Tomlinson C W, Godin D V, Rabkin S W
Biochem Pharmacol. 1985 Nov 15;34(22):4033-41. doi: 10.1016/0006-2952(85)90384-3.
The present study has examined early cellular effects of chronic adriamycin administration to dogs using a protocol (1 mg/kg/week to a total cumulative dose of 240 mg/m2) producing significant but small reductions in ejection fraction and stroke volume as determined echocardiographically prior to the development of clinical or radiological manifestations of heart failure. At this early phase of cardiomyopathy, significant reduction (P less than 0.05) in sarcoplasmic reticulum Ca2+, K+-ATPase was observed without any change in mitochondrial, lysosomal or sarcolemmal marker enzymes. Myocardial calcium (P less than 0.01) and glutathione (P less than 0.001) levels were increased significantly. Detailed analysis of myocardial phospholipid profiles failed to show any significant differences between control and treated dogs. In contrast, red cell membranes showed increased phosphatidylcholine (PC) and decreased phosphatidylserine (PS) contents, resulting in a significant increase in PC/PS ratio (P less than 0.05). No significant changes were detected in activities of catalase, superoxide dismutase or glutathione peroxidase in erythrocytes or myocardial tissue from control and adriamycin-treated animals. A significant (P less than 0.05) elevation in plasma sialic acid was observed following adriamycin treatment. Our results suggest that early adriamycin-induced damage is unlikely to result from alterations in cellular processes protecting tissues against oxidant injury. Regression analysis indicated that, of the various abnormalities observed, only the elevated myocardial calcium levels and the increases in plasma sialic acid correlated with the degree of myocardial functional impairment. Our findings suggest the presence of sarcolemmal alterations in Ca2+ handling in early adriamycin-induced myocardial injury and indicate that measurement of plasma sialic acid should be further investigated as a possible noninvasive indicator of impending adriamycin cardiotoxicity.
本研究采用一种给药方案（1毫克/千克/周，累计总剂量达240毫克/平方米），对犬类进行慢性阿霉素给药，并研究其早期细胞效应。在心力衰竭的临床或放射学表现出现之前，通过超声心动图测定，该方案会使射血分数和每搏输出量出现显著但微小的降低。在心肌病的这个早期阶段，观察到肌浆网Ca2 +、K + -ATP酶显著降低（P小于0.05），而线粒体、溶酶体或肌膜标记酶没有任何变化。心肌钙（P小于0.01）和谷胱甘肽（P小于0.001）水平显著升高。对心肌磷脂谱的详细分析未能显示对照犬和治疗犬之间有任何显著差异。相比之下，红细胞膜显示磷脂酰胆碱（PC）含量增加，磷脂酰丝氨酸（PS）含量降低，导致PC/PS比值显著增加（P小于0.05）。在对照动物和阿霉素治疗动物的红细胞或心肌组织中，过氧化氢酶、超氧化物歧化酶或谷胱甘肽过氧化物酶的活性未检测到显著变化。阿霉素治疗后，血浆唾液酸显著升高（P小于0.05）。我们的结果表明，早期阿霉素诱导的损伤不太可能是由保护组织免受氧化损伤的细胞过程改变引起的。回归分析表明，在观察到的各种异常中，只有升高的心肌钙水平和血浆唾液酸增加与心肌功能损害程度相关。我们的研究结果表明，早期阿霉素诱导的心肌损伤中存在肌膜Ca2 +处理改变，并表明血浆唾液酸的测量应作为即将发生的阿霉素心脏毒性的一种可能的非侵入性指标进行进一步研究。
