Skip to main content

Advertisement

SpringerLink
Log in

Anthracycline cardiomyopathy

  • Published:
Pediatric Cardiology Aims and scope Submit manuscript

Summary

Life-threatening irreversible cardiomyopathy is a major complication of anthracycline therapy, particularly in the pediatric population. The pediatric cardiologist, in concert with the primary oncologist, should therefore play a major role in the care of patients receiving these agents and in clinical trials involving their use. Many risk factors and their relationships to drug pharmacokinetics, mechanisms of action, and toxicity have been identified. These data provide a rational basis for present-day recommendations regarding anthracycline administration and dosage scheduling. They furthermore provide potential avenues for clinical investigation aimed at improving the therapeutic index of these agents: α-tocopherol, cytochrome Q10, and other free radical scavengers may decrease the deleterious effects of free radical generation on the myocardium without apparent interference with tumoricidal effect. The cardiac glycosides may decrease cardiac toxicity by specific myocardial exclusion. Anthracycline analogs have been designed to specifically inhibit myocardial binding and/or free radical generation. Clinical trials involving these agents are difficult to interpret because of variability in front end risk factors and dosage schedules in the study population. Furthermore, the relatively low (5 to 10%) incidence of affected patients implies the need for large numbers to demonstrate a statistically significant benefit. Pediatric protocols addressing these issues are urgently needed. Guidelines for present-day management and future studies are outlined.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Alexander I, Dainiak N, Berger H, Goldman L, Johnstone D, Reduto L, Duffy T, Schwartz T, Gottschalk A, Zaret BL: Serial assessment of doxorubicin cardiotoxicity with quantitative radionucleotide angiocardiography.N Engl J Med 300:278–283, 1979

    Google Scholar 

  2. Anderson B, Beran M: Leukemic cell versus plasma levels of daunorubicin and daunorubicinol after infusion of daunorubicin as free drug or the DNA complex.Cancer Chemother Pharmacol 4:205–207, 1980

    Google Scholar 

  3. Arcamone F, Franceschi GF, Penco S, Selva A: Adriamycin, a novel antitumor antibiotic.Tetrahedron Lett 13:1007–1010, 1969

    Google Scholar 

  4. Arena E, D'Alessandro N, Dusonchet L, Gebbia N, Gerbas, E: Analysis of the pharmacokinetic characteristics, pharmacological and chemotherapeutic activity of 14-hydroxy-daunomycin (Adriamycin), a new drug endowed with an antitumor activity.Arzneim Forsch 21:1258–1263, 1971

    Google Scholar 

  5. Bachur NR: Anthracycline antibiotic pharmacology and metabolism.Cancer Treat Rep 63:817–820, 1979

    Google Scholar 

  6. Bachur NR, Benjamin RS, Hall TC: Proceedings of the Fifth New Drug Seminar on Adriamycin and the Adriamycin New Drug Seminar.Cancer Chemother Rep, Part 3 6:83–397, 1975

    Google Scholar 

  7. Bachur NR, Gordon SL, Gee MV: Anthracycline antibiotic augmentation of microsomal electron transport and free radical formation.Molec Pharmacol 13:901–910, 1977

    Google Scholar 

  8. Bachur NR, Gordon SL, Gee MV: A general mechanism for microsomal activation of quinone anticancer agents to free radicals.Cancer Res 38:1745–1750, 1978

    Google Scholar 

  9. Barlogie B, Drewinko B, Johnston DA, Freireich EJ: The effect of Adriamycin on the cell cycle traverse of a human lymphoid cell line.Cancer Res 36:1975–1979, 1976

    Google Scholar 

  10. Benjamin RS, Riggs CE, Bachur NR: Pharmacokinetics and metabolism of Adriamycin in man.Clin Pharmacol Ther 14:592–600, 1973

    Google Scholar 

  11. Benjamin RS, Riggs CE, Bachur NR: Plasma pharmacokinetics of Adriamycin and its metabolites in humans with normal hepatic and renal function.Cancer Res 37:1416–1420, 1977

    Google Scholar 

  12. Benjamin RS, Riggs CE, Serpick AA, Bachur NR: Human metabolism of Adriamycin. (Abstr).AACR 15:76, 1974

    Google Scholar 

  13. Benjamin RS, Wiernik PH, Bachur NR: Adriamycin chemotherapy—efficacy, safety, and pharmacologic basis of an intermittent single high-dose schedule.Cancer 33:19–27, 1974

    Google Scholar 

  14. Bern MM, McDermott W, Cady B, Oberfield RA, Trey C, Clouse ME, Tullis JL, Parker LM: Intraarterial hepatic infusion and intravenous Adriamycin for treatment of hepatocellular carcinoma. A clinical and pharmacological report.Cancer 42:399–405, 1978

    Google Scholar 

  15. Bhanot P, Cushing B, Philippart A, Das L, Farooki Z: Hepatic irradiation and Adriamycin cardiotoxicity.J Ped 95:561–563, 1979

    Google Scholar 

  16. Biancaniello T, Meyer RA, Wong KY, Sager C, Kaplan S: Doxorubicin cardiotoxicity in children.J Ped 97:45–50, 1980

    Google Scholar 

  17. Bonadonna G, Monfardini S, Delena M, Fossati-Bellani F, Baretta G: Clinical trials with Adriamycin—results of a three year study. In Carter SK, DiMarco A, Ghione M, Krakoff IH, Mathe G. eds.International Symposium on Adriamycin. New York: Springer-Verlag, 1972, pp. 143-152

  18. Bristow MR, Billingham ME, Mason JW, Daniels JR: Clinical spectrum of anthracycline cardiotoxicity.Cancer Treat Rep 62:873–879, 1978

    Google Scholar 

  19. Bristow MR, Mason JW, Billingham ME, Daniels JR: Doxorubicin cardiomyopathy: Evaluation by phonocardiography, endomyocardial biopsy and cardiac catheterization.Ann Int Med 88:168, 1978

    Google Scholar 

  20. Carter SK, DiMarco A, Ghione M, Krakoff IH, Mathe G: eds:International Symposium on Adriamycin, New York: Springer-Verlag, 1972

    Google Scholar 

  21. Chlebowski RT, Paroly WS, Pugh RP, Hueser J, Jacobs EM, Pajak TF, Bateman JR: Adriamycin given as a weekly schedule without a loading course: Clinically effective with reduced incidence of cardiotoxicity.Cancer Treat Rep 64:47–51, 1980

    Google Scholar 

  22. Cortes EP, Gupta M, Chau C, Amin VC, Folkers K: Adriamycin cardiotoxicity: Early detection by systolic time interval and possible prevention by coenzyme Q10.Cancer Treat Rep 62:887–891, 1978

    Google Scholar 

  23. D'Angio GJ, Raney RB, Schnaryer L, Bishop HC, Chatten J, Littman P: Management of children with sacrococcygeal teratoma (ST).ASCO (Abstr C-206)21:386, 1980

    Google Scholar 

  24. Davis HL, Davis TE: Daunorubicin and Adriamycin in cancer treatment: An analysis of their roles and limitations.Cancer Treat Rep 63:809–815, 1979

    Google Scholar 

  25. DiMarco A, Gaetani M, Orezzi PO, Scarpinato BM, Silvestrini R, Soldati M, Dasdia T, Vanentini L: Daunomycin, a new antibiotic of the rhodomycin group.Nature 201:706–707, 1964

    Google Scholar 

  26. DiMarco A, Zunino F, Silvestrini R, Ganbarucii C, Gambetta RA: Interaction of some daunomycin derivatives with deoxyribonucleic acid and their biological activity.Biochem Pharmacol 20:1323–1328, 1971

    Google Scholar 

  27. Doroshow JH, Locke GY, Myers CE: The prevention of doxorubicin cardiac toxicity by N-acetyl-L-cysteine.AACR (Abstr)253, 1979

  28. Evans WE, Crom WR, Yee GC, Green AA, Hayes FA, Pratt CB, Avery L: Adriamycin pharmacokinetics in children.AACR 21 (Abstr 705): 176, 1980

    Google Scholar 

  29. Ferrans VF: Overview of cardiac pathology in relation to anthracycline cardiotoxicity.Cancer Treat Rep 62:955–961, 1978

    Google Scholar 

  30. Gilladoga AC, Manuel C, Tan CT, Wollner N, Sternberg SS, Murphy ML: The cardiotoxicity of Adriamycin and daunomycin in children.Cancer 37 (2 suppl):1070–1078, 1976

    Google Scholar 

  31. Goodman J, Hochstein P: Generation of free radicals and lipid peroxidation by redox cycling of Adriamycin and Daunomycin®.Biochem Biophys Res Commun 77:797–803, 1977

    Google Scholar 

  32. Halazun JR, Wagner HR, Gaeta JR, Sinks LF: Daunorubicin cardiotoxicity in children with acute lymphocytic leukemia.Cancer 33:545–554, 1974

    Google Scholar 

  33. Handa K, Sato S: Generation of free radicals of quinone group-containing anti cancer chemicals in NADPH-microsome systems as evidence by initiation of sulfite oxidation.Gann 60:43–47, 1975

    Google Scholar 

  34. Handa K, Sato S: Stimulation of NADPH oxidation by quinone group containing anti cancer chemicals.Gann 67:523, 1976

    Google Scholar 

  35. Israel M, Modest E, Frei E: N-trifluoracetyl Adriamycin-14-valerate (AD 32), an analog with greater experimental anti-tumor activity and less toxicity than Adriamycin.Cancer Res 35:1365–1368, 1975

    Google Scholar 

  36. Iwamoto Y, Hansen IL, Porte TH, Fokers K: Inhibition of co-enzyme Q10-enzymes, succinoxidase and NADH-oxidase by Adriamycin and other quinones having anti-tumor activity.Biochem Res Commun 58:633–638, 1974

    Google Scholar 

  37. Jaenke RS, Deprez-De Campeneere D, Trouet A: Cardiotoxicity and comparative pharmacokinetics of six anthracyclines in the rabbit.Cancer Res 40:3530–3536, 1980

    Google Scholar 

  38. Kobrinsky NL, Robison LL, Nesbit ME Jr: Acute nonlymphocytic leukemia.Ped Cl NA 27:345–360, 1980

    Google Scholar 

  39. Krivit W: Adriamycin cardiotoxicity amelioration by α-tocopherol.Am J Ped Hematol/Oncol 1:151–153, 1979

    Google Scholar 

  40. Lee Y-TN, Chan KK, Harris PA, Cohen JL: Distribution of Adriamycin in cancer patients. Tissue uptakes, plasma concentration after IV and hepatic IA administration.Cancer 45:2231–2239, 1980

    Google Scholar 

  41. Merski J, Daskal Y, Busch H: Comparison of Adriamycin-induced nucleolar segregation in skeletal muscle, cardiac muscle and liver cells.Cancer Treat Rep 62:771–778, 1978

    Google Scholar 

  42. Michelsen RB, Lin PS, Wallach DFH: Interaction of Adriamycin with human red blood cells: A biochemical and morphological study.J Molec Med 2:33–40, 1977

    Google Scholar 

  43. Middleman E, Luu J, Frei E: Clinical trials with Adriamycin.Cancer 28:844–850, 1970

    Google Scholar 

  44. Mosojczvk AD, Ruymann FB, Mease AD, Bernier RD: Anthracycline cardiomyopathy in children: Report of two cases.Cancer 44:1582–1587, 1979

    Google Scholar 

  45. Myers CE, McGuire WP: Proceedings of the conference on noninvasive and invasive prospective monitoring for anthracycline cardiotoxicity.Cancer Treat Rep 62:885–982, 1978

    Google Scholar 

  46. Myers CE, McGuire WP, Liss RH, Ifrim I, Grotzinger K, Young RC: Adriamycin: The role of lipid peroxidation in cardiac toxicity and tumor response.Science 197:165–167, 1977

    Google Scholar 

  47. Nevstad N: Sister chromatid exchanges and chromosomal aberrations induced in human lymphocytes by the cytostatic drug Adriamycin in vivo and in vitro.Mutation Res 57:253, 1977

    Google Scholar 

  48. Olson HM, Shannon CF: Alterations of lactate dehydrogenase isoenzymes with subacute Adriamycin toxicity.Cancer Treat Rep 63:2057–2059, 1979

    Google Scholar 

  49. Phillips FS, Gilladoga A, Marquardt H, Stenberg SS, Vidal P: Some observations on the cardiotoxicity of Adriamycin (NSC-123127).Cancer Chem Rep (Part 3)6:177–181, 1975

    Google Scholar 

  50. Praga C, Baretta G, Vigo PL, Lenaz GR, Pollini C, Bonadonna G, Canetta R, Castella R, Villa E, Gallagher CG, von Melchner H, Hayat M, Ribaud P, De Wasch G, Mattsson W, Heinz R, Waldnar R, Kolaric K. Buehner R, Bokkel-Huyninck WT, Pererodahikova NI, Mauziuk LA, Senn SHJ, Mayr AC: Adriamycin cardiotoxicity: A survey of 1273 patients.Cancer Treat Rep 63:827–834, 1979

    Google Scholar 

  51. Pratt CB, Ransom JL, Evans WE: Age-related Adriamycin cardiotoxicity in children.Cancer Treat Rep 62:1481–1485, 1978

    Google Scholar 

  52. Proceedings of the NCI-EORTC Symposium on New Drugs in Cancer Therapy.Cancer Treat Rep 63:807–936, 1979

    Google Scholar 

  53. Rahman A, Kessler A, More N, Sikic B, Rowden G, Woolley P, Schein PS: Liposomal protection of Adriamycin-induced cardiotoxicity in mice.Cancer Res 40:1532–1537, 1980

    Google Scholar 

  54. Ramos A, Meyer RA, Korfhagen J, Wong KY, Kaplan S: Echocardiographic evaluation of Adriamycin cardiotoxicity in children.Cancer Treat Rep 60:1281–1284, 1976

    Google Scholar 

  55. Ritchie JL, Singer JW, Thorning D, Sorensen SG, Hamilton GW: Anthracycline cardiotoxicity: Clinical and pathologic outcomes assessed by radionuclide ejection fraction.Cancer 46:1109–1116, 1980

    Google Scholar 

  56. Rozencweig M, DeSloover C, VonHoff DD, Tagnon HJ, Muggia FM: NCI-EORTC Symposium on New Drugs in Cancer Therapy. Introduction: Anthracycline derivatives in New Drug Development Programs.Cancer Treat Rep 63:807–808, 1979

    Google Scholar 

  57. Somberg J, Cagin N, Bovnous H, Levitt HB: The effect of digoxin on the binding of Adriamycin to cat heart muscle (letter).Brit J Cancer 35:123, 1977

    Google Scholar 

  58. Thayer WS: Adriamycin stimulated superoxide formation in submitochondrial particles.Chem Biol Interact 19:265–278, 1977

    Google Scholar 

  59. Trouet A, Sokol G: Clinical studies with daunorubicin-DNA and Adriamycin-DNA complexes: A Review.Cancer Treat Rep 63:895–898, 1979

    Google Scholar 

  60. Ulmer HE, Ludwig R, Geiger H: Assessment of Adriamycin cardiotoxicity in children by systolic time intervals.Eur J Pediatr 131:21–31, 1979

    Google Scholar 

  61. Villani F, Piccinioui F, Merelli P, Favalli L: Influence of Adriamycin on calcium exchangeability in cardiac muscle and its modification by ouabain.Biochem Pharmacol 27:985–987, 1978

    Google Scholar 

  62. VonHoff DD, Layard MW, Basa P, Davis HL Jr, Rozencweig M, Muggia FM: Analysis of risk factors for development of Adriamycin induced congestive heart failure (CHF).AACR (Abst 216)19:54, 1978

    Google Scholar 

  63. VonHoff DD, Layard MW, Basa P, Davis HL Jr, Rozencweig M, Muggia FM: Risk factors for doxorubicin-induced congestive heart failure.Ann Int Med 91:710–717, 1979

    Google Scholar 

  64. VonHoff DD, Rozencweig M, Layard MW, Slavik, Muggia FM: Daunomycin-induced cardiotoxicity in children and adults: A review of 110 cases.Am J Med 62:200–208, 1977

    Google Scholar 

  65. Weiss AJ, Mette GE, Fletcher WS, Wilson WL, Grage TB, Raimirez G: Studies on Adriamycin using a weekly regimen demonstrating its clinical effectiveness and lack of cardiac toxicity.Cancer Treat Rep 60:813–822, 1976

    Google Scholar 

  66. Wortmen JE, Lucas VS, Pharm BS, Schuster E, Thiele D, Logue GL: Sudden death during doxorubicin administration.Cancer 44:1588–1591, 1979

    Google Scholar 

  67. Wright SD, Bachur NR: Alterations in Adriamycin efficacy by phenobarbital.Cancer Res 36:3803, 1976A0946011 00013 CS-SPJRNPDF [HEADSUP]

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Division of Hematology-Oncology, University of Minnesota, Minneapolis, Minnesota

    Nathan L. Kobrinsky, Norma K. C. Ramsay & William Krivit

Authors
  1. Nathan L. Kobrinsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Norma K. C. Ramsay
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. William Krivit
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Supported in part by Hematology Research Training Grant 2T32-HL07145-06A1 and USPH Grant CA 07306. This paper was part of the Ray C. Anderson Symposium

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kobrinsky, N.L., Ramsay, N.K.C. & Krivit, W. Anthracycline cardiomyopathy. Pediatr Cardiol 3, 265–272 (1982). https://doi.org/10.1007/BF02240463

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02240463

Key words

Search

Navigation