Dorr R T, Lagel K, McLean S
Department of Pharmacology, College of Medicine, University of Arizona, Tucson, USA.
Eur J Cancer. 1996;32A Suppl 4:S21-5. doi: 10.1016/s0959-8049(96)00314-0.
Cultured neonatal rat heart myocytes form a synchronously-contracting cell syncytium from one to two days after isolation, plating on plastic and incubation at 37 degrees C. On day 3 after plating, myocytes were exposed to the anthracycline doxorubicin, 0.1-10 micrograms/ml, for 1 h with or without a 15-min pretreatment with the thiophosphate compound amifostine (WR-2721, Ethyol) or its dephosphorylated metabolite, WR-1065. The concentration of each WR-compound was limited to 2 micrograms/ml or 10% of the maximal achievable plasma concentration of amifostine after an intravenous dose of 740 mg/m2. Both amifostine and the free thiol significantly reduced doxorubicin-induced heart-cell toxicity, measured by adenosine triphosphate content normalised to total cellular protein. A concurrent 1-h exposure to these compounds and doxorubicin was also cardioprotective, but neither compound was effective when administered after doxorubicin. Although both amifostine and WR-1065 were approximately equipotent in preventing doxorubicin-induced cardiotoxicity, only amifostine significantly increased glutathione levels in the myocytes. These results complement prior in vitro and in vivo studies in rodents showing cardioprotectant activity for amifostine and its free thiol, WR-1065, when administered prior to doxurubicin.
新生大鼠心脏心肌细胞在分离、接种于塑料培养皿并于37℃孵育1至2天后形成同步收缩的细胞融合体。接种后第3天，心肌细胞暴露于浓度为0.1 - 10微克/毫升的蒽环类药物阿霉素中1小时，同时或不进行硫代磷酸盐化合物氨磷汀（WR - 2721，Ethyol）或其去磷酸化代谢产物WR - 1065的15分钟预处理。每种WR化合物的浓度限制为2微克/毫升或静脉注射剂量740毫克/平方米后氨磷汀可达到的最大血浆浓度的10%。通过将三磷酸腺苷含量标准化为总细胞蛋白来测量，氨磷汀和游离硫醇均显著降低了阿霉素诱导的心脏细胞毒性。这些化合物与阿霉素同时暴露1小时也具有心脏保护作用，但在阿霉素给药后给予这两种化合物均无效。尽管氨磷汀和WR - 1065在预防阿霉素诱导的心脏毒性方面大致等效，但只有氨磷汀显著提高了心肌细胞中的谷胱甘肽水平。这些结果补充了先前在啮齿动物中的体外和体内研究，表明在给予多柔比星之前给予氨磷汀及其游离硫醇WR - 1065具有心脏保护活性。
