Della Torre P, Imondi A R, Bernardi C, Podestà A, Moneta D, Riflettuto M, Mazué G
Worldwide Toxicology, Pharmacia & Upjohn, Nerviano, Italy.
Cancer Chemother Pharmacol. 1999;44(2):138-42. doi: 10.1007/s002800050958.
Results of several clinical studies suggest that the combination of doxorubicin (DOX) and paclitaxel (PTX) is highly active against solid tumors. Both drugs are known to cause adverse cardiac effects, cardiomyopathy in the case of DOX and acute changes in cardiac rhythm in the case of PTX. It has been suggested that the addition of dexrazoxane (DZR) to this regimen may reduce the risk of cardiotoxicity. A model of chronic cardiomyopathy in the rat was used to determine whether DZR was tolerated and cardioprotective in a DOX + PTX combination.
Male rats were treated once weekly for 7 weeks with one of the following vehicle and/or drug sequences: Group A, M/6 sodium lactate/saline/Cremophor EL (CEL); Group B, lactate/DOX/CEL; Group C, DZR/DOX/CEL; Group D, lactate/DOX/PTX; and Group E, DZR/DOX/PTX. DZR and DOX or their respective vehicles were given i.v. whilst PTX or CEL were given i.p. DZR, DOX and PTX were administered at 16 mg/kg, 0.8 mg/kg and 2.4 mg/kg, respectively, doses which caused minimal noncardiac toxicities. The hearts were examined histologically 5 weeks following the last treatment.
There were no deaths and no signs of overt toxicity during the 12 weeks of study. There was a significant decrease (P < 0.01) in white blood cell count in rats treated with DZR + DOX, DOX + PTX or DZR + DOX + PTX but not in those given DOX alone. Liver and kidney weights were increased in rats given DOX (P < 0.05) but not in those given DZR + DOX. PTX had no effect on the DOX-induced liver and kidney changes and did not interfere with the protective effect of DZR on the kidney. The severity and extent of cardiomyopathy expressed as the mean total score (MTS) for each treatment group, was similar for DOX and DOX + PTX (4.6 and 4.2, respectively). DZR provided significant cardioprotection (P < 0.01) when added to either DOX (MTS 2.0) or to DOX + PTX (MTS 2.1).
The results suggest that PTX does not exacerbate the chronic cardiomyopathy caused by DOX and when added to the DOX + PTX combination, DZR retains its protective activity against DOX-induced cardiotoxicity without increasing noncardiac toxicity.
多项临床研究结果表明，阿霉素（DOX）与紫杉醇（PTX）联合使用对实体瘤具有高度活性。已知这两种药物都会引起心脏不良反应，DOX会导致心肌病，PTX会导致心律急性变化。有人提出在此治疗方案中添加右丙亚胺（DZR）可能会降低心脏毒性风险。使用大鼠慢性心肌病模型来确定DZR在DOX + PTX联合用药中是否可耐受以及具有心脏保护作用。
雄性大鼠每周接受一次治疗，共7周，采用以下赋形剂和/或药物组合之一：A组，M/6乳酸钠/生理盐水/Cremophor EL（CEL）；B组，乳酸盐/DOX/CEL；C组，DZR/DOX/CEL；D组，乳酸盐/DOX/PTX；E组，DZR/DOX/PTX。DZR和DOX或其各自的赋形剂通过静脉注射给药，而PTX或CEL通过腹腔注射给药。DZR、DOX和PTX的给药剂量分别为16mg/kg、0.8mg/kg和2.4mg/kg，这些剂量引起的非心脏毒性最小。在最后一次治疗后5周对心脏进行组织学检查。
在12周的研究期间没有死亡，也没有明显的毒性迹象。用DZR + DOX、DOX + PTX或DZR + DOX + PTX治疗的大鼠白细胞计数显著降低（P < 0.01），但单独给予DOX的大鼠白细胞计数没有降低。给予DOX的大鼠肝脏和肾脏重量增加（P < 0.05），但给予DZR + DOX的大鼠没有增加。PTX对DOX引起的肝脏和肾脏变化没有影响，也不干扰DZR对肾脏的保护作用。以每个治疗组的平均总分（MTS）表示的心肌病严重程度和范围，DOX组和DOX + PTX组相似（分别为4.6和4.2）。当添加到DOX（MTS 2.0）或DOX + PTX（MTS 2.1）中时，DZR具有显著的心脏保护作用（P < 0.01）。
结果表明，PTX不会加重DOX引起的慢性心肌病，并且当添加到DOX + PTX联合用药中时，DZR保留其对DOX诱导的心脏毒性的保护活性，而不会增加非心脏毒性。
