Duxorubicin-induced cardiotoxicity

Mukund Joshi, Kuldip Singh Sodhi, Rajesh Pandey, Jasbir Singh, Subhash Goyal

Abstract


The survival rate of cancer patients has greatly increased over the last 20 years. However, to achieve this result, a considerable price has been paid in terms of the side-effects associated with the intensive anticancer treatment. Cardiotoxicity of anticancer drugs is a serious problem. It is defined, by the National Cancer Institute, as the “toxicity that affects the heart.” This definition not only includes a direct effect of the drug on the heart, but also an indirect effect due to enhancement of hemodynamic flow alterations or due to thrombotic events. Cardiotoxicity can develop in a subacute, acute, or chronic manner. The risk for such effects depends upon: cumulative dose, rate of drug administration, mediastinal radiation, advanced age, younger age, female gender, pre-existing heart disease and hypertension. Anthracyclines, such as doxorubicin (DOX), cause serious cardiac side-effects. Acute tachyarrhythmias and acute heart failure (HF) may occur after high doses, but these reactions are now rare due to changed dosage schemes (e.g. slower infusion) with the aim to prevent this. However, the sub-acute or chronic cardiac effects of anthracyclines remain a clinical problem. Clinically, anthracycline induced cardiotoxicity manifests itself as left ventricular failure, which develops insidiously over months to years after completion of the anthracycline based chemotherapy and may result in congestive HF. The mechanism of anthracyclin induced cardiotoxicity is not totally unraveled. It is likely that the decline in myocardial function is related to apoptosis of cardiac myocytes that occurs apparently at random in the myocardium. Anthracyclin induced formation of reactive oxygen species (ROS) in the presence of intracellular iron, impaired homeostasis of intracellular iron and calcium (that may facilitate the apoptosis induced by the ROS) have been put forward as mechanisms. Cardiac protection can be achieved by limitation of the cumulative dose. Further, addition of the antioxidant and iron chelator dexrazoxane to anthracycline therapy has shown to be effective in lowering the incidence of anthracycline induced cardiotoxicity.


Keywords


Cardiotoxicity, Cytotoxic drugs, Cancer, Chemotherapy, Anthracyclines, Duxorubicin

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References


Monsuez JJ, Charniot JC, Vignat N, Artigou JY. Cardiac side-effects of cancer chemotherapy. Int J Cardiol. 2010;144(1):3-15.

Albini A, Pennesi G, Donatelli F, Cammarota R, De Flora S, Noonan DM. Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention. J Natl Cancer Inst. 2010;102(1):14-25.

Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med. 1998;339(13):900-5.

Frishman WH, Sung HM, Yee HC, Liu LL, Keefe D, Einzig AI, et al. Cardiovascular toxicity with cancer chemotherapy. Curr Probl Cancer. 1997;21(6):301-60.

Von Hoff DD, Rozencweig M, Layard M, Slavik M, Muggia FM. Daunomycin-induced cardiotoxicity in children and adults. A review of 110 cases. Am J Med. 1977;62(2):200-8.

Von Hoff DD, Layard MW, Basa P, Davis HL Jr, Von Hoff AL, Rozencweig M, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med. 1979;91(5):710-7.

Haq MM, Legha SS, Choksi J, Hortobagyi GN, Benjamin RS, Ewer M, et al. Doxorubicin-induced congestive heart failure in adults. Cancer. 1985;56(6):1361-5.

Steinherz LJ, Steinherz PG, Tan C. Cardiac failure and dysrhythmias 6-19 years after anthracycline therapy: a series of 15 patients. Med Pediatr Oncol. 1995;24(6):352-61.

Lipshultz SE, Colan SD, Gelber RD, Perez-Atayde AR, Sallan SE, Sanders SP. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med. 1991;324(12):808-15.

Yeung ST, Yoong C, Spink J, Galbraith A, Smith PJ. Functional myocardial impairment in children treated with anthracyclines for cancer. Lancet. 1991;337(8745):816-8.

Ali MK, Ewer MS, Gibbs HR, Swafford J, Graff KL. Late doxorubicin-associated cardiotoxicity in children. The possible role of intercurrent viral infection. Cancer. 1994;74(1):182-8.

Florescu M, Cinteza M, Vinereanu D. Chemotherapy-induced Cardiotoxicity. Maedica (Buchar). 2013;8(1):59-67.

Dolci A, Dominici R, Cardinale D, Sandri MT, Panteghini M. Biochemical markers for predicting chemotherapy-induced cardiotoxicity: systematic review of the literature and recommendations for use. G Ital Cardiol (Rome). 2006;7(9):604-11.

Rathe M, Carlsen NL, Oxhøj H. Late cardiac effects of anthracycline containing therapy for childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2007;48:663-7.

Steinherz LJ, Steinherz PG, Tan CT, Heller G, Murphy ML. Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA. 1991;266(12):1672-7.

van Dalen EC, van der Pal HJ, Kok WE, Caron HN, Kremer LC. Clinical heart failure in a cohort of children treated with anthracyclines: a long-term follow-up study. Eur J Cancer. 2006;42(18):3191-8.

Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Saf. 2000;22(4):263-302.

Ruggiero A, De Rosa G, Rizzo D, Leo A, Maurizi P, De Nisco A, et al. Myocardial performance index and biochemical markers for early detection of doxorubicin-induced cardiotoxicity in children with acute lymphoblastic leukaemia. Int J Clin Oncol. 2013;18(5):927-33.

Gianni L, Herman EH, Lipshultz SE, Minotti G, Sarvazyan N, Sawyer DB. Anthracycline cardiotoxicity: from bench to bedside. J Clin Oncol. 2008;26(22):3777-84.

Adriamycin (doxorubicin) Data Sheet. Auckland, New Zealand: Pfizer New Zealand Ltd; 2011.

Brana I, Tabernero J. Cardiotoxicity. Ann Oncol. 2010;21 Suppl 7:vii173-9.

Keefe DL. Anthracycline-induced cardiomyopathy. Semin Oncol. 2001;28(4 Suppl 12):2-7.

Safra T. Cardiac safety of liposomal anthracyclines. Oncologist. 2003;8 Suppl 2:17-24.

Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783-92.

Harake D, Franco VI, Henkel JM, Miller TL, Lipshultz SE. Cardiotoxicity in childhood cancer survivors: strategies for prevention and management. Future Cardiol. 2012;8(4):647-70.

Lipshultz SE, Rusconi P, Scully RE. Assessment of cardiotoxicity during anti-cancer therapy. In: Januzzi JL, Bayes-Genis A, editors. NT-proBNP as a Biomarker in Cardiovascular Diseases. Chapter 18. Barcelona, Spain: Prous Science SA; 2007: 193-8.

Portera CC, Swain SM. The heart of the matter. J Clin Oncol. 2007;25(25):3794-6.

Prezioso L, Tanzi S, Galaverna F, Frati C, Testa B, Savi M, et al. Cancer treatment-induced cardiotoxicity: a cardiac stem cell disease? Cardiovasc Hematol Agents Med Chem. 2010;8(1):55-75.

Zambetti M, Moliterni A, Materazzo C, Stefanelli M, Cipriani S, Valagussa P, et al. Longterm cardiac sequelae in operable breast cancer patients given adjuvant chemotherapy with or without doxorubicin and breast irradiation. J Clin Oncol. 2001;19(1):37-43.

Köseoglu V, Berberoglu S, Karademir S, Kismet E, Yurttutan N, Demirkaya E, et al. Cardiac troponin I: is it a marker to detect cardiotoxicity in children treated with doxorubicin? Turk J Pediatr. 2005;47:17-22.

Lipshultz SE, Rifai N, Sallan SE, Lipsitz SR, Dalton V, Sacks DB, et al. Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation. 1997;96(8):2641-8.

Missov E, Calzolari C, Davy JM, Leclercq F, Rossi M, Pau B. Cardiac troponin I in patients with hematologic malignancies. Coron Artery Dis. 1997;8(8-9):537-41.

Herman EH, Zhang J, Lipshultz SE, Rifai N, Chadwick D, Takeda K, et al. Correlation between serum levels of cardiac troponin-T and the severity of the chronic cardiomyopathy induced by doxorubicin. J Clin Oncol. 1999;17(7):2237-43.

Kismet E, Varan A, Ayabakan C, Alehan D, Portakal O, Büyükpamukçu M. Serum troponin T levels and echocardiographic evaluation in children treated with doxorubicin. Pediatr Blood Cancer. 2004;42(3):220-4.

Goukassian D, Morgan J, Yan X. Neuregulin1-ErbB signaling in doxorubicin-induced cardiotoxicity. In: Fiuza M, editor. Cardiotoxicity of Oncologic Treatments. InTech; 2012. Available at: http://www.intechopen.com/books/cardiotoxicityofoncologictreatments/neuregulin1-erbb-signaling-in-doxorubicin-induced-cardiotoxicity. Accessed 25 October 2014.

Lebrecht D, Setzer B, Ketelsen UP, Haberstroh J, Walker UA: Time-dependent and tissue-specific accumulation of mtDNA and respiratory chain defects in chronic doxorubicin cardiomyopathy. Available at: http://www.circ.ahajournals.org/content/108/19/2423. Accessed 25 October 2014.

Nakamura T, Ueda Y, Juan Y, Katsuda S, Takahashi H, Koh E. Fas-mediated apoptosis in adriamycin-induced cardiomyopathy in rats: in vivo study. Circulation. 2000;102(5):572-8.

Kalivendi SV, Konorev EA, Cunningham S, Vanamala SK, Kaji EH, Joseph J, et al. Doxorubicin activates nuclear factor of activated T-lymphocytes and Fas ligand transcription: role of mitochondrial reactive oxygen species and calcium. Biochem J. 2005;389(Pt 2):527-39.

Hengartner MO. The biochemistry of apoptosis. Nature. 2000;407(6805):770-6.

Poizat C, Sartorelli V, Chung G, Kloner RA, Kedes L. Proteasome-mediated degradation of the coactivator p300 impairs cardiac transcription. Mol Cell Biol. 2000;20(23):8643-54.

Ito H, Miller SC, Billingham ME, Akimoto H, Torti SV, Wade R, et al. Doxorubicin selectively inhibits muscle gene expression in cardiac muscle cells in vivo and in vitro. Proc Natl Acad Sci U S A. 1990;87(11):4275-9.

Bian Y, Sun M, Silver M, Ho KK, Marchionni MA, Caggiano AO, et al. Neuregulin-1 attenuated doxorubicin-induced decrease in cardiac troponins. Am J Physiol Heart Circ Physiol. 2009;297(6):H1974-83.

Aries A, Paradis P, Lefebvre C, Schwartz RJ, Nemer M. Essential role of GATA-4 in cell survival and drug-induced cardiotoxicity. Proc Natl Acad Sci U S A. 2004;101(18):6975-80.

Sawyer DB, Zuppinger C, Miller TA, Eppenberger HM, Suter TM. Modulation of anthracycline-induced myofibrillar disarray in rat ventricular myocytes by neuregulin-1beta and anti-erbB2: potential mechanism for trastuzumab-induced cardiotoxicity. Circulation. 2002;105(13):1551-4.

Helmes M, Lim CC, Liao R, Bharti A, Cui L, Sawyer DB. Titin determines the Frank-Starling relation in early diastole. J Gen Physiol. 2003;121(2):97-110.

Lim CC, Zuppinger C, Guo X, Kuster GM, Helmes M, Eppenberger HM, et al. Anthracyclines induce calpain-dependent titin proteolysis and necrosis in cardiomyocytes. J Biol Chem. 2004;279(9):8290-9

del MonteF, Harding SE, Schmidt U, Matsui T, Kang ZB, Dec GW, et al. Restoration of contractile function in isolated cardiomyocytes from failing human hearts by gene transfer of SERCA2a. Circulation. 1999;100(3):2308-11.

Wehrens XH, Marks AR. Novel therapeutic approaches for heart failure by normalizing calcium cycling. Nat Rev Drug Discov. 2004;3(7):565-73.

Schmidt U, Hajjar RJ, Helm PA, Kim CS, Doye AA, Gwathmey JK. Contribution of abnormal sarcoplasmic reticulum ATPase activity to systolic and diastolic dysfunction in human heart failure. J Mol Cell Cardiol. 1998;30(10):1929-37.

Schmidt U, Hajjar RJ, Kim CS, Lebeche D, Doye AA, Gwathmey JK. Human heart failure: CAMP stimulation of SR Ca(2+)-ATPase activity and phosphorylation level of phospholamban. Am J Physiol. 1999;277(2Pt2):H474-80

Dodd DA, Atkinson JB, Olson RD, Buck S, Cusack BJ, Fleischer S, et al. Doxorubicin cardiomyopathy is associated with a decrease in calcium release channel of the sarcoplasmic reticulum in a chronic rabbit model. J Clin Invest. 1993;91(4):1697-705.

Boucek RJ Jr, Miracle A, Anderson M, Engelman R, Atkinson J, Dodd DA. Persistent effects of doxorubicin on cardiac gene expression. J Mol Cell Cardiol. 1999;31(8):1435-46.

Gambliel HA, Burke BE, Cusack BJ, Walsh GM, Zhang YL, Mushlin PS, et al. Doxorubicin and C-13 deoxydoxorubicin effects on ryanodine receptor gene expression. Biochem Biophys Res Commun. 2002;291(3):433-8.

Burke BE, Olson RD, Cusack BJ, Gambliel HA, Dillmann WH. Anthracycline cardiotoxicity in transgenic mice overexpressing SR Ca2+-ATPase. Biochem Biophys Res Commun. 2003;303(2):504-7.

Saidi A, Alharethi R. Management of chemotherapy induced cardiomyopathy. Curr Cardiol Rev. 2011;7(4):245-9.

Smith LA, Cornelius VR, Plummer CJ, Levitt G, Verrill M, Canney P, et al. Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials. BMC Cancer. 2010;10:337.

Kalay N, Basar E, Ozdogru I, Er O, Cetinkaya Y, Dogan A, et al. Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol. 2006;48(11):2258-62.

Cardinale D, Colombo A, Sandri MT, Lamantia G, Colombo N, Civelli M, et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation. 2006;114(23):2474-81.

Mankoff SP, Brander C, Ferrone S, Marincola FM. Lost in Translation: obstacles to translational medicine. J Transl Med. 2004;2(1):14.