Molecular and Cellular Biochemistry

, Volume 207, Issue 1–2, pp 77–86 | Cite as

Adriamycin-induced heart failure: mechanisms and modulation

  • Pawan Singal
  • Timao Li
  • Dinender Kumar
  • Igor Danelisen
  • Natasha Iliskovic


Adriamycin (doxorubicin) is one of the most effective chemotherapeutic agents against a variety of cancers, but its usefulness is seriously curtailed by the risk of developing heart failure. Available laboratory evidence suggests that an increase in oxidative stress, brought about by increased free radical production and decreased myocardial endogenous antioxidants, plays an important role in the pathogenesis of heart failure. Adriamycin-induced apoptosis and hyperlipidemia may also be involved in the process. Probucol, a lipid-lowering drug and an antioxidant, completely prevents the occurrence of heart failure by reducing oxidative stress as well as by the modulation of apoptis and high lipid concentrations. Thus, combined therapy with adriamycin and probucol has a high potential for optimizing the treatment of cancer patients.

cardiomyopathy lipid peroxidation superoxide dismutase glutathione peroxidase 


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  1. 1.
    Young RC, Ozols RF, Myers CE: The anthracycline antineoplastic drugs. New Engl J Med 305: 139–153, 1981Google Scholar
  2. 2.
    Booser DJ, Hortobagyi GN: Anthracycline antibiotics in cancer therapy: Focus on drug resistance. Drugs 47: 223–258, 1994Google Scholar
  3. 3.
    Lefrak EA, Pitha J, Rosenheim S, Gottleib JA: A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer 32: 302–314, 1973Google Scholar
  4. 4.
    Singal PK, Deally CMR, Weinberg LE: Subcellular effects of adriamycin in the heart: a concise review. J Mol Cell Cardiol 19: 817–828, 1987Google Scholar
  5. 5.
    Buja LM, Ferrans VJ, Mayers RJ, Robert WC, Henderson ES: Cardiac ultrastructural changes induced by daunorubicin therapy. Cancer 32: 771–778, 1973Google Scholar
  6. 6.
    Singal PK, Iliskovic N: Adriamycin cardiomyopathy. N Engl J Med 339: 900–905, 1998Google Scholar
  7. 7.
    Cortes EP, Lutman G, Wanka J, Wang JJ, Pickren J, Wallace J, Holland JF: Adriamycin (NSC-123127) cardiotoxicity. A clinicopathologic correlation. Cancer Treat Rep 6: 215–225, 1975Google Scholar
  8. 8.
    Von Hoff DD, Layard MW, Basa P, Davis HL, Von Hoff AL, Rozencweig M, Muggia FM: Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91: 710–717, 1979Google Scholar
  9. 9.
    Arcamone F, Cassinelli G, Fantini G, Grein A, Orezzi P, Pol C, Spalla C: Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius. Biotechnol Bioeng 9: 1101–1110, 1969Google Scholar
  10. 10.
    Di Marco A, Gaetani M, Scorpinato B: Adriamycin(NSC-123,127): A new antibiotic with antitumor activity. Cancer Chemother Rep 53: 33–37, 1969Google Scholar
  11. 11.
    Weiss RB: The anthracyclines: will we ever find a better doxorubicin? Semin Oncol 19: 670–686, 1992Google Scholar
  12. 12.
    Arcamone F, Cassinelli G, Franceschi G: Structure and physicochemical properties of adriamycin(doxorubicin). In: S.K. Carter, A. DiMarco and M. Ghione (eds). Int. Symp. Adriamycin. Springer, New York, 1972, pp 9–22Google Scholar
  13. 13.
    Arcamone F, Penco S: Synthesis of new doxorubicin analogs. In: Lown (ed). Anthracycline and anthracycline-based anticancer agents. Elsevier, Amsterdam, 1988, pp 1–53Google Scholar
  14. 14.
    Doroshow JH: Effect of anthracycline antibiotics on oxygen radical formation in rat heart. Cancer Res 43: 460–472, 1983Google Scholar
  15. 15.
    Doroshow JH: Anthracycline antibiotic-stimulated superoxide, hydrogen peroxide and hydroxyl radical production by NADH dehydrogenase. Cancer Res 43: 4543–4551, 1983Google Scholar
  16. 16.
    Bachur NR, Gee MV, Friedman RN: Nuclear catalyzed antibiotic free radical formation. Cancer Res 42: 1078–1081, 1982Google Scholar
  17. 17.
    Svingen, BA, Powis G: Pulse radiolysis studies of antitumor quinones: radical lifetimes, reactivity with oxygen, and oneelectron reduction potentials. Arch Biochem Biophys 209: 119–126, 1981Google Scholar
  18. 18.
    Bristow MR, Thompson PD, Martin RP, Mason JW, Bollingham ME, Harrison DC: Early anthracycline cardiotoxicity. Am J Med 65: 823–832, 1978Google Scholar
  19. 19.
    Jaenke RS, Fajardo LF: Adriamycin-induced myocardial lesions: Report of a workshop. Am J Surg Pathol 1: 55–60, 1977Google Scholar
  20. 20.
    Olson HM, Young DM, Prieur DJ, LeToy AF, Reagan RL: Electrolyte and morphologic alterations of myocardium in adriamycin-treated rabbits. Am J Pathol 77: 439–454, 1974Google Scholar
  21. 21.
    Jaenke RS: An anthracycline antibiotic-induced cardiomyopathy in rabbits. Lab Invest 30: 292–303, 1974Google Scholar
  22. 22.
    Rosenhoff SH, Olson HM, Young DM, Bostic F, Young RC: Adriamycin-induced cardiac damage in the mouse: A small animal model of cardiotoxicity. J Nat Cancer I 55: 191–194, 1975Google Scholar
  23. 23.
    Lambertenghi-Deliliers G, Zanon PL, Pozzoli EF, Bellini O: Myocardial injury by a single dose of adriamycin: An electron microscopic study. Tumori 62: 517–528, 1976Google Scholar
  24. 24.
    Chalscroft SCW, Gavin JB, Herdon PB: Fine structure changes in rat myocardium induced by daunorubicin. Pathology 5: 99–105, 1973Google Scholar
  25. 25.
    Weinberg LE, Singal PK: Refractory heart failure and age-related difference in adriamycin-induced myocardial changes in rats. Can J Physiol Pharm 65: 1957–1965, 1987Google Scholar
  26. 26.
    Singal PK, Iliskovic N, Li T, Kumar D: Adriamycin cardiomyopathy: pathophysiology and prevention. FASEB J 11: 931–936, 1997Google Scholar
  27. 27.
    Tong J, Ganguly PK, Singal PK: Myocardial adrenergic changes at two stages of heart failure due to adriamycin treatment in rats. Am J Physiol 260: H909-H916, 1991Google Scholar
  28. 28.
    Deally CMR, Singal PK: Susceptibility to adriamycin-induced cardiotoxicity increase only up to certain age. J Appl Cardiol 5: 223–228, 1990Google Scholar
  29. 29.
    Mettler FP, Young DM, Ward JM: Adriamycin-induced cardiotoxicity (Cardiomyopathy and Congestive Heart Failure) in rats. Cancer Res 37: 2705–2713, 1977Google Scholar
  30. 30.
    Zbinden G, Bachmann E, Holdiregger C: Model systems for cardiotoxic effects of anthracyclines. Fundamentals in Cancer Chemotherapy. Antibiot Chemother 23: 255–270, 1978Google Scholar
  31. 31.
    Siveski-Iliskovic N, Thomas TP, Kaul N, Slezak J, Singal PK: Doxorubicin-induced cardiomyopathy. A model of congestive heart failure. In: M. Nagano, N. Takeda, N.S. Dhalla (eds). The Cardiomyopathic Heart. Raven Press Ltd., New York, 1994, pp 277–283Google Scholar
  32. 32.
    Steinherz LJ, Steinherz PG, Tan CTC, Heller G, Murphy L: Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA 266: 1672–1677, 1991Google Scholar
  33. 33.
    Bonadonna G, Monfardin S, Lena MD, Fossati-Bellani F, Beretta G: Phase I and preliminary phase II evaluation of adriamycin(NSC 123 127). Cancer Res 30: 2572–2582, 1970Google Scholar
  34. 34.
    Arena E, D'Alessandre N, Dusonchet L, Gerbasi F: DNA, RNA and protein synthesis in heart, liver and brain of mice treated with daunorubicin and adriamycin. Int Res Commun Systemic Med Sci 2: 1053–1061, 1974Google Scholar
  35. 35.
    Bristow MR, Sagaman WS, Scott RH, Billingham ME, Bowden RE, Kernoff RS, Snidow IH, Daniels JR: Acute and chronic cardiovascular effects of doxorubicin in the dog: The cardiovascular pharmacology of drug-induced histamine release. J Cardiovasc Pharm 2: 487–515, 1980Google Scholar
  36. 36.
    Gosalvez M, van Rossum GDV, Blanco MF: Inhibition of sodiumpotassium activated adenosine 5'-triphosphatase and ion transport by adriamycin. Cancer Res 39: 257–261, 1979Google Scholar
  37. 37.
    Singal PK, Segstro RJ, Singh RP, Kutryk MJ: Changes in lysosomal morphology and enzyme activities during the development of adriamycin-induced cardiomyopathy. Can J Cardiol 1: 139–147, 1985Google Scholar
  38. 38.
    Singal PK, Pierce GN: Adriamycin stimulated low-affinity Ca2+ binding and lipid peroxidation but depressed myocardial function. Am J Physiol 250: H419-H425, 1986Google Scholar
  39. 39.
    Singal PK, Panagia V: Direct effect of adriamycin on the rat heart sarcolemma. Res Comm Chem Pathol Pharmacol 43: 67–77, 1984Google Scholar
  40. 40.
    Kalyanaraman B, Perez-Reyes E, Mason RP: Spin-trapping and direct electron spin resonance investigations of the redox metabolism of quinone anticancer drugs. Biochem Biophys Acta 630: 119–130, 1980Google Scholar
  41. 41.
    Revis NW, Marusic N: Glutathione peroxidase activity and selenium concentration in the hearts of doxorubicin-treated rabbits. J Mol Cell Cardiol 10: 945–951, 1978Google Scholar
  42. 42.
    Siveski-Iliskovic N, Kaul N, Singal PK: Probucol promote endogenous antioxidants and provides protection against adriamycin-induced cardiomyopathy in rats. Circulation 89: 2829–2835, 1994Google Scholar
  43. 43.
    Myers CE, McGuire WP, Liss RH, Ifrim I, Young RC: Adriamycin: The role of lipid peroxidation in cardiac toxicity and tumor response. Science 197: 165–167, 1977Google Scholar
  44. 44.
    Doroshow JH, Locher GY, Baldinger J, Myers CE. The effect of doxorubicin on hepatic and cardiac glutathione. Res Commu Chem Pathol Pharmacol 26: 285–295, 1979Google Scholar
  45. 45.
    Olson RD, MacDonald JS, vanBowtel CJ, Boerth RC, Harbison RD, Slonim AE, Freeman RW, Oates JA: Regulatory role of glutathione and soluble sufhydryl groups in the toxicity of adriamycin. J Pharmacol Exp Ther 215: 450–545, 1980Google Scholar
  46. 46.
    Odom AL, Hatwig CA, Stanley JS, Benson AM: Biochemical determinants of adriamycin toxicity in mouse liver, heart and intestine. Biochem Pharmacol 43: 831–836, 1992Google Scholar
  47. 47.
    Zhang J, Clark JR Jr, Herman EH, Ferrans VJ: Doxorubicininduced apoptosis in spontanously hypertensive rats: differential effects in heart, kidney and intestine, and inhibition by ICRF-187. J Mol Cell Cardiol 28:1931–1943, 1996Google Scholar
  48. 48.
    Amin JK, Pimentel DR, Chang DL, Wang J, Colucci WS, Sawyer DB: Preconditioning inhibits anthracycline induced apoptosis in neonatal rat ventricular myocytes. FASEB J 12:A70, 407, 1998Google Scholar
  49. 49.
    Kumar D, Kirshenbaum L, Li T, Danelisen I, Singal PK: Apoptosis in isolated adult cardiomyocytes exposed to adriamycin. Ann N Y Acad Sci 874: 156–168, 1999Google Scholar
  50. 50.
    Kaul N, Siveski-Iliskovic N, Hill M, Slezak J, Singal PK: Free radicals and the heart. J Pharmacol Toxicol Meth 30: 55–67, 1993Google Scholar
  51. 51.
    Fantone JC, Ward PA: Oxygen-derived radicals and their metabolites: Relationship to tissue injury. Current Concepts; A publication of The Upjohn Company, Kalamazoo, Michigan. 1985Google Scholar
  52. 52.
    Thornalley PJ, Dodd NJF: Free radical production from normal and adriamycin-treated rat cardiac sarcosomes. Biochem Pharmacol. 34: 669–674, 1985Google Scholar
  53. 53.
    Costa L, Malatests V, Morazzoni F, Scotti R, Monti E, Paracchini L: Direct detection of paramagnetic species in adriamycin perfused rat hearts. Biochem Biophys Res Comm 153: 275–280, 1988Google Scholar
  54. 54.
    Alegria AE, Samuni A, Mitchell JB, Riesz P, Russo A: Free radicals induced by adriamycin-sensitive and adriamycin-resistant cells: A spin-trapping study. Biochemistry 28: 8653–8658, 1989Google Scholar
  55. 55.
    Iliskovic N, Hasinoff BB, Malisza KL, Li T, Danelisen I, Singal PK: Mechanisms of beneficial effects of probucol in adriamycin cardiomyopathy. Mol Cell Biochem 196: 43–49, 1999Google Scholar
  56. 56.
    Griffin-Green EA, Zaleska MM, Erecinska M: Adriamycininduced lipid peroxidation in mitochondria and microsomes. Biochem Pharmacol 37: 3071–3077, 1988Google Scholar
  57. 57.
    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: 6820–6826, 1985Google Scholar
  58. 58.
    Sinha BK, Polliti PM: Anthracyclines. Cancer Chemother Biol Resp Modifiers Ann 11: 45–57, 1990Google Scholar
  59. 59.
    Doroshow JH, Locker GY, Myers CE: Enzymatic defences of the mouse heart against reactive oxygen metabolites. J Clin Invest 65: 128–135, 1980Google Scholar
  60. 60.
    Jackson JA, Reeves JP, Muntz K, Kruk D, Prough RA, Willerson JR, Buja LM: Evaluation of free radical effects and catecholamine alterations in adriamycin cardiotoxicity. Am J Pathol 117: 140–153, 1984Google Scholar
  61. 61.
    Siveski-Iliskovic N, Hill M, Chow DA, Singal PK: Probucol protects against adriamycin cardiomyopathy without interfering with its anti-tumor properties. Circulation 91: 10–15, 1995Google Scholar
  62. 62.
    Ji LL, Mitchell EW: Effect of adriamycin on heart mitochondrial function in rested and exercised rats. Biochem Pharmacol 47: 877–885, 1994Google Scholar
  63. 63.
    Narula J, Haider N, Virmani R, DiSalvo TG, Kolodgie FD, Hajjar RJ, Schmidt U, Semigran MJ, Dec GW, Khaw BA: Apoptosis in myocytes in end-stage heart failure. N Engl J Med 335: 1182–1189, 1996Google Scholar
  64. 64.
    Sharov VG, Sabbah HN, Shiomoyama H, Goussev AV, Lesch M, Goidstein S: Evidence of cardiocyte apoptosis in myocardium of dogs with chronic heart failure. Am J Pathol 148: 141–149, 1996Google Scholar
  65. 65.
    Saraste A, Pulkki K, Kallajoki M, Henriksen K, Parvinen M, Voipio-Pulkki L-M: Apoptosis in human acute myocardial infarction. Circulation 95: 320–323, 1997Google Scholar
  66. 66.
    Legha SS, Benjamin RS, Mackay B, Ewer M, Wallace S, Valdivieso M, Rasmussen SL, Blumenschein GR, Freireih EJ: Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med 96: 133–139, 1982Google Scholar
  67. 67.
    Shapira J, Foffried M, Lishner M, Ravid M: Reduced cardiotoxicity of doxorubicin by a six hour infusion regimen. Cancer 65: 870–878, 1990Google Scholar
  68. 68.
    Ewer MS, Jaffe N, Reid H, Zietz HA, Benjamin RS: Doxorubicin cardiotoxicity in children: Comparison of a consecutive divided daily dose administration schedule with single dose (rapid) infusion administration. Med Pediatr Oncol 31: 512–515, 1998Google Scholar
  69. 69.
    Speyer JL, Green MD, Dubin N, Blum RH, Wernz JC, Roses D, Sanger J, Myggia FM: Prospective evaluation of cardiotoxicity during a six-hour doxorubicin infusion regimen in women with adenocarcinoma of the breast. Am J Med 78: 555–563, 1985Google Scholar
  70. 70.
    Bates DA, Winterbourn CC: Deoxyribose breakdown by the adriamycin semiquinone and H2O2: Evidence for hydroxyl radical participation. FEBS Lett 145: 137–142, 1982Google Scholar
  71. 71.
    Gutteridge JMC, Toeg D: Adriamycin-dependent damage to deoxyribose: A reaction involving iron, hydroxyl and semiquinone free radicals. FEBS Lett 149: 228–232, 1982Google Scholar
  72. 72.
    Muindi JRF, Sinha BK, Gianni L, Myers CE: Hydroxyl radical production and DNA damage induced by anthracycle-iron complex. FEBS Lett 172: 226–230, 1984Google Scholar
  73. 73.
    Singal PK, Siveski-Iliskovic N, Li T, Seneviratne C: Cardiomyopathy due to adriamycin and its preventions. L'information Cardiology 14: 289–302, 1995Google Scholar
  74. 74.
    Shimpo K, Nagatsu T, Yamada K, Sato T, Niimi H, Shamoto M, Takeuchi T, Umezawa H, Fujita K: Ascorbic acid and adriamycin toxicity. Am J Clin Nutr 54(suppl 6): 1298S-1301S, 1991Google Scholar
  75. 75.
    Doroshow JH, Locker GY, Ifrim I, Myers CE: Prevention of doxorubicin cardiac toxicity in the mouse by N-acetylsysteine. J Clin Invest 68: 1053–1064, 1981Google Scholar
  76. 76.
    Yoda Y, Nakazawa M, Tawakami Z: Prevention of doxorubicin myocardial toxicity in mice by reduced glutathione. Cancer Res 46: 2551–2556, 1986Google Scholar
  77. 77.
    Singal PK, Tong J: Vitamin E deficiency accentuate adriamycininduced cardiomyopathy and cell surface changes. Mol Cell Biochem 84: 163–171, 1988Google Scholar
  78. 78.
    Van Vleet JF, Ferrans VJ, Weirich WE: Cardiac disease induced by chronic adriamycin administration in dogs and evaluation of vitamin E and selenium as cardioprotectants. Am J Pathol 99: 13–42, 1980Google Scholar
  79. 79.
    Breed JGS, Zimmeran ANE, Dormans JAMA, Pinedo HM: Failure of the antioxidant vitamin E to protect against adriamycin-induced cardiotoxicity in rabbit. Cancer Res 40: 2033–2038, 1980Google Scholar
  80. 80.
    Singal PK, Siveski-Iliskovic N, Hill M, Thomas TP, Li T: Combination therapy with probucol prevents adriamycin-induced cardiomyopathy. J Mol Cell Cardiol 27: 1055–1063, 1995Google Scholar
  81. 81.
    Myers CE, Bonow R, Palmeri S, Jenkins J, Corden G, Locker G, Doroshow J, Epstein SA: A randomized controlled trial assessing the prevention of doxorubicin cardiomyopathy by N-acetylcysteine. Semin Oncol 10(suppl. 1): 53–55, 1983Google Scholar
  82. 82.
    Herman EH, Ferrans VJ: Reduction of chronic doxorubicin cardiotoxicity in dogs by pretreatment with (I)-2, 2-Bis(3,5-dioxopoperozinyl-1-yl propane(ICRF-187). Cancer Res 41: 3436–3440, 1981Google Scholar
  83. 83.
    Speyer JL, Green MD, Zeleniuch-Jacquotte A, Wernz JC, Rey M, Sanger J, Kramer E, Ferrans V, Hochster H, Meyers M et al.: ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. J Clin Oncol 10: 117–127, 1992Google Scholar
  84. 84.
    Von Hoff DD, Howser D, Lewis HJ, Holcenberg J, Weiss RB, Young RC: Phase I study of ICRF-187 using daily for 3 days schedule. Cancer Treat Rep 65: 249–252, 1981Google Scholar
  85. 85.
    Sehesled M, Jensen PB, Sorensen BS, Holm B, Friche E, Demant EJ: Antagonistic effect of the cardioprotector (+)-1,2-bis(3,5-dioxopiperaziny-1-yl)propane(ICRF-187) on DNAbreaks and cytotoxicity induced by the topoisomerase II directed drugs daunorubicin and etoposide(VP-16). Biochem Pharmacol 46: 389–393, 1993Google Scholar
  86. 86.
    Seifert CF, Nesser ME, Thompson DF: Dexrazoxane in the prevention of doxorubicin-induced cardiotoxicity. Ann Pharmacother 28: 1063–1072, 1994Google Scholar
  87. 87.
    Vile GF, Winterbourn CC: dl-N,N'-dicarboxiamidomethyl-N,N'-dicarboxylmethyl-1,2-diaminopropane(ICRF-198)and d-1,2-bis(3,5-dioxopiperazine-1-yl) propane(ICRF-187) inhibition of Fe3+ reduction, lipid peroxidation, and CaATPase inactivation in heart microsomes exposed to adriamycin. Cancer Res 50: 2307–2310, 1990Google Scholar
  88. 88.
    Barbhart JW, Sefranka JA, McIntosh DD: Hypocholesterolemic effect of 4,4'-(isopropylidenedithio)-bis-(2,6-di-tertbutylphenol)( probucol). Am J Clin Nutr 23: 1229–1233, 1970Google Scholar
  89. 89.
    Zimetbaum P, Eder H, Frishman W: Probucol: Pharmacology and clinical application. J Clin Pharmacol 30: 3–9, 1990Google Scholar
  90. 90.
    Yamamoto A, Matsuzawa Y, Yokoyama S, Funahashi Y, Yamamura T, Kishino B: Effects of probucol on xanthomata regression in familial hypercholesterolemia. Am J Cardiol 57: 29H-35H, 1986Google Scholar
  91. 91.
    Wissler RW, Vesselinovitch D: Combined effects of cholestyramine and probucol on regression of atherosclerosis in Rhesus monkey aortas. Appl Pathol 1: 89–96, 1983Google Scholar
  92. 92.
    Iliskovic N, Singal PK: Lipid lowering: an important factor in preventing adriamycin-induced heart failure. Am J Pathol 150: 727–734, 1997Google Scholar
  93. 93.
    Iliskovic N, Li T, Khaper N, Palace V, Singal PK: Modulation of adriamycin-induced changes in serum free fatty acids, albumin and cardiac oxidative stress. Mol Cell Biochem 188: 161–166, 1998Google Scholar
  94. 94.
    Kumar D, Li T, Danelisen I, Singal PK: Evidence of cardiomyocyte apoptosis in adriamycin cardiomyopathy. J Mol Cell Cardiol 30: A258, 102, 1998Google Scholar
  95. 95.
    Hiramatsu M, Liu J, Edamatsu R, Ohba S, Kadowaki D, Mori A: Probucol scavenged 1,1-diphenyl-2-picryhydrazyl radicals and inhibited fprmation of thiobarbituric acid reactive substances. Free Rad Biol Med 16: 201–206, 1994Google Scholar
  96. 96.
    Parthasarathy S, Young SG, Witztum JL, Pittman RC, Steinberg D: Probucol inhibits oxidative modification of low density lipoprotein. J Clin Invest 77: 641–644, 1986Google Scholar
  97. 97.
    Pryor WA, Strickland T, Church DF: Comparison of the efficiencies of several natural and synthetic antioxidants in aqueous sodium dodecyl sulfate micelle solutions. J Am Chem Soc 110: 2224–2229, 1988Google Scholar
  98. 98.
    Mao STT, Yates MT, Rechtin AE, Jackson RL, Van Sickle WA: Antioxidant activity of probucol and its analogues in hyperchlosterolemic Watanabe rabbits. J Med Chem 34: 298–302, 1991Google Scholar
  99. 99.
    Kaul N, Siveski-Iliskovic N, Thomas TP, Hill M, Khaper N, Singal PK: Probucol improves antioxidant activity and modulates development of diabetic cardiomyopathy. Nutrition 11: 551–554, 1995Google Scholar
  100. 100.
    Tardif JC, Cote G, Lesperance J, Bourassa M, Lambert J, Doucet S, Bilodeau L, Nattel S, de Guise P: Probucol and multivitamins in the prevention of restenosis after coronary angioplasty. N Engl J Med 337: 365–372, 1997Google Scholar
  101. 101.
    Yokoi H, Daida H, Kuwabara Y, Nishikawa H, Takatsu F, Tomihara H, Nakata Y, Kutsumi Y, Ohshima S, Nishiyama S, Seki A, Kata K, Nishimura S, Kanoh T, Yamaguchi H: Effectiveness of an antioxidant in preventing restenosis after percutaneous transluminal coronary angioplasty: The probucol angioplasty restenosis trial. J Am Coll Cardiol 30: 855–862, 1997Google Scholar
  102. 102.
    Singal PK, Kirshenbaum LA: A relative deficit in antioxidant reserve may contribute in cardiac failure. Can J Cardiol 6: 47–49, 1990Google Scholar
  103. 103.
    Li T, Danelisen I, Singal PK: Antioxidant enzyme gene expression in adriamycin cardiomyopathy. J Mol Cell Cardiol 31: A38, 1999Google Scholar
  104. 104.
    Kunotomo M, Yamaguchi Y, Matsushima K, Futagawa Y, Bando Y: Hyperlipidemic effects of adriamycin in rats. Jpn J Pharmacol 39: 323–329, 1985Google Scholar
  105. 105.
    Joles JA, van Tol A, Jansen EHJM, Doomans HA, Rabelink TJ, Grond J, van Goor H: Plasma lipoproteins and renal apolipoproteins in rats with chronic adriamycin nephrosis. Nephrol Dial Transplant 8: 831–838, 1993Google Scholar
  106. 106.
    Oliver MF, Kurien VA, Greenwood TW: Relation between serum free fatty acids and arrhythmias and death after acute myocardial infarction. Lancet 1: 710–715, 1968Google Scholar
  107. 107.
    Willebrands AF, Ter Welle HF, Tasseron JA: The effect of a high molar FFA/albumin rtatio in the perfusion medium on rhythm and contractility of the isolated heart. J Mol Cell Cardiol 5: 259–273, 1973Google Scholar
  108. 108.
    Skutelsky E, Hartzan S, Socher R, Gafter U: Modifications in glomerular polyanion distribution in adriamycin nephrosis. J Am Soc Nephrol 5: 1799–1805, 1995Google Scholar
  109. 109.
    Senekowitsch R, Lohninger A, Kriegel H, Stanick H, Kreiglsteiner H-P, Kaiser E: Protective effects of carnitine on adriamycin toxicity to heart. In: H. Kaiser, A. Lohninger (eds). Carnitine-Its Role in Lung and Heart Disorders. Proc Satell Symp ZAK, Graz, 1985, pp 126–137Google Scholar
  110. 110.
    Bremer J: Carnitine metabolism and function. Physiol Rev 63: 1420–1480, 1983Google Scholar

Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Pawan Singal
    • 1
  • Timao Li
    • 1
  • Dinender Kumar
    • 1
  • Igor Danelisen
    • 1
  • Natasha Iliskovic
    • 1
  1. 1.Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre and Department of Physiology, Faculty of MedicineUniversity of ManitobaWinnipegCanada

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