Platel D, Bonoron-Adèle S, Dix R K, Robert J
Institut Bergonié, Bordeaux, France.
Br J Cancer. 1999 Sep;81(1):24-7. doi: 10.1038/sj.bjc.6690646.
Cardiotoxicity represents the major side-effect limiting the clinical use of anthracyclines, especially doxorubicin, in cancer chemotherapy. The use of non-toxic prodrugs, or of liposome-encapsulated drugs, allows a better targeting of the tumours and may, therefore, improve the tolerance to the treatment. Using the model of isolated perfused rat heart, we have evaluated the cardiotoxicity of a novel prodrug of doxorubicin, HMR-1826, which consists of the association of doxorubicin to glucuronic acid. We have compared the cardiac effects (developed pressure, contractility and relaxation of the left ventricle) induced by HMR-1826 to those induced by doxorubicin and Doxil, a liposomal form of doxorubicin. HMR-1826 was administered intravenously every other day for 11 days at doses of 50-200 mg kg(-1) per injection while doxorubicin was administered according to the same protocol at doses of 1-3 mg kg(-1) per injection. Doxorubicin strongly decreased the cardiac functional parameters at the doses of 2.5 and 3 mg kg(-1) per injection. Doxil (3 mg kg(-1) and HMR-1826 (50-150 mg kg(-1)) were largely devoid of cardiotoxicity. HMR-1826 only induced significant alterations of the cardiac function at the highest dose used (200 mg kg(-1) per injection). These alterations were much lower than those of doxorubicin at 2.5 mg kg(-1) per injection, despite similar general toxicity symptoms (weight loss, nose bleeding and diarrhoea) at these respective doses. Thus, HMR-1826 appeared about 100-fold less cardiotoxic than doxorubicin.
心脏毒性是限制蒽环类药物尤其是阿霉素在癌症化疗中临床应用的主要副作用。使用无毒前体药物或脂质体包裹的药物，可以更好地靶向肿瘤，因此可能提高对治疗的耐受性。我们使用离体灌注大鼠心脏模型，评估了一种新型阿霉素前体药物HMR - 1826的心脏毒性，该药物由阿霉素与葡萄糖醛酸结合而成。我们比较了HMR - 1826、阿霉素和阿霉素脂质体形式Doxil对心脏的影响（左心室的发展压力、收缩性和舒张性）。HMR - 1826每隔一天静脉注射一次，共注射11天，每次注射剂量为50 - 200 mg·kg⁻¹，而阿霉素按照相同方案给药，每次注射剂量为1 - 3 mg·kg⁻¹。阿霉素在每次注射剂量为2.5和3 mg·kg⁻¹时，强烈降低心脏功能参数。Doxil（3 mg·kg⁻¹）和HMR - 1826（50 - 150 mg·kg⁻¹）在很大程度上没有心脏毒性。HMR - 1826仅在所用最高剂量（每次注射200 mg·kg⁻¹）时引起心脏功能的显著改变。尽管在这些相应剂量下有相似的一般毒性症状（体重减轻、鼻出血和腹泻），但这些改变远低于每次注射2.5 mg·kg⁻¹的阿霉素。因此，HMR - 1826的心脏毒性似乎比阿霉素低约100倍。
