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The protective activity of ICRF-187 against doxorubicin-induced cardiotoxicity in the rat

  • Original Articles
  • ICRF-187, Cardiotoxicity, Doxorubicin
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Summary

The protective activity of the bisdioxopiperazine ICRF-187 against the cardiotoxicity of doxorubicin was evaluated in the rat using both functional and histological assays. Animals that had received a single i. v. dose of doxorubicin (4 mg/kg) alone were compared with those that had been pretreated with a single i. v. injection of saline or ICRF-187 (40 or 60 mg/kg). All rats showed a transient reduction in body weight during the first 3 weeks after drug administration. The greatest reduction (∼16%) was observed in animals that had received a combination of ICRF-187 (40 or 60 mg/kg) and doxorubicin. Deaths related to cardiotoxicity were observed only in rats that had received doxorubicin alone and in those treated with saline; most of the deaths occurred at between 8 and 13 weeks after drug administration. Sequential assessments of heart function showed a persistent depression of cardiac output in animals that had received doxorubicin, with or without pretreatment with ICRF-187. The reduction in cardiac output observed in rats that had been pretreated with ICRF-187 (40 or 60 mg/kg) amounted to ∼15% and ∼30% after 12 and 20 weeks, respectively, indicating that cardioprotection was only partial. Nevertheless, this represented a marked improvement as compared with the ∼35% reduction in cardiac output measured at 12 weeks in animals that had received doxorubicin but without pretreatment with ICRF-187. Histological examination of animals that had died during the course of the study and had received doxorubicin after pretreatment with saline revealed severe myocardial lesions typical of doxorubicin-induced damage. In contrast, animals that had been pretreated with ICRF-187 and survived for up to 20 weeks after treatment showed a marked amelioration of these lesions. The present findings may be interpreted as a true cardioprotection or a delay in the onset of the cardiotoxicity of doxorubicin resulting from pretreatment with the bisdioxopiperazine ICRF-187. Although prior and ongoing clinical trials clearly indicate that ICRF-187 protects patients well against doxorubicin-induced heart damage, further investigations are required beforehigh doses of ICRF-187 can be used as a means of increasing the protective activity of this drug against doxorubicin-induced cardiotoxicity.

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Authors and Affiliations

  1. CRC Normal Tissue Radiobiology Research Group, (University of Oxford), Churchill Hospital, OX3 7LJ, Oxford, UK

    Tai K. Yeung, Dilys Wilding & John W. Hopewell

  2. Department of Pathology, College of Veterinary Medicine and Biomedical Sciences, 89 523, Fort Collins, Colorado, USA

    Roger S. Jaenke

  3. Cellular Pharmacology and Antitumour Chemistry Laboratory, ICRF Laboratories, Lincoln's Inn Fields, P. O. Box 123, WC2A 3PX, London, UK

    Andrew M. Creighton

Authors
  1. Tai K. Yeung
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  2. Roger S. Jaenke
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  3. Dilys Wilding
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  4. Andrew M. Creighton
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  5. John W. Hopewell
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This work was supported by the Cancer Research Campaign

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Yeung, T.K., Jaenke, R.S., Wilding, D. et al. The protective activity of ICRF-187 against doxorubicin-induced cardiotoxicity in the rat. Cancer Chemother. Pharmacol. 30, 58–64 (1992). https://doi.org/10.1007/BF00686486

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  • DOI: https://doi.org/10.1007/BF00686486

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