Anthracycline Cardiotoxicity

  • Victor J. Ferrans
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 161)


The clinical and pathological features of the cardiotoxicity produced by antineoplastic antibiotics of the anthracycline type are reviewed. The mechanisms by which these changes are produced are discussed, and new data concerning the prevention of this cardiotoxicity are presented.


Sarcoplasmic Reticulum Cardiac Muscle Cell Keshan Disease Cancer Treatment Report Total Cumulative Dose 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Bertazzoli, C., Sala, L., Solcia, E., & Ghione M. Experimental adriamycin cardiotoxicity prevented by ubiquinone in vivo in rabbits. IRCS Journal of Medical Scienee 3, 468 (1975).Google Scholar
  2. 2.
    Billingham, M. E., Bristow, M. R., Glatstein, E., Mason, J. W., Masek, M. A. & Daniels, J. R., Adriamycin cardiotoxicity: endomyocardial biopsy evidence of enhancement by irradiation. American Journal of Surgical Pathology 1, 17–23 (1977).PubMedCrossRefGoogle Scholar
  3. 3.
    Billingham, M. E., Mason, J. W., Bristow, M. R. & Daniels, J. R. Anthracycline cardiomyopathy monitored by morphologic changes. Cancer Treatment Reports 62, 865–872 (1978).PubMedGoogle Scholar
  4. 4.
    Breed, J. G. S., Zimmerman, A. N. E., Dormans, J. A. M., & Pinedo, H. M. Failure of the antioxidant vitamin E to protect against adriamycin-induced cardiotoxicity in the rabbit. Cancer Research 40, 2033–2038 (1980).PubMedGoogle Scholar
  5. 5.
    Bristow, M. R., Mason, J. W., Billingham, M. E., & Daniels, J. R. Doxorubicin cardiomyopathy. Evaluation by phonocardiography, endomyocardial biopsy, and cardiac catheterization. Annals of Internal Medicine 88, 168–175 (1978).PubMedGoogle Scholar
  6. 6.
    Bristow, M. R., Minobe, W. A., Billingham, M. E., Marmor, J. B. Johnson, G. A., Ishimoto, B. M., Sageman, W. S. & Daniels, J. R. Anthracycline-associated cardiac and renal damage in rabbits: evidence for mediation by vasoactive substances. Laboratory Investigation 45, 157–168 (1981).PubMedGoogle Scholar
  7. 7.
    Bristow, M. R., Thompson, P. D., Martin, R. P., Mason, J. W., Billingham, M. E. & Harrison, D. C. Early anthracycline cardiotoxicity. American Journal of Medicine 65, 823–832 (1978).PubMedCrossRefGoogle Scholar
  8. 8.
    Buja, L. M., Ferrans, V. J., & Maron, B. J. Intracytoplasmic junctions in cardiac muscle cells. American Journal of Pathology 74, 613–648 (1974).PubMedGoogle Scholar
  9. 9.
    Buja, L. M., Ferrans, V. J-, Mayer, R. J., Roberts, W. C. & Henderson, E. S. Cardiac ultrastructural changes induced by daunorubicin therapy. Cancer 32, 771–788 (1973).PubMedCrossRefGoogle Scholar
  10. 10.
    Buja, L. M., Ferrans, V. J. & Rabson, A. S. Letter: Unusual nuclear alterations. Lancet 1, 402–403 (1974).PubMedCrossRefGoogle Scholar
  11. 11.
    Caulfield, J. B., Shelton, R. W. & Burke, J. F. Cytotoxic effects of oxygen on striated muscle. Archives of Pathology 94, 127–132 (1972).PubMedGoogle Scholar
  12. 12.
    Chalcroft, S. C. W., Gavin, J. B. & Herdson, P. B. Fine structural changes in rat myocardium induced by daunorubicin. Pathology 5, 99–105 (1973).PubMedCrossRefGoogle Scholar
  13. 13.
    Cortes, E. P., Lutman, G., Wanka, J., Wang, J. J., Pickren, J., Wallace, J. & Holland, J. F. Adriamycin (NSC-123127) cardiotoxicity. A clinicopathologic correlation. Cancer Treatment Reports 6, 215–225 (1975).Google Scholar
  14. 14.
    Daskal, Y., Woodard, C., Crooke, S. T. & Busch, H. Comparative ultrastructural studies of nucleoli of tumor cells treated with Adriamycin and the newer anthracyclines, Carminomycin and Marcellomycin. Cancer Research 38, 467–473 (1978).PubMedGoogle Scholar
  15. 15.
    Egorin, M. J., Hildebrand, R. C., Cimino, E. F. & Bachur, N. R. Cytofluorescence localization of adriamycin and daunorubicin. Cancer Research 34, 2243–2245 (1974).PubMedGoogle Scholar
  16. 16.
    El-Hage, A. N., Herman, E. H. & Ferrans, V. J. Reduction in the diabetogenic effect of alloxan in mice by treatment with the antineoplastic agent ICRF-187. Research Communications in Chemical Pathology and Pharmacology 33, 509–523 (1981).PubMedGoogle Scholar
  17. 17.
    Eltringham, J. R., Fajardo, L. F. & Stewart R. Adriamycin cardiomyopathy: enhanced cardiac damage in rabbits with combined drug and cardiac irradiation. Radiology 115, 471–472 (1975).PubMedGoogle Scholar
  18. 18.
    Fajardo, L. F., Eltringham, J. R. & Stewart, J. R. Combined cardiotoxicity of Adriamycin and X-radiation. Laboratory Investigation 34, 86–96 (1976).PubMedGoogle Scholar
  19. 19.
    Fajardo, L. F. & Stewart, J. R. Pathogenesis of radiation-induced myocardial fibrosis. Laboratory Investigation 29, 244–257 (1973).PubMedGoogle Scholar
  20. 20.
    Ferrans, V. J. Overview of cardiac pathology in relation to anthracycline cardiotoxicity. Cancer Treatment Reports 62, 955–961 (1978).PubMedGoogle Scholar
  21. 21.
    Ferrans, V. J. & Butany, J. W. Ultrastructural pathology of the heart. In Diagnostic Electron Microscopy, Vol. 4. B. Trump & R. Jones, Eds. New York: John Wiley & Sons, Inc. (in press, 1982).Google Scholar
  22. 22.
    Ferrans, V. J., Hibbs, R. G., Walsh, J. J. & Burch, G. E. Histo-chemical and electron microscopical studies on the cardiac necroses produced by sympathomimetic agents. Annals of the New York Academy of Sciences 156, 309–332 (1969).PubMedCrossRefGoogle Scholar
  23. 23.
    Ferrans, V. J., Hibbs, R. G.., Weily, H. S., Weilbaecher, D. G., Walsh, J. J. & Burch, G. E. A histochemical and electron microscopic study of epinephrine-induced myocardial necrosis. Journal of Molecular and Cellular Cardiology 1, 11–22 (1970).PubMedCrossRefGoogle Scholar
  24. 24.
    Ferrans, V. J., Thiedemann, K.-U., Maron, B. J. & Roberts, W. C. Spherical micropartides in human myocardium. An ultra-structural study. Laboratory Investigation 35, 349–368 (1976).PubMedGoogle Scholar
  25. 25.
    Franco-Browder, S., Guerrero, M., Gorodezky, M., Bravo, L. M. & Aceves, S. Lesiones miocárdicas producidas por liberadores de histamina en ratas. Archivos del Instituto de Cardiologia de Mexico 30, 720–728 (1960).PubMedGoogle Scholar
  26. 26.
    Gandolfi, A. Cardiotossicità cronica da adriamicina: studio morfologico ultrastrutturale sul miocardio ventricolare e sul sistema di conduzione del cuore di coniglio. Ateneo Parmense. Sezione 1. Acta Bio-Medica 47, 69–78 (1976).Google Scholar
  27. 27.
    Gilladoga, A. C., Manuel, C., Tan, C. C., Wollner, N. & Murphy, M. L. Cardiotoxicity of adriamycin (NSC-123127) in children. Cancer Chemotherapy Reports 6, 209–214 (1975).Google Scholar
  28. 28.
    Gilladoga, A. C., Manuel, C., Tan, C., Wollner, N., Sternberg, S. S. & Murphy, M. L. The cardiotoxicity of adriamycin and daunomycin in children. Cancer 37, 1070–1078 (1976).PubMedCrossRefGoogle Scholar
  29. 29.
    Gosalvez, M., van Rossum, G. D. V., & Blanco, M. F. Inhibition of sodium-potassium-activated adenosine 5’-triphosphatase and ion transport by Adriamycin. Cancer Research 39, 257–261 (1979).PubMedGoogle Scholar
  30. 30.
    Halazun, J. F., Wagner, H. R., Gaeta, J. F. & Sinks, L. F. Daunorubicin cardiac toxicity in children with acute lymphocytic leukemia. Cancer 33, 545–554 (1974).PubMedCrossRefGoogle Scholar
  31. 31.
    Herman, E. H. & Ferrans, V. J. Reduction of chronic doxorubicin cardiotoxicity in dogs by pretreatment with (±)-1,2-Bis (3,5-dioxopiperazinyl-l-yl) propane (ICRF-187). Cancer Research 41, 3436–3440 (1981).PubMedGoogle Scholar
  32. 32.
    Herman, E. H. & Ferrans, V. J. ICRF-187 reduction of chronic daunorubicin and doxorubicin cardiotoxicity in rabbits and beagle dogs. Chemioterccpia Oncologica 5, 37–41 (1981).Google Scholar
  33. 33.
    Herman, E. H., Ferrans, V. J., Jordan, W. & Ardalan, B. Reduction of chronic daunorubicin cardiotoxicity by ICRF-187 in rabbits. Research Communications in Chemical Pathology and Pharmacology 31, 85–97 (1981).PubMedGoogle Scholar
  34. 34.
    Herman, E., Young, R., & Krop, S. Doxorubicin-induced hypotension in the Beagle dog. Agents and Actions 8, 551–557 (1978).PubMedCrossRefGoogle Scholar
  35. 35.
    Isner, J. M., Ferrans, V. J., Cohen, S. R., Witkind, B. G., Virmani, R., Gottdiener, J. S. & Roberts, W. C. Variability of cardiac histologic toxicity in patients treated with anthra-cycline chemotherapy. American Journal of Cardiology 45, 396 (1980).CrossRefGoogle Scholar
  36. 36.
    Jaenke, R. S. An anthracycline antibiotic-induced cardiomyopathy in rabbits. Laboratory Investigation 30, 292–304 (1974).PubMedGoogle Scholar
  37. 37.
    Lambertenghi-Deliliers, G., Zanon, P. L., Pozzoli, E. F. & Bellini, O. Myocardial injury induced by a single dose of adriamycin: an electron microscopic study. Tumori 62, 517–529 (1976).PubMedGoogle Scholar
  38. 38.
    Lefrak, E. A., Pitha, J., Rosenheim, S. & Gottlieb, J. A clini-copathologic analysis of adriamycin cardiotoxicity. Cancer 32, 302–314 (1973).PubMedCrossRefGoogle Scholar
  39. 39.
    Merski, A., Daskal, I., & Busch, H. Effects of adriamycin on ultrastructure of nucleoli in the heart and liver cells of the rat. Cancer Research 36, 1580–1584 (1976).PubMedGoogle Scholar
  40. 40.
    Minow, R. A., Benjamin, R. S., Lee, E. T. & Gottlieb, J. A. Adriamycin cardiomyopathy-risk factors. Cancer 39, 1397–1402 (1977).PubMedCrossRefGoogle Scholar
  41. 41.
    Myers, C. E., Gianni, L., Simone, C. B., Hendrickson, M., Klecker, R.& Greene, R. Oxidative destruction of erythrocyte ghost membranes catalyzed by the doxorubicin-iron complex. Biochemistry (in press, 1982).Google Scholar
  42. 42.
    Myers, C. E., McGuire, W. P., Liss, R. H., Ifrim, I., Grot-zinger, K., & Young, R. G. Adriamycin: the role of lipid peroxidation in cardiac toxicity and tumor response. Science 197, 165–167 (1977).PubMedCrossRefGoogle Scholar
  43. 43.
    Myers, C. E., McGuire, W. P., & Young, R. C. Adriamycin: amelioration of toxicity by a-tocopherol. Cancer Treatment Reports 60, 961–962 (1976).PubMedGoogle Scholar
  44. 44.
    Olson, H. M., Young, D. M., Prieur, D. J., LeRoy, A. F. & Reagan, R. L. Electrolyte and morphologic alterations of myocardium in adriamycin-treated rabbits. American Journal of Pathology 77, 439–454 (1974).PubMedGoogle Scholar
  45. 45.
    Regal, E., Kaliner, M., El-Hage, A., Ferrans, V. J., Kawanami, O., & Herman, E. H. Anthracycline-induced histamine release from rat mast cells. Agents and Actions (in press, 1982).Google Scholar
  46. 46.
    Rosenoff, S. H., Olson, H. M., Young, D. M., Bostick, F. & Young, R. C. Adriamycininduced cardiac damage in the mouse. A small animal model of cardiotoxicity. JNCI. Journal of the National Cancer Institute 55, 191–194 (1975).Google Scholar
  47. 47.
    Unuma, T., Senda, R., & Muramatsu, M. Mechanism of nucleolar segregation-differences in effects of actinomycin D and cycloheximide on nucleoli of rat liver cells. Journal of Electron Microscopy (Tokyo) 22, 205–216 (1973).Google Scholar
  48. 48.
    VanVleet, J. F. & Ferrans, V. J. Cutaneous lesions and hematologic alterations in chronic adriamycin intoxication in dogs with and without vitamin E and selenium supplementation. American Journal of Veterinary Research 41, 691–699 (1980).Google Scholar
  49. 49.
    VanVleet, J. F. & Ferrans, V. J. Evaluation of vitamin E and selenium protection against chronic adriamycin toxicity in rabbits. Cancer Treatment Reports 64, 315–317 (1980).Google Scholar
  50. 50.
    VanVleet, J. F., Ferrans, V. J. & Ruth, G. R. Ultrastructural alterations in nutritional cardiomyopathy of selenium-vitamin E deficient swine. I. Fiber lesions. Laboratory Investigation 37, 188–200 (1977).Google Scholar
  51. 51.
    VanVleet, J. F., Ferrans, V. J. & Ruth, G. R. Ultrastructural alterations in nutritional cardiomyopathy of selenium-vitamin E deficient swine. II. Vascular lesions. Laboratory Investigation 37, 201–211 (1977).CrossRefGoogle Scholar
  52. 52.
    VanVleet, J. F., Ferrans, V. J. & Weirich, W. E. Cardiac disease induced by chronic adriamycin administration in dogs and an evaluation of vitamin E and selenium as cardioprotectants. American Journal of Pathology 99, 13–42 (1980).Google Scholar
  53. 53.
    VanVleet, J. F., Greenwood, L. A., & Ferrans, V. J. Pathologic features of adriamycin toxicosis in young pigs: nonskeletal lesions. American Journal of Veterinary Research 40, 1537–1552 (1979).Google Scholar
  54. 54.
    VanVleet, J. F., Greenwood, L., Ferrans, V. J. & Rebar, A. H. Effect of selenium-vitamin E on adriamycin-induced cardiomyopathy in rabbits. American Journal of Veterinary Research 39, 997–1010 (1978).Google Scholar
  55. 55.
    Von Hoff, D. D., Rozencweig, M., Layard, M., Slavik, M. & Muggia, F. M. Daunomycin-induced cardiotoxicity in children and adults. A review of 110 cases. American Journal of Medicine 62, 200–208 (1977)CrossRefGoogle Scholar
  56. 56.
    Wang, Y., Madanat, F. F., Kimball, J. C., Gleiser, C. A., Ali, M. K., Kaufman, M. W. & Van Eys, J. Effect of vitamin E against adriamycin-induced toxicity in rabbits. Cancer Research 40, 1022–1027 (1980).PubMedGoogle Scholar
  57. 57.
    Young, R. C., Ozols, R. F. & Myers, C. E. The anthracycline antineoplastic drugs. New England Journal of Medicine 305, 139–153 (1981).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1983

Authors and Affiliations

  • Victor J. Ferrans
    • 1
  1. 1.Pathology Branch, National Heart, Lung, and Blood InstituteNational Institutes of HealthBethesdaUSA

Personalised recommendations