Cancer Chemotherapy and Pharmacology

, Volume 31, Issue 3, pp 200–204 | Cite as

Prevention of doxorubicin-induced myocardial and haematological toxicities in rats by the iron chelator desferrioxamine

  • M. M. Al-Harbi
  • Naji M. Al-Gharably
  • Othman A. Al-Shabanah
  • Abdullah M. Al-Bekairi
  • Abdel Moneim M. Osman
  • Hassan N. Tawfik
Original Articles Myocardial Toxicity, Haematological Toxicity, Doxorubicin, Iron Chelator Desferrioxamine

Summary

Biochemical and histopathological evaluations of the protective effects of the iron-chelator desferrioxamine against the cardiac and haematological toxicities of doxorubicin in normal rats were carried out. A single dose of doxorubicin (15 mg/kg, i. v.) caused myocardial damage that manifested biochemically as an elevation of serum cardiac enzyme [glutamic oxaloacetic transaminase (GOT), lactic dehydrogenase (LDH) and creatine phosphokinase (CPK)] and cardiac isoenzyme levels and histopathologically as a swelling and separation of cardiac muscle fibers. Doxorubicin caused severe leucopenia and decreases in red blood cell counts and haemoglobin concentrations at 72 h after its administration. Desferrioxamine treatment (250 mg/kg, i.p.) carried out 30 min before doxorubicin administration protected the heart and blood elements from the toxic effects of doxorubicin as indicated by the recovery of levels of cardiac enzymes and isoenzymes and of red blood cell counts to normal values and by the absence of significant myocardial lesions. The findings of this study suggest that desferrioxamine can potentially be used clinically to prevent doxorubicin-induced cardiac and haematological toxicities.

Keywords

Doxorubicin Creatine Haematological Toxicity Iron Chelator Myocardial Damage 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Bachur NR, Gordon SL, Gee MV (1978) A general mechanism for microsomal activation of quinone anticancer agents to free radicals. Cancer Res 38: 1745–1750Google Scholar
  2. 2.
    Barbey MM, Fels LM, Poelstra K, Gwinner W, Bakker W, Stalte H (1989) Adriamycin affects glomerular renal function: evidence for involvement of oxygen radicals. Free Radical Res Commun 7: 195–203Google Scholar
  3. 3.
    Bergmeyer HU, Bernt E (1974) Lactate dehydrogenase isoenzymes. UV assay after separation on DEAE-sephadex. In: Bermeyer HU (ed) Methods of enzymatic analysis. Verlag Chemie, Weinheim/Academic Press, New York London, p 590Google Scholar
  4. 4.
    Blum RH, Carter SL (1974) Adriamycin. A new anticancer drug with significant clinical activity. Ann Intern Med 80: 249–259Google Scholar
  5. 5.
    Bonaddona G, Monfardinin S, Lena MDE, Fossati-Bellani F (1969) Clinical evaluation of Adriamycin, a new antitumour antibiotic. BMJ: 503–506Google Scholar
  6. 6.
    Bristow MR (1980) Anthracycline cardiotoxicity. In: Bristow MR (ed) Drug-induced heart disease. Elsevier/North Holland, Amsterdam, pp 191–215Google Scholar
  7. 7.
    Calabresi P, Parks RE Jr (1982) Chemotherapy of neoplastic disease. In: Gilman AG, Goodman LS, Rall TW, Murad F (eds) The pharmacological basis of therapeutics. Macmillan, New York Toronto London, p 1284Google Scholar
  8. 8.
    Dardir M, Herman EH, Ferrans VJ (1989) Effects of ICRF-187 on the cardiac and renal toxicity of epirubicin in spontaneously hypertensive rats. Cancer Chemother Pharmacol 23:269–275Google Scholar
  9. 9.
    David SS, Berner DL, Kasten JR, Wayne RD, William L (1984) Red and white cell count. In: Jacobs DS, Kasten RL Jr, Demott WR, Wolfson WL (eds) Laboratory test handbook with DRG index. Mosby Lexi, St. Louis, pp 326–347Google Scholar
  10. 10.
    El-Hage A, Herman EH, Ferrans VJ (1981) Reduction in the diabetogenic effect of alloxan in mice by pretreatment with antineoplastic agent ICRF-187. Res Commun Chem Pathol Pharmacol 33: 509–523Google Scholar
  11. 11.
    El-Hage A, Herman EH, Yang GC, Crouch PK, Ferrans VJ (1986) Mechanism of protective activity of ICRF-187 against alloxan-induced diabetes in mice. Res Commun Chem Pathol Pharmacol 52: 341–360Google Scholar
  12. 12.
    Gruiber W (1978) Inhibition of creatine kinase activity by Ca2+ and reversing effect of EDTA. Clin Chem 24: 177Google Scholar
  13. 13.
    Herman EL, El-Hage A, Ferrans VJ (1988) Protective effect of ICRF-187 on doxorubicin-induced cardiac and renal toxicity in spontaneously hypertensive (SHR) and normotensive (WKY) rats. Toxicol Appl Pharmacol 92: 42–53Google Scholar
  14. 14.
    Kachmar JF, Moss DW (1982) Enzymes. In: Teitz W (ed) Fundamentals of clinical chemistry. W. B. Saunders, Philadelphia London Mexico City, pp 565–595Google Scholar
  15. 15.
    Klaasen CD (1982) Heavy metals and heavy metal antagonists. In: Gilman AG, Goodman LS, Rall TW, Murad F (eds) The pharmacological basis of therapeutics. Macmillan, New York Toronto London, p 16224Google Scholar
  16. 16.
    Leisy SF, Milais J, Gonzales FBS, Boversis A (1990) Myocardial damage induced by doxorubicins: hydroperoxide-initiated chemiluminescence and morphology. Free Radical Biol Med 8: 259–264Google Scholar
  17. 17.
    Marco A, Gaetani M, Oressi P, Scardinato BM, Silvestrin R, Soldati M, Dasaia TI, Valentini L (1964) Daunomycin, a new antibiotic of the rhodomycin group. Nature 20: 706–707Google Scholar
  18. 18.
    Marco A, Gaetani M, Scarpinato B (1969) Adriamycin: a new antibiotic with antitumour activity. Cancer Chemother Rep 53: 33–37Google Scholar
  19. 19.
    Mettler FP, Young DM, Ward JM (1977) Adriamycin-induced cardiotoxicity (cardiomyopathy and congestive failure) in rats. Cancer Res 237: 2705–2713Google Scholar
  20. 20.
    Minotti G, Aust SD (1989) The role of iron in oxygen radical mediated lipid peroxidation. Chem Biol Interact 71: 1–29Google Scholar
  21. 21.
    Myers C, Gianni L, Simone CB, Klecher R, Creene R (1982) Oxidative distruption of erythrocyte ghost membrane catalized by doxorubicin-iron complex. Biochemistry 21: 1707–1713Google Scholar
  22. 22.
    Olsen HM, Capen CC (1978) Chronic cardiotoxicity of Adriamycin in the rat: morphologic and biochemical investigations. Toxicol Appl Pharmacol 44: 606–616Google Scholar
  23. 23.
    Pannacciulli IM, Lerza RA, Boglialo GV, Mencoboni MP, Saviance AG (1980) Effect of diethyldithiocarbamate on the toxicity of doxorubicin, cyclophosphamide andcis-diamminedichloroplatinum(II) on mouse haemopoietic progenitor cells. Br J Cancer 59: 371–374Google Scholar
  24. 24.
    Reitman S, Frankel S (1957) A colourimetic method for determination of serum glutamic oxaloacetic and glutamic pyruvic transminase. Am J Clin Pathol 28: 56–60Google Scholar
  25. 25.
    Rosenoff SH, Olsen MH, Young MD, Bostick F, Young CR (1975) Brief communication: Adriamycin-induced cardiac damage in the mouse: a small-animal model of cardiotoxicity. J Natl Cancer Inst 55: 191–193Google Scholar
  26. 26.
    Singh J, Garge KN, Garge D, Chugh K, Lal H (1989) Effect of aspartate and glutamate on experimental myocadial infarction in rats. Indian J Exp Biol 27: 621–624Google Scholar
  27. 27.
    Swanson JR, Wilkinson JH (1972) Measurement of creatine kinase in serum. In: Cooper GR (ed) Standard methods of clinical chemistry, vol 7. Academic Press, New York, pp 33–42Google Scholar
  28. 28.
    Van Jaarsveld H, Kuyl JM, Gorenewald AJ, Potgieter GM (1990) Effect of desferrioxamine on reperfusion damage of rat heart mitochondria. S Afr Med J 78: 263–265Google Scholar
  29. 29.
    Virgil F, Fairbanks MD (1982) Hemoglobin, hemoglobin derivatives and myoglobin. In: Tietz NW (ed) Fundamentals of clincial chemistry. W. S. Saunders, Philadelphia London Mexico City, pp 411–413Google Scholar
  30. 30.
    Yoda Y, Nakazawa M, Abe N, Kawakami S (1986) Prevention of doxorubicin myocardial toxocity in mice by reduced glutathione. Cancer Res 46: 2551–2556Google Scholar
  31. 31.
    Zbinden G, Bachmann E, Holdergger C (1978) Model system for cardiotoxic effects of anthracyclines. Antibiotic Chemother 23: 255–270Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • M. M. Al-Harbi
    • 1
  • Naji M. Al-Gharably
    • 1
  • Othman A. Al-Shabanah
    • 1
  • Abdullah M. Al-Bekairi
    • 1
  • Abdel Moneim M. Osman
    • 1
  • Hassan N. Tawfik
    • 2
  1. 1.Department of Pharmacology, College of PharmacyKing Saud UniversityRiyadhSaudi Arabia
  2. 2.Department of Pathology, College of MedicineKing Saud UniversityRigadhSaudi Arabia

Personalised recommendations