Evaluation of Anthracycline Cardiotoxicity with the Model of Isolated, Perfused Rat Heart: Comparison of New Analogues Versus Doxorubicin

Overview

Journal Cancer Chemother Pharmacol

Specialty Oncology

Date 1995 Jan 1

PMID 7805186

Citations 4

Authors

P Pouna

G Gouverneur

L Tariosse

P Besse

J Robert

Affiliations

Soon will be listed here.

Abstract

We have compared the cardiotoxicity 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.

Citing Articles

Cisplatin and cisplatin analogues perfusion through isolated rat heart: the effects of acute application on oxidative stress biomarkers.

Stojic I, Zivkovic V, Srejovic I, Nikolic T, Jeremic N, Jeremic J Mol Cell Biochem. 2017; 439(1-2):19-33.

PMID: 28766171 DOI: 10.1007/s11010-017-3132-8.

Pirarubicin versus doxorubicin in neoadjuvant/adjuvant chemotherapy for stage IIB limb high-grade osteosarcoma: does the analog matter?.

Yu W, Tang L, Lin F, Yao Y, Shen Z Med Oncol. 2014; 32(1):307.

PMID: 25432694 DOI: 10.1007/s12032-014-0307-y.

Epirubicin. An updated review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of breast cancer.

Coukell A, Faulds D Drugs. 1997; 53(3):453-82.

PMID: 9074845 DOI: 10.2165/00003495-199753030-00008.

Development of the model of rat isolated perfused heart for the evaluation of anthracycline cardiotoxicity and its circumvention.

Pouna P, Gouverneur G, Tariosse L, Besse P, Robert J Br J Pharmacol. 1996; 117(7):1593-9.

PMID: 8730759 PMC: 1909465. DOI: 10.1111/j.1476-5381.1996.tb15326.x.

References

Kunimoto S, Miura K, Takahashi Y, Takeuchi T, Umezawa H . Rapid uptake by cultured tumor cells and intracellular behavior of 4'-O-tetrahydropyranyladriamycin. J Antibiot (Tokyo). 1983; 36(3):312-7. DOI: 10.7164/antibiotics.36.312. View

de Jong J, Guerand W, Schoofs P, Bast A, van der Vijgh W . Simple and sensitive quantification of anthracyclines in mouse atrial tissue using high-performance liquid chromatography and fluorescence detection. J Chromatogr. 1991; 570(1):209-16. DOI: 10.1016/0378-4347(91)80218-2. View

Ganzina F, Di Pietro N, Magni O . Clinical toxicity of 4'-epi-doxorubicin (epirubicin). Tumori. 1985; 71(3):233-40. DOI: 10.1177/030089168507100304. View

de Leiris J, Harding D, Pestre S . The isolated perfused rat heart: a model for studying myocardial hypoxia or ischaemia. Basic Res Cardiol. 1984; 79(3):313-21. DOI: 10.1007/BF01908032. View

Temma K, Akera T, Chugun A, Kondo H, Hagane K, Hirano S . Comparison of cardiac actions of doxorubicin, pirarubicin and aclarubicin in isolated guinea-pig heart. Eur J Pharmacol. 1993; 234(2-3):173-81. DOI: 10.1016/0014-2999(93)90951-d. View

Hirano S, Agata N, Hara Y, Iguchi H, Shirai M, Tone H . Effects of pirarubicin, an antitumor antibiotic, on the cardiovascular system. Cancer Chemother Pharmacol. 1991; 28(4):266-72. DOI: 10.1007/BF00685533. View

Lee V, Randhawa A, Singal P . Adriamycin-induced myocardial dysfunction in vitro is mediated by free radicals. Am J Physiol. 1991; 261(4 Pt 2):H989-95. DOI: 10.1152/ajpheart.1991.261.4.H989. View

Cini Neri G, Neri B, Bandinelli M, Del Tacca M, Danesi R, Riccardi R . Anthracycline cardiotoxicity: in vivo and in vitro effects on biochemical parameters and heart ultrastructure of the rat. Oncology. 1991; 48(4):327-33. DOI: 10.1159/000226952. View

Maehara Y, Sakaguchi Y, Kusumoto T, Kusumoto H, Sugimachi K . 4'-O-tetrahydropyranyladriamycin has greater antineoplastic activity than adriamycin in various human tumours in vitro. Anticancer Res. 1989; 9(2):387-9. View

10.

Robert J, David M, Huet S, Chauvergne J . Pharmacokinetics and metabolism of pirarubicin in advanced cancer patients. Eur J Cancer Clin Oncol. 1988; 24(8):1289-94. DOI: 10.1016/0277-5379(88)90217-9. View

11.

Herait P, Poutignat N, Marty M, Bugat R . Early assessment of a new anticancer drug analogue--are the historical comparisons obsolete? The French experience with pirarubicin. Eur J Cancer. 1992; 28A(10):1670-6. DOI: 10.1016/0959-8049(92)90066-b. View

12.

CASAZZA A . Preclinical selection of new anthracyclines. Cancer Treat Rep. 1986; 70(1):43-9. View

13.

Keizer H, Pinedo H, Schuurhuis G, Joenje H . Doxorubicin (adriamycin): a critical review of free radical-dependent mechanisms of cytotoxicity. Pharmacol Ther. 1990; 47(2):219-31. DOI: 10.1016/0163-7258(90)90088-j. View

14.

Sweatman T, Israel M . Comparative metabolism and elimination of adriamycin and 4'-epiadriamycin in the rat. Cancer Chemother Pharmacol. 1987; 19(3):201-6. DOI: 10.1007/BF00252973. View

15.

Bonfante V, Ferrari L, Brambilla C, Rossi A, Villani F, Crippa F . New anthracycline analogs in advanced breast cancer. Eur J Cancer Clin Oncol. 1986; 22(11):1379-85. DOI: 10.1016/0277-5379(86)90149-5. View

16.

Kusuoka H, Futaki S, Koretsune Y, Kitabatake A, Suga H, Kamada T . Alterations of intracellular calcium homeostasis and myocardial energetics in acute adriamycin-induced heart failure. J Cardiovasc Pharmacol. 1991; 18(3):437-44. DOI: 10.1097/00005344-199109000-00017. View

17.

Weenen H, Lankelma J, Penders P, McVie J, Ten Bokkel Huinink W, de Planque M . Pharmacokinetics of 4'-epi-doxorubicin in man. Invest New Drugs. 1983; 1(1):59-64. DOI: 10.1007/BF00180192. View

18.

van der Vijgh W, Maessen P, Pinedo H . Comparative metabolism and pharmacokinetics of doxorubicin and 4'-epidoxorubicin in plasma, heart and tumor of tumor-bearing mice. Cancer Chemother Pharmacol. 1990; 26(1):9-12. DOI: 10.1007/BF02940286. View

19.

Andersson M, Domellof L, Eksborg S, Haggmark S, Johansson G, Reiz S . Pharmacokinetics and central haemodynamic effects of doxorubicin and 4'epi-doxorubicin in the pig. Acta Oncol. 1989; 28(5):709-14. DOI: 10.3109/02841868909092298. View

20.

Cummings J, Anderson L, Willmott N, Smyth J . The molecular pharmacology of doxorubicin in vivo. Eur J Cancer. 1991; 27(5):532-5. DOI: 10.1016/0277-5379(91)90209-v. View