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Evaluation of anthracycline cardiotoxicity with the model of isolated, perfused rat heart: comparison of new analogues versus doxorubicin

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Abstract

We have compared the cardiotixicity of 3 anthracyclines in a model of isolated perfused rat heart using the Langendorff technique. The contractile state and ventricular compliance were studied. Doxorubicin, epirubicin and pirarubicin were perfused at concentrations of 10−6 and 10−5 M during 70 min. The cardiac accumulation of the drugs was studied by HPLC. No significant alteration of cardiac functional parameters was observed at 10−6 M. At 10−5 M, epirubicin produced a significantly greater alteration of cardiac contractility than doxorubicin, whereas pirarubicin exerted first an inotropic effect followed by a recovery to initial values at the 60th min. Anthracycline accumulation in the heart was dose-dependent; epirubicin accumulated to a 30% greater extent than doxorubicin and pirarubicin heart concentrations were 4–5 times higher than those of doxorubicin at the end of the perfusion. These results suggest that doxorubicin and epirubicin have the same intrinsic cardiac toxicity, and that their distinct clinical cardiotoxicity must be explained by pharmacokinetic differences, whereas pirarubicin is much less cardiotoxic than the other anthracyclines because of different pharmacodynamic properties.

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References

  1. 1.

    Unverferth DV, Magorien RD, Leier CV, Balcerzak SP (1982) Doxorubicin cardiotoxicity. Cancer Treat Rev 9: 149

  2. 2.

    Casazza AM (1986) Preclinical selection of new anthracyclines. Cancer Treat Rep 70: 43

  3. 3.

    Cummings J, Anderson L, Willmott N, Smyth JF (1991) The molecular pharmacology of doxorubicin in vivo. Eur J Cancer 27: 532

  4. 4.

    Ganzina F (1983) 4′-Epi-doxorubicin, a new analogue of doxorubicin: a preliminary overview of preclinical and clinical data. Cancer Treat Rev 10: 1

  5. 5.

    Maehara Y, Sakaguchi Y, Kusumoto T, Kusumoto H, Sugimachi K (1989) 4′-O-Tetrahydropyranyladriamycin has greater antineoplastic activity than doxorubicin in various human tumours in vitro. Anticancer Res 9: 387

  6. 6.

    Hérait P, Poutignat N, Marty M, Bugat R (1992) Early assessment of a new anticancer drug analogue. Are the historical comparisons obsolete? The French experience with pirarubicin. Eur J Cancer 28A: 1670

  7. 7.

    Ganzina F, Di Pietro N, Magni O (1985) Clinical toxicity of 4′-epidoxorubicin (epirubicin). Tumori 71: 233

  8. 8.

    Keizer HG, Pinedo HM, Schuurhuis GJ, Joenje H (1990) Doxorubicin (adriamycin): a critical review of free radical-dependent mechanisms of cytotoxicity. Pharmacol Ther 47: 219

  9. 9.

    Lorell BH, Wexler LF, Momomura S, Weinberg E, Apstein CS (1986) The influence of pressure overload left ventricular hypertrophy on diastolic properties during hypoxia in isovolumically contracting rat hearts. Circ Res 58:653

  10. 10.

    Baurain R, Deprez-De Campaneere D, Trouet A (1979) Rapid determination of doxorubicin and its fluorescent metabolites by high pressure liquid chromatography. Anal Biochem 94:112

  11. 11.

    De Jong J, Guérand WS, Schoofs PR, Bast A, Vijgh WJF van der (1991) Simple and sensitive quantification of anthracyclines in mouse atrial tissue using high-performance liquid chromatography and fluorescence detection. J Chromatogr 570:209

  12. 12.

    Piazza E, Natale N, Trabattoni A, Mariscotti C, Mosca L, Libretti A, Ottolenghi L, Morasca L (1981) Plasma and tissue distribution of adriamycin in patients with pelvic cancer. Tumori 67:533

  13. 13.

    Pelikan PCD, Weisfieldt ML, Jacobus WE, Miceli MV, Bulkley BH, Gerstenblith G (1986) Acute doxorubicin cardiotoxicity: functional, metabolic, and morphologic alterations in isolated, perfused rat heart. J Cardiovasc Pharmacol 8:1058

  14. 14.

    Rabkin SW (1983) Interaction of external calcium concentration and verapamil on the effects of doxorubicin (adriamycin) in the isolated heart preparation. J Cardiovasc Pharmacol 5:848

  15. 15.

    Lee V, Randhawa AK, Singal PK (1991) Adriamycin-induced myocardial dysfunction in vitro is mediated by free radical. Am J Physiol 261H:989

  16. 16.

    Kusuoka H, Futaki S, Koretsune Y, Kitabatake A, Suga H, Kamada T, Inoue M (1991) Alterations of intracellular calcium homeostasis and myocardial energetics in acute adriamycin-induced heart failure. J Cardiovasc Pharmacol 18:437

  17. 17.

    Olson RD, Mushlin PS, Brenner DE, Fleischer S, Cusack BJ, Chang BK, Boucek RJ (1988) Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol. Proc Natl Acad Sci USA 85:3585

  18. 18.

    Llesuy SF, Milei J, Molina H, Boveris A, Milei S (1985) Comparison of lipid peroxidation and myocardial damage induced by adriamycin and 4′-epiadriamycin in mice. Tumori 71:241

  19. 19.

    Cini-Neri G, Neri B, Bandinelli M, Del Tacca M, Danesi R (1991) Anthracycline cardiotoxicity: in vivo and in vitro effects on biochemical parameters and heart ultrastructure of the rat. Oncology 48:327

  20. 20.

    Bonfante V, Ferrari L, Brambilla C, Rossi A, Villani F, Crippa F, Valagussa P, Bonadonna G (1986) New anthracycline analogs in advanced breast cancer. Eur J Cancer Clin Oncol 22:1379

  21. 21.

    Weenen H, Lankelma J, Penders PGM, McVie JG, Bokkel Huinink WW ten, De Planque MM, Pinedo HM (1983) Pharmacokinetics of 4′-epi-doxorubicin in man. Invest New Drugs 1:59

  22. 22.

    Vijgh WJF van der, Maessen PA, Pinedo HM (1990) Comparative metabolism and pharmacokinetics of doxorubicin and 4′-epidoxorubicin in plasma heart and tumor of tumor-bearing mice. Cancer Chemother Pharmacol 26:9

  23. 23.

    Andersson M, Domellöf L, Eksborg S, Häggmark S, Johansson G, Reiz S, Herslöf A (1989) Pharmacokinetics and central haemodynamic effects of doxorubicin and 4′-epi-doxorubicin in the pig. Acta Oncol 28:709

  24. 24.

    Iguchi H, Tone H, Ishikura T, Takeuchi T, Umezawa H (1985) Pharmacokinetics and disposition of 4′-O-tetrahydropyranyladriamycin in mice by HPLC analysis. Cancer Chemother Pharmacol 15:132

  25. 25.

    Kunimoto S, Miura K, Takahashi Y, Takeuchi T, Umezawa H (1983) Rapid uptake by cultured tumor cells and intracellular behavior of 4′-O-tetrahydropyranyladriamycin. J Antibiot 36:312

  26. 26.

    Mushlin SP, Cusack BJ, Boucek RJ, Andrejuk T, Li X, Olson RD (1993) Time-related increases in cardiac concentrations of doxorubicinol could interact with doxorubicin to depress myocardial contractile function. Br J Pharmacol 110:975

  27. 27.

    Sweatman TW, Israel M (1987) Comparative metabolism and elimination of adriamycin and 4′-epiadriamycin in the rat. Cancer Chemother Pharmacol 19:201

  28. 28.

    Robert J, David M, Huet S, Chauvergne J (1988) Pharmacokinetics and metabolism of pirarubicin in advanced cancer patients. Eur J Cancer Clin Oncol 24:1289

  29. 29.

    Del Tacca M, Danesi R, Solaini G, Bernardini MC, Bertelli A (1987) Effects of 4′-O-tetrahydropyranyl-doxorubicin on isolated perfused rat heart and cardiac mitochondrial cytochrome C oxidase activity. Anticancer Res 7:803

  30. 30.

    Leiris J de, Harding DP, Pestre S (1984) The isolated perfused rat heart: a model for studying myocardial hypoxia or ischaemia. Basic Res Cardiol 79:313

  31. 31.

    Hirano S, Agata N, Hara Y, Iguchi H, Shirai, Tone H, Urakawa (1991) Effects of pirarubicin, an antitumor antibiotic, on the cardiovascular system. Cancer Chemother Pharmacol 28:266

  32. 32.

    Temma K, Akera T, Chugun A, Kondo H, Hagane K, Hirano S (1993) Comparison of cardiac actions of doxorubicin, pirarubicin and aclarubicin in isolated guinea-pig heart. Eur J Pharmacol 234:173

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Correspondence to Jacques Robert.

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Pouna, P., Bonoron-Adèle, S., Gouverneur, G. et al. Evaluation of anthracycline cardiotoxicity with the model of isolated, perfused rat heart: comparison of new analogues versus doxorubicin. Cancer Chemother. Pharmacol. 35, 257–261 (1995). https://doi.org/10.1007/BF00686558

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Key words

  • Anthracyclines
  • Cardiotoxicity
  • Isolated perfused rat heart