Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Acute cardiac toxicity in patients after doxorubicin treatment and the effect of combined tocopherol and nifedipine pretreatment


In two groups of female patients with metastatic breast cancer who had all been pretreated with doxorubicin (350 mg/m2), acute cardiac effects following i.v. doxorubicin bolus injection (60 mg/m2) were recorded on the basis of systolic time intervals (STI). In six patients who received doxorubicin only the ratio between the heart-beat-corrected preejection period and left ventricular ejection time (PEPI:LVETI) as well as the PEP index were found to be significantly increased with a peak at 6 h following drug infusion (P<0.001). Another six patients received an identical chemotherapeutic regimen and, in addition, a combination of tocopherol (200 mg i.m. 6 h before treatment) and nifedipine (60 mg p.o. daily from 2 days before doxorubicin infusion). In the pretreatment group, the PEPI: LVETI ration and PEP index remained unchanged during the posttreatment period. Pharmacokinetic analysis of drug concentrations in the plasma revealed a significantly accelerated distribution and elimination of doxorubicin after combined tocopherol and nifedipine pretreatment, although no statistically significant differences could be found in calculated drug levels in the peripheral compartment between both treatment groups. Our results indicate that acute cardiac reactions reflected by changes in STI values can be prevented by combined tocopherol and nifedipine pretreatment.

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


  1. Bristow MR, Mason JW, Billingham ME, Daniels JR (1981) Dose-effect and structure-function relationships in doxorubicin cardiomyopathy. Am Heart J 102:709–718

  2. Benjamin RS, Mackay B, Ewer M, Wallace S, Valdivieso M, Rasmussen SL Blumenschein GR, Freireich EJ (1982) Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med 96:133–139

  3. Bühner R, Biedert S, Miura D (1980) Erhöhung des frei-ionisierten zytoplasmatischen Calciums als Ursache der Adriamycin-Kardiomyopathie. Klin Wochenschr 58:747–748

  4. Chan KK, Cohen JL, Gross JF, Himmelstein KJ, Bateman, JR, Tsu-Lee Y, Marlis AS (1978) Predicition of adriamycin disposition in cancer patients using a physiologic, pharmacokinetic model. Cancer Treat Rep 62:1161–1171

  5. Di Fronzo G, Bertuzzi A, Ronchi E, Villani FP, Ronchetti L (1979) Evaluation of cardiac activity and pharmacokinetic analysis of 3H-adriamycin in patients pretreated with beta-methyldigoxin. Cancer Chemother Pharmacol 2:169–173

  6. Domae N, Sawada H, Matsuyama E, Konishi T, Uchino H (1981) Cardiomyopathy and other chronic toxic effects induced in rabbits by doxorubicin and possible prevention by coenzyme Q10. Cancer Treat Rep 6579–91

  7. Ehninger G, Stocker HJ, Proksch B, Wilms K (1980) Die Pharmakokinetik von Adriamycin und Adriamycin-Metaboliten. Klin Wochenschr 58:927–934

  8. Fleckenstein A (1977) Specific pharmacology of calcium in myocardium, cardiac pace markers, and vascular smooth muscle. Ann Rev Pharmacol Toxicol 17:149–166

  9. Gomeni C, Gomeni R (1978) IGPHARM: Interactive graphic package for pharmacokinetic analysis. Comput Biomed Res 11:345–361

  10. Gosalvez M, Rossum G, Blanco MF (1979), Inhibition of sodium-potassium activated adenosine 5,4-triphosphatase and ion transport by adriamycin. Cancer Res 39:257–261

  11. Khalil MA, Soto AP, Maroongroge D, Bekheit-Saad S, Buzdar AU, Blumenschein GR, Hortobagyi N, Tashima CK, Wiseman CL, Schullenberger CC (1979) Electrocardiographic changes after adriaycin chemotherapy. Cancer 43:465–471

  12. Lefrak EA, Pitha J, Rosenheim S, Gottlieb JA (1973) A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer 32:302–314

  13. Lenaz L, Page JA (1976) Cardiotoxicity of adriamycin and related anthracyclines. Cancer Treat Rev 3:111–120

  14. Lenzhofer R, Magometschnigg D, Dudczak, Czerni C, Bolebruch C, Moser K (1983a) Indication of reduced doxorubicin induced cardiac toxicity by additional treatment with antioxidative substances. Experientia 39:62–64

  15. Lenzhofer R, Bolebruch C, Moser K (1983b) Experimental studies on the prevention of adriamycin induced cardiomyopathy. Z Krebsforsch Klin Onkol 105/2: Ex 13

  16. Moore L, Landon EJ, Cooney DA (1977) Inhibition of the cardiac mitochondrial calcium pump by adriamycin in vitro. Biochem Med 18:131–138

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

  18. Olson HM, Young DM, Prieur DJ, Le Roy AF, Reagan RL (1974) Electrolyte and morphologic alterations of myocardium in adriamycin-treated rabbits. Am J Pathol 77:439–454

  19. Schildberg FW, Fleckenstein A, Klek J (1964) Die Bedeutung der extrazellulären Calziumkonzentration für die Spaltung von energiereichem Phosphat in ruhendem und tätigem Myokardgewebe. Pflügers Arch 283:137–150

  20. Taylor D, Hochstein P (1978) Inhibition by adriamycin of a Metmyoglobin reductase from beef-heart. Biochem Pharmacol 27:2079–2082

  21. Von Hoff DD, Layard MW, Basa P, Davis HL, Von Hoff AL, Rozencweig M, Muggia FM (1979) Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91710–717

  22. Weissler AM, Harris WS, Schoenfeld CD (1969) Bedside technics for the evaluation of ventricular funtion in man. Am J Cardiol 23:577–583

  23. Wortman JE, Lucas VS, Thiele D, Logue GL (1979) Sudden death during doxorubicin administration. Cancer 44:1588–1591

  24. Zähringer J (1981) The regulation of protein synthesis in heart muscle under normal conditions and in the adriamycin-cardiomyopathy. Klin Wochenschr 59:1273–1287

  25. Zunino F, Gambetta R, Di Marco A, Zaccara A (1972) Interactions of daunomycin and its derivatives with DNA. Biochem Biophys Acta 277:489–498

Download references

Author information

Correspondence to R. Lenzhofer.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lenzhofer, R., Ganzinger, U., Rameis, H. et al. Acute cardiac toxicity in patients after doxorubicin treatment and the effect of combined tocopherol and nifedipine pretreatment. J Cancer Res Clin Oncol 106, 143–147 (1983).

Download citation

Key words

  • Doxorubicin
  • Acute cardiac toxicity
  • Prevention