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Acute effect of calcium channel blockers on adriamycin exposed isolated adult cardiocytes

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Summary

When tested with isolated, calcium-resistant resting rat cardiocytes in an in vitro assay system, adriamycin exerted a dose-dependent cytotoxic effect which could easily be assessed by the ATP depletion of the heart cells and the loss of vitality as monitored by morphological changes (blebbing, spherical contraction). Apart from extremely high non pharmacological concentrations of verapamil and diltiazem, both calcium antagonists left the cardiocytes intact and without loss of internal ATP when given alone to the medium. Coincubation of adriamycin and verapamil or diltiazem did not increase adriamycin toxicity to the cardiocytes; instead a remarkable ATP preservation by verapamil could be demonstrated when both drugs (adriamycin and verapamil) were incubated simultaneously with the heart cells. This acute protective effect was limited in time and could no longer be detected after 9 hours. Diltiazem in coincubation experiments exerted neither a toxic nor an acute protective effect on adriamycin-exposed heart cells.

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References

  1. Arena E, Arico M, Biondo F, D'Alessandro N, Dusonchet L, Gabbia N, Gerbasi F, Sanguedolce R, Ranse L (1975) Analysis of some probable factor responsible for adriamycin induced cardiotoxicity. Adriamycin review Part II:160–172

    Google Scholar 

  2. Azuma J, Sperelakis N, Hawegawa H, Tanimoto T, Vogel S, Ogura K, Awato N, Sawamura A, Horada H, Ishiyama T, Monta Y, Yamamura Y (1981) Adriamycin cardiotoxicity: Possible pathogenetic mechanisms. J Mol Cell Cardio 13:381–397

    Article  Google Scholar 

  3. Bachmann E, Zbinden G (1979) Effect of doxorubicin and rubidazone on respiratory function and Ca21 transport in rat heart mitochondria. Toxicol Lett 3:29–34

    Article  Google Scholar 

  4. Bachur NR, Gordon SL, Gee MV (1972) Anthracycline antibiotic augmentation of microsomal electron transport and free radical formation. Mol Pharmacol 13:901–910

    Google Scholar 

  5. Berndt H (1983) Zum Stand der Krebstherapie mit Adriamycin. (Status of adriamycin in cancer therapy.) Arch Geschwulstforsch 52(7):585–596

    Google Scholar 

  6. Billingham ME, Mason JW, Briston MR, Daniels JR (1978) Anthracycline cardiomyopathy monitored by morphologic changes. Cancer Treatment Rep 62:865–872

    Google Scholar 

  7. Binah O, Cohen IS, Rosen MR (1983) The effects of adriamycin on normal and ouabain toxic canine Purkinje and ventricular muscle fibers. Circ Res 53:655–662

    PubMed  Google Scholar 

  8. Bristow MR, Thompson PD, Martin RP, Mason JW, Billingham ME, Harrison DC (1978) Early anthracycline cardiotoxicity. Am J Med 65:823–832

    Article  PubMed  Google Scholar 

  9. Bristow MR (1980) Anthracycline cardiotoxicity. In: Bristow MR (ed) Drug-induced heart disease. Elsevier/North-Holland Biomedical Press pp 191–215

  10. Bristow MR (1980) Protection against doxorubicin cardiomyopathy in rabbits by coenzyme Q10: Evidence for non-specific myocardial preservation. Biomed Clin Aspects coenzyme 2:179–188

    Google Scholar 

  11. Bristow MR, Ginsburg R, Laser J, McAuley B, Minobe W (1984) Tissue response selectivity of calcium antagonists is not due to heterogeneity of (3H) nitrendipine binding sites. Br J Pharmacol 82(2):309–320

    PubMed  Google Scholar 

  12. Buehner R, Biedert S, Miura D (1980) Experimentelle Untersuchungen zur Klärung der Pathogenese der durch Adriamycin induzierten Kardiomyopathie. Arzneimittel-Forsch 30(7):1065–1070

    Google Scholar 

  13. Caroni P, Villani F, Carafoli E (1981) The cardiotoxic antibiotic doxorubicin inhibits the Na+/Ca2+ exchange of dog heart sarcolemmal vesicles. FEBS Lett 130:184–186

    PubMed  Google Scholar 

  14. Daniels JR, Margaret E, Billingham ME, Gelbert A, Bristow MR (1976) Effect of verapamil and propranolol on adriamycin-induced cardiomyopathy in rabbits. Circulation 53 & 54 (Suppl 2):70

    Google Scholar 

  15. Favalli L, Ferrari CC, Monti E, Piccinini F, Villani F (1981) Effect of verapamil on the relationship between calcium turnover and early cardiotoxicity of doxorubicin. IRCS Pharmacol 9(5):397–398

    Google Scholar 

  16. Ganapathi R, Grabowski D (1983) Enhancement of sensitivity to adriamycin in resistant P388 leukemia by the calmodulin inhibitor trifluoperazine. Cancer Res 43(8):3696–3699

    PubMed  Google Scholar 

  17. Garbrecht M, Müllerleile U, Hanrath P, Langenstein B, Bieber K, Krüger W (1981) Eine mögliche Prävention der adriamycininduzierten Kardiomyopathie durch Kalziumantagonisten. Beitr Onkol 9:pp 43–48

    Google Scholar 

  18. Hauder K, Sato S (1975) Generation of free radicals of quinone group containing anticancer chemicals in RADPH-microsome system as evidenced by initiation of sulfize oxidation. Gann 66:43–47

    PubMed  Google Scholar 

  19. Ito H, Hidaka H (1983) Antitumor effect of a calmodulin antagonist on the growth of solid sarcoma-180. Cancer Lett 19(2):215–220

    Article  PubMed  Google Scholar 

  20. Iwamoto Y, Hansen IL, Porter TH, Folkers K (1974) Inhibition of coenzyme Q10-enzymes, succinoxidase and NADH-oxidase by adriamycin and other quinons having antitumor activity. Biochem Biophys Res 58:633–638

    Google Scholar 

  21. Klugmann S, Klugmann FB, Decorti G, Gori D, Silvestri F, Camerini F (1980) Effects of two calcium antagonistic agents in the experimental cardiomyopathy induced by adriamycin in Swiss mice. In: Zanchetti A (ed) International Symposium on Calciumantagonism in cardiovascular therapy. Experience with Verapamil, 27–29

  22. Klugmann S, Klugmann FB, Decorti G, Gori D, Silvestri F, Camerini F (1981) Adriamycin experimental cardiomyopathy in Swiss mice. Different effects of two calcium antagonistic drugs on ADM-induced cardiomyopathy. Pharmacol Res Comm 13(8):769–776

    Google Scholar 

  23. Lewis W, Galizi M, Puszkin S (1983) Compartmentalization of adriamycin and daunomycin in cultured chick cardiac myocytes. Effects on synthesis of contractile and cytoplasmic proteins. Circ Res 53:352–362

    PubMed  Google Scholar 

  24. Maisch B (1981) Enrichment of vital adult cardiac muscle cells by continuous silica sol gradient centrifugation. Basic Res Cardiol 76:622–629

    PubMed  Google Scholar 

  25. Maisch B, Wilke H, Gunzer U, Marcin S, Salzer E (1982) Antimyocardial antibodies. — A diagnostic marker in adriamycin-induced cardiomyopathy. Circulation 66(II):247

    Google Scholar 

  26. Maisch B, Gregor O, Zeuss M, Kochsiek K (1985) Protektive Wirkung von Kalziumantagonisten auf adriamycinexponierte isolierte Kardiozyten. Klin Wschr 63:158(A 382)

    Article  PubMed  Google Scholar 

  27. Maisch B, Wilke H, Marcin S, Werner C, Gebhardt W (1984) Adriamycin cardiotoxicity. — An echocardiographic and immunological follow-up study. Circulation 70, part II:149

    Google Scholar 

  28. Marafino BJ, Giri Jr and SN (1981) Effects of nutrition, dose and verapamil treatment on the cardiotoxicity of doxorubicin. Pharmacol 23:154

    Google Scholar 

  29. Milei J, Busch L, Marantz H, Bolomo N (1980) Prenylamine inhibition of adriamycin cardiomyopathy in mice. Proc Am Assoc Cancer Res 21:330

    Google Scholar 

  30. Mizuno S, Ishida A (1982) Potentiation of Bleomycin cytotoxicity by membrane-interacting drugs and increased calcium ions. Biochem Biophys Res Comm 107:1021–1027

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  33. Müllerleile U, Garbrecht M, Hanrath P, Bieber K, Thier W, Hossfeld DK (1983) Prävention der durch Adriamycin induzierten Kardiomyopathie mit Verapamil. Verh Deutsch Ges f inn Med 89:583–585

    Google Scholar 

  34. Olsen HM, Young DM, Prieur DJ, Le Roy AF, Reagan RL (1974) Electrolyte and morphologic alterations of myocardium in adriamycin treated rats. Am J Pathol 77:439–450

    PubMed  Google Scholar 

  35. Powell R, Twist VW (1976) A rapid technique for the isolation and purification of adult cardiac muscle cells having respiratory control and tolerance to calcium. Biochem Biophys Res Commun 72:327–333

    Article  PubMed  Google Scholar 

  36. Rabkin SW (1983) Interaction of external calcium concentrations and verapamil on the effects of doxorubicin (adriamycin) in the isolated heart preparation. J Cardiovasc Pharmacol 5:848–855

    PubMed  Google Scholar 

  37. Rosenoff SH, Brooks E, Bostick F, Young RC (1975) Alterations in DNA synthesis in cardiac tissue induced by adriamycin in vivo — relationship to fatal toxicity. Biochem Pharmacol 24:1898–1901

    Article  PubMed  Google Scholar 

  38. Sawada H, Dohmae N, Tashima M, Usui T, Konishi H, Kita K, Ohkubo T, Uehara N, Uchino H (1980) Chronic cardiotoxicity of adriamycin and possible prevention by coenzyme Q10 in rabbits. Biomed Clin Aspects Coenzyme Q 2:189–204

    Google Scholar 

  39. Skovsgaard T, Friche E (1982) Circumvention of resistance to daunorubicin. In: Anthracyclines and cancer therapy. Proceedings of a Symposium, Ronneby Brunn, Sweden. Excerpta Medica:39–48

  40. Slater LM, Murray SL, Wetzel MW, Wisdom RM, DuVall EM (1983) Verapamil restoration of daunorubicin responsiveness in daunorubicin-resistant Ehrlich ascites carcinoma. J Clin Invest 70:1131–1134

    Google Scholar 

  41. Suzuki T, Kanda H, Kawai Y, Tominaga K, Murata K (1979) Cardiotoxicity of anthracycline antineoplastic drugs. Clinicopathological and experimental studies. Jap Circ J 43:1000–1008

    PubMed  Google Scholar 

  42. Tsuruo T, Iida H, Nojiri M, Tsukagoshi S, Sakurai Y (1983) Potentiation of chemotherapeutic effect of vincristine in vincristine resistant tumor bearing mice by calmodulin inhibitor clomipramine. J Pharmacobiodyn 6:145–147

    PubMed  Google Scholar 

  43. Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y (1981) Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res 41:1967–1972

    PubMed  Google Scholar 

  44. Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y (1983) Potentiation of vincristine and adriamycin effects in human hemopoietic tumor cell lines by calcium antagonists and calmodulin inhibitors. Cancer Res 43:2267–2272

    PubMed  Google Scholar 

  45. Tsuruo T, Iida H, Yamashiro M, Tsukagoshi S, Sakurai Y (1983) Enhancement of vincristine- and adriamycin-induced cytotoxicity by verapamil in P388 leukemia and its sublines resistant to vincristine and adriamycin. Biochem Pharmacol 31:3138–3140

    Article  Google Scholar 

  46. Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y (1983) Increased accumulation of vincristine and adriamycin in drug-resistant P 388 tumor cells following incubation with calcium antagonists and calmodulin inhibitors. Cancer Res 42:4730–4733

    Google Scholar 

  47. Tsuruo T, Iida H, Naganuma K, Tsukagoshi S, Sakurai Y (1983) Promotion by verapamil of vincristine responsiveness in tumor cell lines inherently resistant to the drug. Cancer Res 43:808–813

    PubMed  Google Scholar 

  48. Tsuruo T, Iida H, Nojiri M, Tsukagoshi S, Sakurai Y (1983) Circumvention of vincristine and adriamycin resistance in vitro and in vivo by calcium influx blockers. Cancer Res 43:2905–2910

    PubMed  Google Scholar 

  49. Villani F, Guidani A, Favalli L, Chiari C, Monti E, Piccinini F (1981) Role of cell calcium in the early and delayed cardiotoxicity of anthracyclines. Proc A Assoc Cancer Res 22:30

    Google Scholar 

  50. Wikman-Coffelt J, Rapcsak M, Sievers R, Rouleau JL, Parmley WW (1983) Verapamil, propranolol, and hydralazine protect against the acute cardiac depression induced by adriamycin. Cardiovasc Res 17:43–49

    PubMed  Google Scholar 

  51. Young DM, Mettler FP, Fioravanti JL (1975/1976) Adriamycin, verapamil and calcium metabolism. Proc Am Assoc Cancer Res 16 und 17:90

    Google Scholar 

  52. Zähringer J (1983) Gen-Expression und Protein-Synthese im normalen Herzmuskel und bei der Adriamycin-Kardiomyopathie. Fortschriff der Med 101:805–807

    Google Scholar 

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Devoted to my distinguished academic teacher in cardiac physiology Prof. Dr. Ruthard Jacob on the occasion of his 60th birthday

Supported in part by DFG-grants MA 780/1-5

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Maisch, B., Gregor, O., Zeuss, M. et al. Acute effect of calcium channel blockers on adriamycin exposed isolated adult cardiocytes. Basic Res Cardiol 80, 626–635 (1985). https://doi.org/10.1007/BF01907861

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