单克隆抗体与阿霉素给药时间间隔对小鼠阿霉素诱导的心脏毒性保护作用的影响。

The influence of the time interval between monoHER and doxorubicin administration on the protection against doxorubicin-induced cardiotoxicity in mice.

作者信息

Bruynzeel Anna M E, Mul Paula P N, Berkhof Johannes, Bast Aalt, Niessen Hans W M, van der Vijgh Wim J F

机构信息

Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.

出版信息

Cancer Chemother Pharmacol. 2006 Nov;58(5):699-702. doi: 10.1007/s00280-006-0206-9. Epub 2006 Mar 25.

DOI:10.1007/s00280-006-0206-9

PMID:16565833

Abstract

PURPOSE

Despite its well-known cardiotoxicity, the anthracyclin doxorubicin (DOX) continues to be an effective and widely used chemotherapeutic agent. DOX-induced cardiac damage presumably results from the formation of free radicals by DOX. Reactive oxygen species particularly affect the cardiac myocytes because these cells seem to have a relatively poor antioxidant defense system. The semisynthetic flavonoid monohydroxyethylrutoside (monoHER) showed cardioprotection against DOX-induced cardiotoxicity through its radical scavenging and iron chelating properties. Because of the relatively short final half-life of monoHER (about 30 min), it is expected that the time interval between monoHER and DOX might be of influence on the cardioprotective effect of monoHER. Therefore, the aim of the present study was to investigate this possible effect.

METHODS

Six groups of 6 BALB/c mice were treated with saline, DOX alone or DOX (4 mg/kg i.v.) preceded by monoHER (500 mg/kg i.p.) with an interval of 10, 30, 60 or 120 min. After a 6-week treatment period and additional observation for 2 weeks, the mice were sacrificed. Their cardiac tissues were processed for light microscopy, after which cardiomyocyte damage was evaluated according to Billingham (in Cancer Treat Rep 62(6):865-872, 1978). Microscopic evaluation revealed that treatment with DOX alone induced significant cardiac damage in comparison to the saline control group (P<0.001).

RESULTS

The number of damaged cardiomyocytes was 9.6-fold (95% CI 4.4-21.0) higher in mice treated with DOX alone than that in animals of the control group. The ratio of aberrant cardiomyocytes in mice treated with DOX preceded by monoHER and those in mice treated with saline ranged from 1.6 to 2.8 (mean 2.2, 95% CI 1.2-4.1, P=0.019). The mean protective effect by adding monoHER before DOX led to a significant 4.4-fold reduction (P<0.001, 95% CI 2.3-8.2) of abnormal cardiomyocytes. This protective effect did not depend on the time interval between monoHER and DOX administration (P=0.345).

CONCLUSION

The results indicate that in an outpatient clinical setting monoHER may be administered shortly before DOX.

摘要

目的

尽管蒽环类药物阿霉素（DOX）具有众所周知的心脏毒性，但它仍然是一种有效且广泛使用的化疗药物。DOX诱导的心脏损伤可能是由于DOX形成自由基所致。活性氧特别影响心肌细胞，因为这些细胞似乎具有相对较差的抗氧化防御系统。半合成类黄酮单氢乙芦丁（monoHER）通过其自由基清除和铁螯合特性对DOX诱导的心脏毒性具有心脏保护作用。由于monoHER的最终半衰期相对较短（约30分钟），预计monoHER与DOX之间的时间间隔可能会影响monoHER的心脏保护作用。因此，本研究的目的是调查这种可能的影响。

方法

将六组每组6只BALB/c小鼠分别用生理盐水、单独的DOX或在注射DOX（4mg/kg静脉注射）前10、30、60或120分钟腹腔注射monoHER（500mg/kg）进行处理。经过6周的治疗期并额外观察2周后，处死小鼠。对其心脏组织进行光学显微镜检查，然后根据比林厄姆（《癌症治疗报告》62(6):865 - 872, 1978）的方法评估心肌细胞损伤情况。显微镜评估显示，与生理盐水对照组相比，单独使用DOX治疗会导致显著的心脏损伤（P<0.001）。

结果

单独用DOX治疗的小鼠中受损心肌细胞数量比对照组动物高9.6倍（95%可信区间4.4 - 21.0）。在DOX注射前给予monoHER的小鼠与给予生理盐水的小鼠中异常心肌细胞的比例在1.6至2.8之间（平均2.2，95%可信区间：1.2 - 4.1，P = 0.019）。在DOX之前添加monoHER的平均保护作用导致异常心肌细胞显著减少4.4倍（P<0.001，95%可信区间2.3 - 8.2）。这种保护作用不依赖于monoHER与DOX给药之间的时间间隔（P = 0.345）。