced cardiac functional and histologic changes.