Summary
The long-term protective effect of ICRF-187 against chronic daunorubicin cardiotoxicity was examined. Rabbits were given 3.2 mg daunorubicin/kg, with or without pretreatment with 25 mg ICRF-187/kg, once every 3 weeks over an 18-week period (6 doses). The experiment was terminated 3 months after the last treatment. At this time, all seven rabbits given daunorubicin alone had evidence of myocardial alterations ranging from minimal (2 animals) to mild (5 animals). Pretreatment with ICRF-187 caused a significant reduction in both the incidence and the severity of cardiac lesions. Hearts from the majority (5 of 7) of animals given the combination of ICRF-187 and daunorubicin were normal; myocardial alterations were minimal in the remaining rabbits treated with ICRF-187. In previous studies ICRF-187 was found to cause a reduction in cardiotoxicity 1–3 weeks after the final anthracycline dose. The results of the present study demonstrate that pretreatment with ICRF-187 provides prolonged protection against the cardiomyopathy, as opposed to producing only a delay in the appearance of cardiac alterations.
Similar content being viewed by others
References
Breed JGS, Zimmerman ANE, Dormans JAMA, Pinedo HM (1980) Failure of the antioxidant vitamin E to protect against adriamycin-induced cardiotoxicity in the rabbit. Cancer Res 40:2033
Bristow MR, Billingham ME, Mason JW, Daniels TR (1978) Clinical spectrum of anthracycline antibiotic cardiotoxicity. Cancer Treat Rep 62:873
El-Hage A, Herman EH, Ferrans VJ (1981) Reduction in the diabetic effect of alloxan in mice by pretreatment with the antineoplastic agent ICRF-187. Res Commun Chem Pathol Pharmacol 23:509
Ferrans VJ (1978) Overview of cardiac pathology in relation to anthracycline cardiotoxicity. Cancer Treat Rep 62:955
Friedman MJ, Ewy GA, Jones SE, Cruze D, Moon TE (1979) 1-year followup of cardiac status after adriamycin therapy. Cancer Treat Rep 63:1809
Gottdiener JS, Mathiser DJ, Borer JS, Bonow RO, Myers CE, Barr LH, Schwartz DE, Bachrach SL, Green ML, Rosenberg SP (1981) Doxorubicin cardiotoxicity: Assessment of late left ventricular dysfunction by radionuclide cineangiography. Ann Intern Med 94:430
Herman EH, Ferrans VJ (1981) Reduction of chronic doxorubicin cardiotoxicity in dogs by pretreatment with (±)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF-187). Cancer Res 41:3436
Herman EH, Ferrans VJ (1983) Influence of vitamin E and ICRF-187 on chronic doxorubicin cardiotoxicity in miniature swine. Lab Invest 49:69
Herman E, Ardalan B, Bier C, Warakdevar V (1979) Reduction of daunorubicin lethality and myocardial cellular alterations by pretreatment with ICRF-187 in Syrian golden hamsters. Cancer Treat Rep 63:89
Herman EH, Ferrans VJ, Jordan W, Ardalen B (1981) Reduction of chronic daunorubicin cardiotoxicity by ICRF-187 in rabbits. Res Commun Chem Pathol Pharmacol 31:85
Jaenke RS (1974) An anthracycline antibiotic-induced cardiomyopathy in rabbits. Lab Invest 30:292
Jaenke RS (1976) Delayed and progressive myocardial lesions after adriamycin administration in the rabbit. Cancer Res 36: 2958
Legha SS, Wang Y-M, Mackay B, Ewer M, Hortobagyi GN, Benjamin RS, Ali MK (1982) Clinical and pharmacologic investigation of the effects of α-tocopherol on adriamycin cardiotoxicity. Ann NY Acad Sci 393:411
Long HJ, Diamond SS, Raflo CP, Burningham RA (1984) Dose-response relationships of chronic adriamycin toxicity in rabbits. Eur J Cancer Clin Oncol 20:129
Mimnaugh EG, Siddik ZH, Drew R, Rikic BI, Gram TE (1979) The effects of α-tocopherol on the toxicity, disposition and metabolism of adriamycin in mice. Toxicol Appl Pharmacol 49:115
Moral R, Bourat C, Ducrot R, Fournal J, Ganter P, Julow L, Kornig F, Myon J, Pascal S, Pasquet J, Populaire P, de Ratuld Y, Werner GH (1976) Etude toxicologique et activité antitumorale expérimentale de la rubidomycine (13-057RP). Pathol Biol Semaine Hop 15:903
Myers CE, McGuire WP, Young R (1976) Adriamycin: Amelioration of toxicity by α-tocopherol. Cancer Treat Rep 60:501
Myers CE, McGuire WP, Liss RH, Ifrim I, Grotzinger K, Young RC (1977) Adriamycin: The role of lipid peroxidation in cardiac toxicity and tumor response. Science 197:165
Myers CE, Gianni L, Simore CB, Klecker R, Greene R (1983) Oxidative destruction of erythrocyte ghost membranes catalyzed by the doxorubicin-iron complex. Biochemistry 21:1707
Saltiel E (1978) Doxorubicin (adriamycin) cardiomyopathy. West J Med 139:332
Sonneveld P (1978) Effect of α-tocopherol on the cardiotoxicity of adriamycin in the rat. Cancer Treat Rep 62:1033
Tan C, Tasaka H, Yu KP, Murphy ML, Karnovsky DM (1970) Daunomycin, an antitumor antibiotic in the treatment of neoplastic disease. Clinical evaluation with special reference to childhood leukemia. Cancer 20:333
Van Vleet JF, Ferrans VJ (1980) Clinical and pathologic features of chronic adriamycin toxicosis in the rabbit. Am J Vet Res 41:1462
Von Hoff DD, Layard MW (1982) Risk factors for the development of daunorubicin cardiotoxicity. Cancer Treat Rep 65 [Suppl 4]:15
Von Hoff DD, Layard MW, Basa P, Davis HL, Von Hoff AL, Rosencweig M, Muggia FM (1979) Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91:710
Wang Y-M, Madanot FF, Kimball JC, Gleiser CA, Ali MK, Kaufman MW, Van Eys J (1980) Effect of vitamin E against adriamycin toxicity in rabbits. Cancer Res 40:1022
Young DM (1975) Pathologic effects of adriamycin (NSC 123127) in experimental systems. Cancer Chemother Rep 6 (2):159
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Herman, E.H., Ferrans, V.J. Pretreatment with ICRF-187 provides long-lasting protection against chronic daunorubicin cardiotoxicity in rabbits. Cancer Chemother. Pharmacol. 16, 102–106 (1986). https://doi.org/10.1007/BF00256157
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00256157