Imondi A R, Della Torre P, Mazué G, Sullivan T M, Robbins T L, Hagerman L M, Podestà A, Pinciroli G
Pharmacia and Upjohn, Inc., Columbus, Ohio 43216, USA.
Cancer Res. 1996 Sep 15;56(18):4200-4.
Dexrazoxane [(DZR), ADR 529, ICRF-187] ameliorates doxorubicin (DOX)-induced cardiotoxicity in animals, and is recommended as a cardioprotectant in patients receiving cumulative doses of DOX above 300 mg/m2. A DZR:DOX dose ratio of 10:1 is recommended based on studies in patients receiving 50 mg/m2. Since DOX may be used at much higher doses in certain clinical settings, we evaluated the ability of DZR to protect against cardiomyopathy in animals given bolus doses of DOX at varying dose levels. The severity and extent of the cardiomyopathy were evaluated histologically and expressed as the mean total score (MTS). Mice were given 10 doses of DOX (2 or 4 mg/kg) over a 7-week period. Without DZR, the MTS 4 weeks after the last treatment was 3.7 with 4 mg/kg DOX and 1.3 with 2 mg/kg DOX. DZR at 5:1, 10:1, and 20:1 dose ratios caused a dose-dependent decrease in the MTS but was less efficacious with the higher, more cardiotoxic dose of DOX. Rats were given DOX at 0.2, 0.4, and 0.8 mg/kg with a 20:1 ratio of DZR weekly for 13 weeks. Cardiomyopathy was most severe with the highest dose of DOX in the absence of DZR, especially in males, and progressed during the 6 weeks following the last treatment. DZR reduced the MTS in both sexes but in the males given the highest dose of DOX, there was still a significant amount of cardiac damage compared to vehicle-treated controls. Dogs were given 0.1, 0.3, and 0.8 mg/kg DOX with 20:1 DZR for 13 weeks. DZR reduced the MTS significantly (P < 0.05) in males and females but cardiac lesions were still present in each of the DZR-treated dogs. The results indicate that although DZR is highly effective in attenuating the cardiomyopathy caused by DOX, dose ratios of DZR:DOX capable of providing total or nearly complete cardioprotection at low doses of DOX are less efficacious at higher doses of DOX. One possible explanation for this effect is the marked pharmacokinetic difference between DZR and DOX, with DZR undergoing a much more rapid rate of elimination from the body compared to DOX. These findings point to the need for further studies to optimize the dose scheduling of DZR before using it clinically with bolus doses of DOX above those currently recommended.
右丙亚胺[（DZR），ADR 529，ICRF - 187]可改善阿霉素（DOX）诱导的动物心脏毒性，对于接受累积剂量超过300mg/m²DOX的患者，推荐使用右丙亚胺作为心脏保护剂。基于对接受50mg/m²DOX患者的研究，推荐右丙亚胺与阿霉素的剂量比为10:1。由于在某些临床情况下可能会使用更高剂量的阿霉素，我们评估了右丙亚胺在给予不同剂量水平大剂量阿霉素的动物中预防心肌病的能力。通过组织学评估心肌病的严重程度和范围，并以平均总分（MTS）表示。在7周内给小鼠注射10次阿霉素（2或4mg/kg）。在没有右丙亚胺的情况下，末次治疗后4周，给予4mg/kg阿霉素时MTS为3.7，给予2mg/kg阿霉素时MTS为1.3。右丙亚胺与阿霉素剂量比为5:1、10:1和20:1时，MTS呈剂量依赖性降低，但在阿霉素剂量更高、心脏毒性更大时效果较差。给大鼠每周注射阿霉素0.2、0.4和0.8mg/kg，右丙亚胺与阿霉素剂量比为20:1，持续13周。在没有右丙亚胺的情况下，阿霉素剂量最高时心肌病最严重，尤其是雄性大鼠，且在末次治疗后的6周内病情进展。右丙亚胺降低了两性的MTS，但在给予最高剂量阿霉素的雄性大鼠中，与给予赋形剂的对照组相比，仍有大量心脏损伤。给犬注射阿霉素0.1、0.3和0.8mg/kg，右丙亚胺与阿霉素剂量比为20:1，持续13周。右丙亚胺显著降低了雄性和雌性犬的MTS（P<0.05），但在接受右丙亚胺治疗的每只犬中仍存在心脏病变。结果表明，尽管右丙亚胺在减轻阿霉素引起的心肌病方面非常有效，但在低剂量阿霉素时能够提供完全或几乎完全心脏保护的右丙亚胺与阿霉素剂量比，在高剂量阿霉素时效果较差。这种效应的一个可能解释是右丙亚胺和阿霉素之间存在显著的药代动力学差异，与阿霉素相比，右丙亚胺从体内消除的速度要快得多。这些发现表明，在临床使用高于目前推荐剂量的大剂量阿霉素之前，需要进一步研究以优化右丙亚胺的给药方案。
