Cardiotoxicity in childhood cancer survivors: strategies for prevention and management

Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

References

• 1  Mariotto AB, Rowland JH, Yabroff KR et al. Long-term survivors of childhood cancers in the United States. Cancer Epidemiol. Biomarkers Prev.18,1033–1040 (2009).
  MedlineGoogle Scholar
• 2  Hinkle AS, Proukou C, French CA et al. A clinic-based, comprehensive care model for studying late effects in long-term survivors of pediatric illnesses. Pediatrics113(Suppl. 4),1141–1145 (2004).
  MedlineGoogle Scholar
• 3  Reulen RC, Winter DL, Frobisher C et al. Long-term cause-specific mortality among survivors of childhood cancer. JAMA304(2),172–179 (2010).
  Medline CASGoogle Scholar
• 4  Mulrooney DA, Yeazel MW, Kawashima T et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor study cohort. BMJ339,b4606 (2009).
  MedlineGoogle Scholar
• 5  van der Pal HJ, van Dalen EC, van Delden E et al. High risk of symptomatic cardiac events in childhood cancer survivors. J. Clin. Oncol.30(13),1429–1437 (2012).
  MedlineGoogle Scholar
• 6  Lipshultz SE, Adams MJ. Cardiotoxicity after childhood cancer: beginning with the end in mind. J. Clin. Oncol.28(8),1276–1281 (2010).▪▪ Critically analyzes various aspects of the association between specific treatments and specific cardiovascular causes of death in childhood cancer treatment. It raises several critical questions in determining which screening modalities could be most useful.
  MedlineGoogle Scholar
• 7  Hudson MM, Mertens AC, Yasui Y et al. Health status of adult long-term survivors of childhood cancer: a report from the childhood cancer survivor study. JAMA290(12),1583–1592 (2003).
  Medline CASGoogle Scholar
• 8  Mody R, Li S, Dover DC et al. Twenty-five-year follow-up among survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor study. Blood111(12),5515–5523 (2008).
  Medline CASGoogle Scholar
• 9  Miller TL, Lipsitz SR, Lopez-Mitnik G et al. Characteristics and determinants of adiposity in pediatric cancer survivors. Cancer Epidemiol. Biomarkers Prev.19(8),2013–2022 (2010).▪ Determined that emerging long-term complications of childhood cancer survivors, such as adiposity, should be closely monitored.
  MedlineGoogle Scholar
• 10  National Research Council. Chapter 4: late effects of childhood cancer. In: Childhood Cancer Survivorship: Improving Care and Quality of Life. Hewitt M, Weiner SL, Simone JV (Eds). National Academic Press, DC, USA, 48–49 (2003).
  Google Scholar
• 11  Alvarez JA, Scully RE, Miller TL et al. Long-term effects of treatments for childhood cancers. Curr. Opin. Pediatr.19,23–31 (2007).
  MedlineGoogle Scholar
• 12  van Dalen EC, Raphaël MF, Caron HN, Kremer LC. Treatment including anthracyclines versus treatment not including anthracyclines for childhood cancer. Cochrane Database Syst. Rev.1,CD006647 (2009).
  Google Scholar
• 13  Fulbright JM, Huh W, Anderson P, Chandra J. Can anthracycline therapy for pediatric malignancies be less cardiotoxic? Curr. Oncol. Rep.12(6),411–419 (2010).
  MedlineGoogle Scholar
• 14  Herman EH, Ferrans VJ, Jordan W, Ardalan B. Reduction of chronic daunorubicin cardiotoxicity by ICRF-187 in rabbits. Res. Commun. Chem. Pathol. Pharmacol.31(1),85–97 (1981).
  Medline CASGoogle Scholar
• 15  Herman EH, el-Hage AN, Ferrans VJ, Ardalan B. Comparison of the severity of the chronic cardiotoxicity produced by doxorubicin in normotensive and hypertensive rats. Toxicol. Appl. Pharmacol.78(2),202–214 (1985).
  Medline CASGoogle Scholar
• 16  Outomuro D, Grana DR, Azzato F, Milei J. Adriamycin-induced myocardial toxicity: new solutions for an old problem? Int. J. Cardiol.117(1),6–15 (2007).
  MedlineGoogle Scholar
• 17  Mordente A, Meucci E, Martorana GE, Giardina B, Minotti G. Human heart cytosolic reductases and anthracycline cardiotoxicity. IUBMB Life52,83–88 (2001).
  Medline CASGoogle Scholar
• 18  Wouters KA, Kremer LC, Miller TL, Herman EH, Lipshultz SE. Protecting against anthracycline-induced myocardial damage: a review of the most promising strategies. Br. J. Haematol.131(5),561–578 (2005).
  Medline CASGoogle Scholar
• 19  Gianni L, Zweier JL, Levy A, Myers CE. Characterization of the cycle of iron-mediated electron transfer from adriamycin to molecular oxygen. J. Biol. Chem.260(11),6820–6826 (1985).
  Medline CASGoogle Scholar
• 20  Olson RD, Mushlin PS. Doxorubicin cardiotoxicity: analysis of prevailing hypothesis. FASEB J.4(13),3076–3086 (1990).
  Medline CASGoogle Scholar
• 21  Milei J, Boveris A, Llesuy S et al. Amelioration of adriamycin-induced cardiotoxicity in rabbits by prenylamine and vitamins A and E. Am. Heart J.111,95–102 (1986).
  Medline CASGoogle Scholar
• 22  Ferrero ME, Ferrero E, Gaja U. Adriamycin: energy metabolism and mitochondrial oxidations in the heart of treated rabbits. Biochem. Pharmacol.25(2),125–130 (1976).
  Medline CASGoogle Scholar
• 23  Earm YE, Ho WK, So I. Effects of adriamycin on ionic currents in single cardiac myocytes of the rabbit. J. Mol. Cell. Cardiol.26(2),163–172 (1994).
  Medline CASGoogle Scholar
• 24  Olson RD, Li X, Palade P et al. Sarcoplasmic reticulum calcium release is stimulated and inhibited by daunorubicin and daunorubicinol. Toxicol. Appl. Pharmacol.169(2),168–176 (2000).
  Medline CASGoogle Scholar
• 25  Gozalvez M, Blanco M. Inhibition of NA-K ATPase by the antitumor antibiotic adriamycin. 5th International Biophysics Congress, Copenhagen. Cancer Res.39(1),257–261 (1979).
  MedlineGoogle Scholar
• 26  Lou H, Danelisen I, Singal PK. Cytokines are not upregulated in adriamycin-induced cardiomyopathy and heart failure. J. Mol. Cell. Cardiol.36(5),683–690 (2004).
  Medline CASGoogle Scholar
• 27  Lenaz L, Page JA. Cardiotoxicity of adriamycin and related anthracyclines. Cancer Treat. Rev.3(3),111–120 (1976).
  Medline CASGoogle Scholar
• 28  Lipshultz SE, Rusconi P, Scully RE. Chapter 18: assessment of cardiotoxicity during anti-cancer therapy. In: NT-proBNP as a Biomarker in Cardiovascular Diseases. Januzzi JL, Bayes-Genis A (Eds). Prous Science SA, Barcelona, Spain, 193–198 (2007).
  Google Scholar
• 29  Pointon AV, Walker TM, Phillips KM et al. Doxorubicin in vivo rapidly alters expression and translation of myocardial electron transport chain genes, leads to ATP loss and caspase 3 activation. PLoS ONE5(9),e12733 (2010).
  MedlineGoogle Scholar
• 30  Gonzalvez F, Gottlieb E. Cardiolipin: setting the beat of apoptosis. Apoptosis12(5),877–885 (2007).
  Medline CASGoogle Scholar
• 31  Goormaghtigh E, Brasseur R, Huart P, Ruysschaert JM. Study of the adriamycin cardiolipin complex structure using attenuated total reflection infrared spectroscopy. Biochemistry26(6),1789–1794 (1987).
  Medline CASGoogle Scholar
• 32  Garcia Fernandez M, Troiano L, Moretti L. Early changes in intramitochondrial cardiolipin distribution during apoptosis. Cell Growth Differ.13(9),449–455 (2002).
  MedlineGoogle Scholar
• 33  Aguilar L, Ortega-Pierres G, Campos B et al. Phospholipid membranes form specific nonbilayer molecular arrangements that are antigenic. J. Biol. Chem.274(36),25193–25196 (1999).
  Medline CASGoogle Scholar
• 34  Vlasova II, Tyurin VA, Kapralov AA et al. Nitric oxide inhibits peroxidase activity of cytochrome C cardiolipin complex and blocks cardioliopin oxidation. J. Biol. Chem.281(21),14554–14562 (2006).
  Medline CASGoogle Scholar
• 35  Arola OJ, Saraste A, Pulkki K, Kallajoki M, Parvinen M, Voipio-Pulkki LM. Acute doxorubicin cardiotoxicity involves cardiomyocte apoptosis. Cancer Res.60(7),1789–1792 (2000).
  Medline CASGoogle Scholar
• 36  Zhang YQ, Shi J, Li YJ, Wei L. Cardiomyocyte death in doxorubicin-induced cardiotoxicity. Arch. Immunol. Ther. Exp.57(6),435–445 (2009).
  Medline CASGoogle Scholar
• 37  Adams MJ, Lipshultz SE. Pathophysiology of anthracycline- and radiation-associated cardiomyopathies: implications for screening and prevention. Pediatr. Blood Cancer44(7),600–606 (2005).
  MedlineGoogle Scholar
• 38  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.324(12),808–815 (1991).▪ Established that that doxorubicin impairs myocardial growth resulting in reduced contractility in a dose-dependent manner.
  Medline CASGoogle Scholar
• 39  Sorensen K, Levitt G, Bull C, Chessells J, Sullivan I. Anthracycline dose in childhood acute lymphoblastic leukemia: issues of early survival versus late cardiotoxicity. J. Clin. Oncol.15(1),61–68 (1997).
  Medline CASGoogle Scholar
• 40  Giantris A, Abdurrahman L, Hinkle A et al. Anthracycline-induced cardiotoxicity in children and young adults. Crit. Rev. Oncol. Hematol.27,53–68 (1998).
  Medline CASGoogle Scholar
• 41  Doroshow JH, Locker GY, Myers CE. Enzymatic defenses of the mouse heart against reactive oxygen metabolites: alterations produced by doxorubicin. J. Clin. Invest.65(1),128–135 (1980).
  Medline CASGoogle Scholar
• 42  Cascales A, Sanchez-Vega B, Navarro N, Pastor-Quirante F, Corral J, Vicente V, de la Pena FA. Clinical and genetic determinants of anthracycline-induced cardiac iron accumulation. Int. J. Cardiol.154(3),282–286 (2010).
  MedlineGoogle Scholar
• 43  Arai M, Yoguchi A, Takizawa T et al. Mechanism of doxorubicin-induced inhibition of sarcoplasmic reticulum Ca²⁺-ATPase gene transcription. Circ. Res.86(1),8–14 (2000).
  Medline CASGoogle Scholar
• 44  Jeyaseelan R, Poizat C, Wu HY, Kedes L. Molecular mechanisms of doxorubicin-induced cardiomyopathy. Selective suppression of Reiske iron-sulfur protein, ADP/ATP translocase, and phosphofructokinase genes is associated with ATP depletion in rat cardiomyocytes. J. Biol. Chem.272(9),5828–5832 (1997).
  Medline CASGoogle Scholar
• 45  Lebrecht DMS, Setzer B, Ketelsen UP, Haberstroh J, Walker UA. Time-dependant and tissue-specific accumulation of mtDNA and respiratory chain defects in chronic doxorubicin cardiomyopathy. Circulation108(19),2423–2429 (2003).
  Medline CASGoogle Scholar
• 46  Arola OJ, Saraste A, Pulkki K, Kallajoki M, Parvinen M, Voipio-Pulkki LM. Acute doxorubicin cardiotoxicity involves cardiomyocte apoptosis. Cancer Res.60(7),1789–1792 (2000).
  Medline CASGoogle Scholar
• 47  Childs AC, Phaneuf SL, Dirks AJ, Phillips T, Leeuwenburgh C. Doxorubicin treatment in vivo causes cytochrome C release and cardiomyocyte apoptosis, as well as increased mitochondrial efficiency, superoxide dismutase activity, and Bcl-2:Bax ratio. Cancer Res.62(16),4592–4598 (2002).
  Medline CASGoogle Scholar
• 48  Von Hoff DD, Layard M, Basa P et al. Risk factors for doxorubicin-induced congestive heart failure. Ann. Intern. Med.91(5),710–717 (1979).
  Medline CASGoogle Scholar
• 49  Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer97(11),2869–2879 (2003).
  Medline CASGoogle Scholar
• 50  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. Cancer42(18),3191–3198 (2006).
  Medline CASGoogle Scholar
• 51  van der Pal HJ, van Dalen EC, Hauptmann M et al. Cardiac function in 5-year survivors of childhood cancer: a long-term follow-up study. Arch. Intern. Med.170(14),1247–1255 (2010).
  Medline CASGoogle Scholar
• 52  Blanco JG, Sun CL, Landier W et al. Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes – a report from the Children’s Oncology Group. J. Clin. Oncol.30(13),1415–1421 (2012).
  Medline CASGoogle Scholar
• 53  van Dalen EC, Caron HN, Dickinson HO, Kremer LCM. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst. Rev.25(1),CD003917. Update in: Cochrane Database Syst. Rev.2011(6),CD003917 (2005).
  Google Scholar
• 54  Lipshultz SE, Lipsitz SR, Sallen SE et al. Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. J. Clin. Oncol.23(12),2629–2636 (2005).▪▪ Cardiac dysfunction can be persistent and progressive in childhood survivors of acute lymphoblastic leukemia. Dilated cardiomyopathy can develop in these children after treatment; however, this study also found that as time passed the children expressed a restrictive cardiomyopathy pattern in their measurements.
  Medline CASGoogle Scholar
• 55  Davies SM. Getting to the heart of the matter. J. Clin. Oncol.30(13),1399–1400 (2012).
  MedlineGoogle Scholar
• 56  Visscher H, Ross CJD, Rassekh SR et al. Pharmacogenomic prediction of anthracycline-induced cardiotoxicity in children. J. Clin. Oncol.30(13),1422–1428 (2012).
  MedlineGoogle Scholar
• 57  Krischer JP, Epstein S, Cuthbertson DD, Goorin AM, Epstein ML, Lipshultz SE. Clinical cardiotoxicity following anthracycline treatment for childhood cancer: the Pediatric Oncology Group experience. J. Clin. Oncol.15,1544–1552 (1997).
  Medline CASGoogle Scholar
• 58  Sorensen K, Levitt GA, Bull C, Dorup I, Sullivan ID. Late anthracycline cardiotoxicity after childhood cancer: a prospective longitudinal study. Cancer97(8),1991–1998 (2003).
  Medline CASGoogle Scholar
• 59  Nysom K, Holm K, Lipsitz SR et al. Relationship between cumulative anthracycline dose and late cardiotoxicity in childhood acute lymphoblastic leukemia. J. Clin. Oncol.2,545–550 (1998).
  Google Scholar
• 60  Lipshultz SE, Lipsitz SR, Mone SM et al. Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N. Engl. J. Med.332(26),1738–1743 (1995).
  Medline CASGoogle Scholar
• 61  Steinherz LJ, Steinherz PG, Tan CT, Heller G, Murphy ML. Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA266(12),1672–1677 (1991).
  Medline CASGoogle Scholar
• 62  Anderlini P, Bengamin RS, Wong FC et al. Idarubicin cardiotoxicity: a retrospective study in acute myeloid leukemia and myelodysplasia. J. Clin. Oncol.13(11),2827–2834 (1995).
  Medline CASGoogle Scholar
• 63  Sorensen K, Levitt G, Sebag-Montefiore D, Bull C, Sullivan I. Cardiac function in Wilms’ tumor survivors. J. Clin. Oncol.13(7),1546–1556 (1995).
  Medline CASGoogle Scholar
• 64  Nysom K, Colan DC, Lipshultz SE. Late cardiotoxicity following anthracycline therapy for childhood cancer. Prog. Pediatr. Cardiol.8,121–138 (1998).
  Google Scholar
• 65  Green DM, Grigoriev YA, Nan B et al. Congestive heart failure after treatment for Wilms’ tumor: a report from the National Wilms’ Tumor Study Group. J. Clin. Oncol.19(7),1926–1934 (2001).
  Medline CASGoogle Scholar
• 66  Kremer LCM, van Dalen EC, Offringa M, Ottenkamp J, Voûte PA. Anthracycline-induced clinical heart failure in a cohort of 607 children: long-term follow-up study. J. Clin. Oncol.19(1),191–196 (2001).
  Medline CASGoogle Scholar
• 67  Tukenova M, Guibout C, Oberlin O et al. Role of cancer treatment in long-term overall and cardiovascular mortality after childhood cancer. J. Clin. Oncol.28(8),1308–1315 (2010).
  MedlineGoogle Scholar
• 68  Rodvold KA, Rushing DA, Tewksbury DA. Doxorubicin clearance in the obese. J. Clin. Oncol.6(8),1321–1327 (1998).
  Google Scholar
• 69  Bristow MR, Thompson PD, Martin RP, Mason JW, Billingham ME, Harrison DC. Early anthracycline cardiotoxicity. Am. J. Med.65(5),823–832 (1978).
  Medline CASGoogle Scholar
• 70  Lipshultz SE, Miller TM, Scully RE et al. Changes in cardiac biomarkers during doxorubicin treatment of pediatric patients with high-risk acute lymphoblastic leukemia: associations with long-term echocardiographic outcomes. J. Clin. Oncol.30(10),1042–1049 (2012).▪▪ Early detection of damage or death to the cardiomyocytes is crucial to individualization of treatment and effective prevention. This study found that cardiac troponin T and N-terminal probrain natriuretic peptide hold promise as biomarkers of cardiotoxicity for children with high-risk acute lymphoblastic leukemia.
  Medline CASGoogle Scholar
• 71  Ali MK, Ewer MS, Gibbs HR, Swafford J, Graff KL. Late doxorubicin-associated cardiotoxicity in children. The possible role of intercurrent viral infection. Cancer74(1),182–188 (1994).
  Medline CASGoogle Scholar
• 72  Tolba KA, Deliargyris EN. Cardiotoxicity of cancer therapy. Cancer Invest.17(6),408–422 (1999).
  Medline CASGoogle Scholar
• 73  Lipshultz SE, Alvarez JA, Scully RE. Anthracycline associated cardiotoxicity in survivors of childhood cancer. Heart94(4),525–533 (2008).
  Medline CASGoogle Scholar
• 74  Grenier MA, Lipshultz ME. Epidemiology of anthracycline cardiotoxicity in children and adults. Semin. Oncol.25(4 Suppl. 10),72–85 (1998).
  Medline CASGoogle Scholar
• 75  Simbre VC, Duffy SA, Dadlani GH, Miller TL, Lipshultz SE. Cardiotoxicity of cancer chemotherapy: implications for children. Paediatr. Drugs7,187–202 (2005).
  MedlineGoogle Scholar
• 76  Barry E, Alvarez JA, Scully RE, Miller TL, Lipshultz SE. Anthracycline-induced cardiotoxicity: course, pathophysiology, prevention and management. Expert Opin. Pharmacother.8,1039–1058 (2007).
  Medline CASGoogle Scholar
• 77  Herman EH, Zhang J, Lipshultz SE et al. Correlation between serum levels of cardiac troponin-T and the severity of the chronic cardiomyopathy induced by doxorubicin. J. Clin. Oncol.17,2237–2243 (1999).
  Medline CASGoogle Scholar
• 78  Lipshultz SE, Sanders SP, Goorin AM, Krischer JP, Sallan SE, Colan SD. Monitoring for anthracycline cardiotoxicity. Pediatrics93,433–437 (1994).
  Medline CASGoogle Scholar
• 79  Carver JR, Shapiro CL, NG A et al. ASCO Cancer Survivorship Exert Panel. American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects. J. Clin. Oncol.25,3991–4008 (2007).
  Medline CASGoogle Scholar
• 80  Steinhertz LJ, Graham T, Hurwitz R et al. Guidelines for cardiac monitoring of children during and after anthracycline therapy: Report of the cardiology committee of the Children’s Cancer Study Group. Pediatrics89,942–949 (1992).
  MedlineGoogle Scholar
• 81  Lipshultz SE, Sanders SP, Colan SD, Goorin AM, Sallan SE, Krischer JP. Letter to the Editor. Pediatrics94,781 (1994)
  Google Scholar
• 82  Adams MJ, Lipshultz SE, Schwartz C, Fajardo LF, Coen V, Constine LS. Radiation-associated cardiovascular disease: manifestations and management. Semin. Radiat. Oncol.13(3),346–356 (2003).
  MedlineGoogle Scholar
• 83  Adams MJ, Hardenbergh PH, Constine LS, Lipshultz SE. Radiation-associated cardiovascular disease. Crit. Rev. Oncol. Hematol.45(1),55–75 (2003).
  MedlineGoogle Scholar
• 84  Lipshultz SE, Rifai N, Dalton VM et al. The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N. Engl. J. Med.351(2),145–153 (2004).
  Medline CASGoogle Scholar
• 85  Ganame J, Claus P, Eyskens B et al. Acute cardiac functional and morphological changes after anthracycline infusions in children. Am. J. Cardiol.99(7),974–977 (2007).
  Medline CASGoogle Scholar
• 86  Ganame J, Claus P, Uyttebroeck A et al. Myocardial dysfunction late after low-dose anthracycline treatment in asymptomatic pediatric patients. J. Am. Soc. Echocardiogr.20(12),1351–1358 (2007).
  MedlineGoogle Scholar
• 87  Colan SD, Borrow KM, Neuman A. Left ventricular end-systolic wall stress-velocity of fiber shortening relation: a load independent index of myocardial contractility. J. Am. Coll. Cardiol.4,715–724 (1984).
  Medline CASGoogle Scholar
• 88  Lipshultz SE, Colan SD. The use of echocardiography and holter monitoring in the assessment of anthracycline-treated patients. In: Cardiac Toxicity After Treatment for Childhood Cancer. Wiley-Liss, NY, USA, 45–62 (1993).
  Google Scholar
• 89  Mitani I, Jain D, Joska TM, Burtness B, Zaret BL. Doxorubicin cardiotoxicity: Prevention of congestive heart failure with serial cardiac function monitoring with equilibrium radionuclide angiocardiography in the current era. J. Nucl. Cardiol.10(2),132–139 (2003).
  MedlineGoogle Scholar
• 90  Glanzmann C, Huguenin P, Lutolf UM, Maire R, Jenni R, Gumppenberg V. Cardiac lesions after mediastinal radiation for Hodgkin’s disease. Radiother. Oncol.30(1),43–54 (1994).
  Medline CASGoogle Scholar
• 91  Lipshultz SE, Rifai N, Sallan SE et al. Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation96(8),2641–2648 (1997).
  Medline CASGoogle Scholar
• 92  Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N. Engl. J. Med.339(5),321–328 (1998).
  Medline CASGoogle Scholar
• 93  Cowie MR, Mendez GF. BNP and congestive heart failure. Prog. Cardiovasc. Dis.44(4),293–321 (2002).
  Medline CASGoogle Scholar
• 94  Linssen GC, Bakker SJ, Voors AA et al. N-terminal pro-B-type natriuretic peptide is an independent predictor of cardiovascular morbidity and mortality in the general population. Eur. Heart J.31(1),120–127 (2010).
  Medline CASGoogle Scholar
• 95  Bibbins-Domingo K, Gupta R, Na B et al. N-terminal fragment of the prohormone brain-type natriuretic peptide (NT-proBNP), cardiovascular events, and mortality in patients with stable coronary heart disease. JAMA297,169–176 (2007).
  Medline CASGoogle Scholar
• 96  Trachtenberg BH, Landy DC, Franco VI et al. Anthracycline-associated cardiotoxicity in survivors of childhood cancer. Pediatr. Cardiol.32,342–353 (2011).
  MedlineGoogle Scholar
• 97  Franco VI, Henkel JM, Miller TL, Lipshultz SE. Cardiovascular effects in childhood cancer survivors treated with anthracyclines. Cardiol. Res. Pract.10,134679 (2011).
  Google Scholar
• 98  Schwartz CL, Hobbie WL, Truesdell S, Constine LC, Clark EB. Corrected QT interval prolongation in anthracycline-treated survivors of childhood cancer. J. Clin. Oncol.11(10),1906–1910 (1993).
  Medline CASGoogle Scholar
• 99  Larsen RL, Barber G, Heise CT, August CS. Exercise assessment of cardiac function in children and young adults before and after bone marrow transplantation. Pediatrics89(4 Pt 2),722–729 (1992).
  Medline CASGoogle Scholar
• 100  Weesner KM. Exercise echocardiography in the detection of anthracycline cardiotoxicity. Cancer68(2),435–438 (1991).
  Medline CASGoogle Scholar
• 101  Adams MJ, Lipsitz SR, Colan SD et al. Cardiovascular status in long-term survivors of Hodgkin’s disease treated with chest radiotherapy. J. Clin. Oncol.22(15),3139–3148 (2004).▪ Identifies several, often unsuspected, cardiovascular abnormalities found in long-term survivors of Hodgkin’s disease.
  MedlineGoogle Scholar
• 102  Hogenhuis J, Jaarsma T, Voors AA, Hillege HL, Lesman I, van Veldhuisen DJ. Correlates of B-type natriuretic peptide and 6-min walk in heart failure patients. Int. J. Cardiol.108(1),63–67 (2006).
  MedlineGoogle Scholar
• 103  Ryberg M, Nielsen D, Skovsgaard T, Hansen J, Jensen BV, Dombernowsky P. Epirubicin cardiotoxicity: an analysis of 469 patients with metastatic breast cancer. J. Clin. Oncol.16(11),3502–3508 (1998).
  Medline CASGoogle Scholar
• 104  Legha SS, Benjamin RS, Mackay B et al. Adriamycin therapy by continuous intravenous infusion in patients with metastatic breast cancer. Cancer49(9),1762–1766 (1982).
  Medline CASGoogle Scholar
• 105  Hortobagyi GN, Frye D, Buzdar AU et al. Decreased cardiac toxicity of doxorubicin administered by continuous intravenous infusion in combination chemotherapy for metastatic breast carcinoma. Cancer63(1),37–45 (1989).
  Medline CASGoogle Scholar
• 106  Shapira J, Gotfried M, Lishner M, Ravid M. Reduced cardiotoxicity of doxorubicin by a 6-hour infusion regiment. A prospective evaluation. Cancer65(4),870–873 (1990).
  Medline CASGoogle Scholar
• 107  Lipshultz SE, Giantris AL, Lipsitz SR et al. Doxorubicin administration by continuous infusion is not cardioprotective: the Dana-Farber 91–01 Acute Lymphoblastic Leukemia protocol. J. Clin. Oncol.20(6),1677–1682 (2002).▪▪ Pediatric protocols have incorporated continuous infusion of anthracyclines as a means of cardioprotection based on adult findings. However, this study found that continuous doxorubicin infusion over 48 h provided no cardioprotective advantage when compared with bolus infusion. Additionally, continuous infusion can result in longer hospital stays and decreased quality of life for the patient.
  Medline CASGoogle Scholar
• 108  Levitt GA, Dorup I, Sorensen K, Sullivan I. Does anthracycline administration by infusion in children affect late cardiotoxicity? Br. J. Haematol.24(4),463–468 (2004).
  Google Scholar
• 109  Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N. Engl. J. Med.339(13),900–905 (1998).
  Medline CASGoogle Scholar
• 110  Weiss RB. The anthracyclines: will we ever find a better doxorubicin? Semin. Oncol.19(6),670–686 (1992).
  Medline CASGoogle Scholar
• 111  Ganzina F 4´-epi-doxorubicin, a new analogue of doxorubicin: a preliminary overview of preclinical and clinical data. Cancer Treat. Rev.10(1),1–22 (1983).
  Medline CASGoogle Scholar
• 112  Lahtinen R, Kuikka J, Nousiainene T, Uusituoa M, Lansimies E. Cardiotoxicity of epirubicin and doxorubicin: a double-blind randomized study. Eur. J. Haematol.46(5),301–305 (1991).
  Medline CASGoogle Scholar
• 113  Cottin Y, Touzery C, Dalloz F et al. Comparison of epirubicin and doxorubicin cardiotoxicity induced by low doses: evolution of the diastolic and systolic parameters studies by radionuclide angiography. Clin. Cardiol.21(9),665–670 (1998).
  Medline CASGoogle Scholar
• 114  Dorr RT, Shipp NG, Lee KM. Comparison of cytotoxicity in heart cells and tumor cells exposed to DNA intercalating agents in vitro. Anticancer Drugs2(1),27–33 (1991).
  Medline CASGoogle Scholar
• 115  Alderton PM, Gross J, Green MD. Comparative study of doxorubicin, mitoxantrone, and epirubicin in combination with ICRF-187 (ADR-529) in a chronic cardiotoxicity animal model. Cancer Res.52(1),194–201 (1992).
  Medline CASGoogle Scholar
• 116  Herman EH, Zhang J, Hasinoff BB, Clark JRJ, Ferrans VJ. Comparison of the structural changes induced by doxorubicin and mitoxantrone in the heart, kidney and intestine and characterization of the Fe(III)-mitoxantrone complex. J. Mol. Cell. Cardiol.29(9),2415–2430 (1997).
  Medline CASGoogle Scholar
• 117  Creutzig U, Ritter J, Zimmermann M et al. Idarubicin improves blast cell clearance during induction therapy in children with AML: results of study AML-BFM 93. AML-BFM Study Group. Leukemia15(3),348–354 (2001).
  Medline CASGoogle Scholar
• 118  Tardi PG, Boman NL, Cullis PR. Liposomal doxorubicin. J. Drug Target.4(3),129–140 (1996).
  Medline CASGoogle Scholar
• 119  Batist G, Ramakrishnan G, Rao CS et al. Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer. J. Clin. Oncol.19(5),1444–1454 (2001).
  Medline CASGoogle Scholar
• 120  Harris L, Batist G, Belt R et al. Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multi-center trial as first-line therapy of metastatic breast carcinoma. Cancer94(1),25–36 (2002).
  Medline CASGoogle Scholar
• 121  Safra T. Cardiac safety of liposomal anthracyclines. Oncologist8(2),17–24 (2003).
  Medline CASGoogle Scholar
• 122  Gabizon AA. Liposomal anthracyclines. Hematol. Oncol. Clin. North Am.8(2),431–450 (1994).
  Medline CASGoogle Scholar
• 123  Money-Kyrle JF, Bates F, Ready J, Gazzard BG, Phillips RH, Boag FC. Liposomal daunorubicin in advanced Kaposi’s sarcoma: a Phase II study. Clin. Oncol. (R. Coll. Radiol.)5(6),367–371 (1993).
  Medline CASGoogle Scholar
• 124  Gill PS, Wernz J, Scadden DT. Randomized Phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi’s sarcoma. J. Clin. Oncol.14(8),2353–2364 (1996).
  Medline CASGoogle Scholar
• 125  O’Brien ME, Wigler N, Inbar M et al. Reduced cardiotoxicity and comparable efficacy in a Phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann. Oncol.15(3),440–449 (2004).
  MedlineGoogle Scholar
• 126  Sieswerda E, Kremer LC, Caron HN, van Dalen EC: The use of liposomal anthracycline analogues for childhood malignancies: a systematic review. Eur. J. Cancer47(13),2000–2008 (2011).
  Medline CASGoogle Scholar
• 127  Zimethbaum P, Eder H, Frishman W. Probucol: pharmacology and clinical application. J. Clin. Pharmacol.30(1),3–9 (1990).
  MedlineGoogle Scholar
• 128  Carew TE, Schwenke DC, Steinberg D. Antiatherogenic effect of probucol unrelated to its hypocholesterolemic effect: evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. Proc. Natl Acad. Sci. USA84(21),7725–7729 (1987).
  Medline CASGoogle Scholar
• 129  Kuzuya M, Kuzuya F. Probucol as an antioxidant and antiatherogenic drug. Free Radic. Biol. Med.14(1),67–77 (1993).
  Medline CASGoogle Scholar
• 130  Siveski-Iliskovic N, Hill M, Chow DA, Singhal PK. Probucol protects against doxorubicin cardiomyopathy without interfering with its antitumor effect. Circulation91(1),10–15 (1995).
  Medline CASGoogle Scholar
• 131  Singal PK, Deally CM, Weinberg LE. Subcellular effects of doxorubicin in the heart. A concise review. J. Mol. Cell. Cardiol.19(8),817–828 (1987).
  Medline CASGoogle Scholar
• 132  Iliskovic N, Singal PK. Lipid lowering: an important factor in preventing doxorubicin-induced heart failure. Am. J. Pathol.150(2),727–734 (1997).
  Medline CASGoogle Scholar
• 133  Iliskovic N, Hasinoff BB, Malisza KL, Li T, Danelisen I, Singal PK. Mechanisms of beneficial effects of probucol in doxorubicin cardiomyopathy. Mol. Cell. Biochem.196(1–2),43–49 (1999).
  Medline CASGoogle Scholar
• 134  Li T, Danelisen I, Bello-Klein A, Singal PK. Effects of probucol on changes of antioxidant enzymes in doxorubicin-induced cardiomyopathy in rats. Cardiovasc. Res.46(3),523–530 (2000).
  Medline CASGoogle Scholar
• 135  Li T, Singal PK. Adriamycin-induced early changes in myocardial antioxidant enzymes and their modulation by probucol. Circulation102(17),2105–2110 (2000).
  Medline CASGoogle Scholar
• 136  De Flora S, Bennicelli C, Serra D, Izzotti A, Cesarone CF. Role of glutathione and N-acetylcysteine on the mutagenicity and carcinogenesis. In: Absorption and Utilization of Amino Acids (Volume 3). Friedman M (Ed.). CRC Press, FL, USA, 19–53 (1989).
  Google Scholar
• 137  Myers CE, Bonow R, Palmeri S et al. A randomized controlled trial assessing the prevention of doxorubicin cardiomyopathy by N-acetylcysteine. Semin. Oncol.10(1),53–55 (1983).
  Medline CASGoogle Scholar
• 138  Frishman WH. Carvedilol. Drug Therapy339(24),1759–1765 (1998).
  CASGoogle Scholar
• 139  Yue TL, Cheng HY, Lysko PG et al. Carvedilol, a new vasodilator and beta adrenoreceptor antagonist, is an antioxidant and free radical scavenger. J. Pharmacol. Exper. Therap.263(1),92–98 (1992).
  Medline CASGoogle Scholar
• 140  Feuerstein GZ, Ruffolo RR Jr. Carvedilol, a novel multiple action antihypertensive agent with antioxidant activity and the potential for myocardial and vascular protection. Eur. Heart J.16,38–42 (1995).
  Medline CASGoogle Scholar
• 141  Noguchi N, Nishino K, Niki E. Antioxidant action of the antihypertensive drug, carvedilol, against lipid peroxidation. Biochem. Pharmacol.59(9),1069–1076 (2000).
  Medline CASGoogle Scholar
• 142  Matsui H, Morishima I, Numaguchi Y, Toki Y, Okumura K, Hayakawa T. Protective effects of carvedilol against doxorubicin-induced cardiomyopathy in rats. Life Sci.65(12),1265–1274 (1999).
  Medline CASGoogle Scholar
• 143  Fazio S, Palmieri EA, Ferravante B, Bone F, Biondi B, Sacca L. Doxorubicin-induced cardiomyopathy treated with carvedilol. Clin. Cardiol.21(10),777–779 (1998).
  Medline CASGoogle Scholar
• 144  Spallarossa P, Garibaldi S, Altieri P et al. Carvedilol prevents doxorubicin-induced free radical release and apoptosis in cardiomyocytes in vitro. J. Mol. Cell. Cardiol.37(4),837–846 (2004).
  Medline CASGoogle Scholar
• 145  Nakamae H, Tsumura K, Terada Y et al. Notable effects of angiotensin II receptor blocker, valsartan, on acute cardiotoxic changes after standard chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone. Cancer104(11),2492–2498 (2005).
  Medline CASGoogle Scholar
• 146  Tokudome T, Mizushige K, Noma T et al. Prevention of doxorubicin (adriamycin)-induced cardiomyopathy by simultaneous administration of angiotensin-converting enzyme inhibitor assessed by acoustic densitometry. J. Cardiovasc. Pharmacol.36(3),361–368 (2000).
  Medline CASGoogle Scholar
• 147  Fischer PW, Salloum F, Das A, Hyder H, Kukreja RC. Phosphodiesterase-5 inhibition with Sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic model of doxorubicin cardiotoxicity. Circulation111(13),1601–1610 (2005).
  MedlineGoogle Scholar
• 148  Hanley PJ, Dröse S, Brandt U et al. 5-hydroxydecanoate is metabolised in mitochondria and creates a rate-limiting bottleneck for beta-oxidation of fatty acids. J. Physiol.562(2),307–318 (2005).
  Medline CASGoogle Scholar
• 149  Di X, Gennings C, Bear HD et al. Influence of the phosphodiesterase-5 inhibitor, Sildenafil, on sensitivity to chemotherapy in breast tumor cells. Breast Cancer Res. Treat.124(2),349–360 (2010).
  Medline CASGoogle Scholar
• 150  Essayan DM. Cyclic nucleotide phosphodiesterases. J. Allergy Clin. Immunol.108(5),671–680 (2001).
  Medline CASGoogle Scholar
• 151  Asmis R, Wang Y, Xu L, Ksgati M, Begley JG, Mieyal JJ. A novel thiol oxidation-based mechanism for adriamycin-induced cell injury in human macrophages. FASEB J.19(13),1866–1868 (2005).
  Medline CASGoogle Scholar
• 152  Li W, Lam MS, Birkeland A et al. Cell-based assays for profiling activity and safety properties of cancer drugs. J. Pharmacol. Toxicol. Methods.54(3),313–319 (2006).
  Medline CASGoogle Scholar
• 153  Raja SG, Danton MD, MacArthur, KJ, Pollock JC. Effects of escalating doses of sildenafil on hemodynamics and gas exchange in children with pulmonary hypertension and congenital cardiac defects. J. Cardiothorac. Vasc. Anesth.21(2),203–207 (2007).
  Medline CASGoogle Scholar
• 154  Karatza AA, Bush A, Magee AG. Safety and efficacy of sildenafil therapy in children with pulmonary hypertension. Int. J. Cardiol.100(2),267–273 (2005).
  MedlineGoogle Scholar
• 155  Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics117(4),1077–1083 (2006).
  MedlineGoogle Scholar
• 156  Juliana AE, Abbad FCB. Severe persistent pulmonary hypertension of the newborn in a setting where limited resources exclude the use of inhaled nitric oxide: successful treatment with sildenafil. Eur. J. Pediatr.164(10),626–629 (2005).
  MedlineGoogle Scholar
• 157  Diez JJ, Iglesias P. The role of the novel adipocyte-derived hormone adiponectin in human disease. Eur. J. Endocrinol.148(3),293–300 (2003).
  Medline CASGoogle Scholar
• 158  Konishi M, Haraguchi G, Ohigashi H et al. Adiponectin protects against doxorubicin-induced cardiomyopathy by anti-apoptotic effects through AMPK upregulation. Cardiovasc. Res.89(2),309–319 (2011).
  Medline CASGoogle Scholar
• 159  Li L, Takemura G, Li Y et al. Preventive effect of erythropoietin on cardiac dysfunction in doxorubicin-induced cardiomyopathy. Circulation113(4),535–543 (2006).
  Medline CASGoogle Scholar
• 160  Hasinoff BB. The interaction of the cardioprotective agent ICRF-187 [+)-1, 2-bis(3, 5 dioxopiperazinyl-1-yL)propane); its hydrolysis product (ICRF-198); and other chelating agents with the Fe(III) and Cu(II) complexes of doxorubicin. Agents Actions26(3–4),378–385 (1989).
  Medline CASGoogle Scholar
• 161  Speyer JL, Green MD, Zeleniuch-Jacquotte A et al. ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. J. Clin. Oncol.10(1),117–127 (1992).
  Medline CASGoogle Scholar
• 162  Swain SM, Whaley FS, Gerber MC, Ewer MS, Bianchine JR, Gams RA. Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicin-containing therapy. J. Clin. Oncol.15(4),1333–1340 (1997).
  Medline CASGoogle Scholar
• 163  Wexler LH, Andrich MP, Venzon D et al. Randomized trial of the cardioprotective agent ICRF-187 in pediatric sarcoma patients treated with doxorubicin. J. Clin. Oncol.14(2),362–372 (1996).
  Medline CASGoogle Scholar
• 164  Swain SM, Whaley FS, Gerber MC et al. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J. Clin. Oncol.15(4),1318–1332 (1997).
  Medline CASGoogle Scholar
• 165  Lopez M, Vici P, Di Lauro L et al. Randomized prospective clinical trial to evaluate cardioprotection of dexrazoxane in patients with advanced breast cancer and soft tissue sarcomas. J. Clin. Oncol.16(1),86–92 (1998).
  Medline CASGoogle Scholar
• 166  Lipshultz SE, Scully RE, Lipsitz SR et al. Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial. Lancet Oncol.11(10),950–961 (2010).▪▪ Dexrazoxane is a clinically important cardioprotectant. This study found that dexrazoxane provides long-term cardioprotection in children with high-risk acute lymphoblastic leukemia without compromising the oncological efficacy of doxorubicin.
  Medline CASGoogle Scholar
• 167  Tebbi CK, London WB, Friedman D et al. Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin’s disease. J. Clin. Oncol.25,493–500 (2007).
  Medline CASGoogle Scholar
• 168  Herman EH, Zhang J, Rifai N et al. The use of serum levels of cardiac troponin T to compare the protective activity of dexrazoxane against doxorubicin- and mitoxantrone-induced cardiotoxicity. Cancer Chemother. Pharmacol.48(4),297–304 (2001).
  Medline CASGoogle Scholar
• 169  Barry EV, Vrooman LM, Dahlberg SE et al. Absence of secondary malignant neoplasms in children with high-risk acute lymphoblastic leukemia treated with dexrazoxane. J. Clin. Oncol.26,1106–1111 (2008).▪▪ It has been hypothesized that dexrazoxane treatment increases risk of secondary malignant neoplasms. This study found that dexrazoxane was not associated with increased risk of secondary malignant neoplasms in children treated for high-risk acute lymphoblastic leukemia.
  Medline CASGoogle Scholar
• 170  Vrooman LM, Neuber DS, Stevenson KE et al. The low incidence of secondary acutemyelogenous leukaemia in children and adolescents treated with dexrazoxane for acute lymphoblastic leukaemia: a report from the Dana-Farber Cancer Institute ALL Consortium. Eur. J. Cancer47(9),1373–1379 (2011).
  Medline CASGoogle Scholar
• 171  Schuchter LM, Hensley ML, Meropol NJ, Winer EP. Update of recommendations for the use of chemotherapy and radiotherapy protectants: clinical practice guidelines of the American Society of Clinical Oncology. J. Clin. Oncol.20(12),2895–2903 (2002).
  MedlineGoogle Scholar
• 172  Yang JL, Fernandes DJ, Speicher L, Capizzi RL. Biochemical determinants of the cytoprotective effect of amifostine. Proc. Am. Cancer Res.36,3725 (1995).
  Google Scholar
• 173  Calabro-Jones PM, Aguilera JA, Ward JF, Smoluk GD, Fahey RC. Uptake of WR-2721 derivatives by cells in cultures: identification of the transported form of the drug. Cancer Res.48(13),3634–3640 (1988).
  Medline CASGoogle Scholar
• 174  Nazeyrollas P, Frances C, Prevost A et al. Efficiency of amifostine as a protection against doxorubicin toxicity in rats during a 12-day treatment. Anticancer Res.23(1A),405–409 (2003).
  Medline CASGoogle Scholar
• 175  Dragojevic-Simic VM, Dobric SL, Bokonjic DR et al. Amifostine protection against doxorubicin cardiotoxicity in rats. Anticancer Drugs15(2),169–178 (2004).
  Medline CASGoogle Scholar
• 176  Herman EH, Ferrans VJ. Reduction of chronic doxorubicin cardiotoxicity in dogs by pretreatment with (+/-)-1, 2-bis (3, 5-dioxopipreazine-1-yl) propane (ICRF-187). Cancer Res.41(9 Pt 1),3436–3440 (1981).
  Medline CASGoogle Scholar
• 177  The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N. Engl. J. Med.325(5),293–302 (1991).
  MedlineGoogle Scholar
• 178  Haq MM, Legha SS, Choski J et al. Doxorubicin-induced congestive heart failure in adults. Cancer56(6),1361–1365 (1985).
  Medline CASGoogle Scholar
• 179  Redfield MM, Gersh BJ, Bailey KR, Rodeheffer RJ. Natural history of incidentally discovered asymptomatic idiopathic dilated cardiomyopathy. Am. J. Cardiol.74(7),737–739 (1994).
  Medline CASGoogle Scholar
• 180  Sieswerda E, van Dalen EC, Postma A, Cheuk DK, Caron HN, Kremer LC: Medical interventions for treating anthracycline-induced symptomatic and asymptomatic cardiotoxicity during and after treatment for childhood cancer. Cochrane Database Syst. Rev.7(9),CD008011 (2011).
  Google Scholar
• 181  Lipshultz SE, Vlach SA, Lipsitz SR et al. Cardiac changes associated with growth hormone therapy among children treated with anthracyclines. Pediatrics115,1613–1622 (2005).
  MedlineGoogle Scholar
• 182  Silber JH, Cnaan A, Clark BJ et al. Enalapril to prevent cardiac function decline in long-term survivors of pediatric cancer exposed to anthracyclines. J. Clin. Oncol.22(5),820–828 (2004).
  Medline CASGoogle Scholar
• 183  Lipshultz SE, Lipsitz SR, Sallan SE et al. Long-term enalapril therapy for left ventricular dysfunction in doxorubicin-treated survivors of childhood Cancer J. Clin. Oncol.20,4517–4522 (2002).
  Medline CASGoogle Scholar
• 184  Mertens AC, Sencer S, Myers CD et al. Complementary and alternative therapy use in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor study. Pediatr. Blood Cancer50,90–97 (2008).
  MedlineGoogle Scholar
• 185  Ibsen S, Zahavy E, Wrasdilo W, Berns M, Chan M, Esener S. A novel doxorubicin prodrug with controllable photolysis activation for cancer chemotherapy. Pharm. Res.27(9),1848–1860 (2010).
  Medline CASGoogle Scholar
• 186  Young K, Hare JM. Stem cells in cardiopulmonary development: Implications for novel approaches to therapy for pediatric cardiopulmonary diseases. Progr. Pediatr. Cardiol.25(3),37–49 (2008).
  Google Scholar
• 187  Assmus B, Schachinger V, Teupe C et al. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation106(24),3009–3017 (2002).
  MedlineGoogle Scholar
• 188  Schachinger V, Assmus B, Britten MB et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI trial. J. Am. Coll. Cardiol.44(8),1690–1699 (2004).
  MedlineGoogle Scholar
• 189  Wollert KC, Meyer GP, Lotz J et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomized controlled clinical trial. Lancet364,10–16 (2004).
  MedlineGoogle Scholar
• 190  Meyer GP, Wollert KC, Lotz J et al. Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months’ follow-up data from the randomized, controlled BOOST (BOnemarrOw transfer to enhance ST-elevation infarct regeneration)trial. Circulation113(10),1287–1294 (2006).
  MedlineGoogle Scholar
• 191  Pillekamp F, Reppel M, Brockmeier K, Hescheler J. Stem cells and their potential relevance to paediatric cardiology. Cardiol. Young16(2),117–124 (2006).
  MedlineGoogle Scholar
• 201  Childrens Oncology Group. Long-term follow-up guidelines for survivors of childhood, adolescent and young adult cancers (2008). www.survivorshipguidelines.org
  Google Scholar