Implications of Free Radical Activation for Improved Anthracycline Therapy

  • D. D. Pietronigro
Part of the Developments in Oncology book series (DION, volume 10)


The anthracyclines are an effective new class of antitumor antibiotics. Adriamycin (ADM) is the most extensively investigated member of this class. In addition to its clinically advantageous tumor cell toxicity (TCT), it exhibits diverse biologic actions. These include unwanted side toxicities which limit its usefulness. The exact mechanisms by which ADM exerts both TCT and side toxicities remain to be elucidated. In the past three or four years, much interest has been generated concerning the possible involvement of ADM radicals (ADM·) in these toxicities. This interest has been fueled by the realizations that ADM is activated to ADM· throughout biologic systems, that ADM side toxicities can be inhibited by a number of antioxidants, and that ADM-stimulated radical formation produces DNA damage.


Free Radical Reaction Ehrlich Ascites Tumor Cell Free Radical Activation Antitumor Antibiotic Acute Lethality 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Pietronigro DO, McGiriness JE, Koren MJ, Crippa R, Seligman ML, Demopoulos HB. Spontaneous generation of adriamycin semiquinone radicals at physiologic pH. Physiol. Chem. Phys. 11: 405–414, 1979.PubMedGoogle Scholar
  2. 2.
    Pietronigro DO, Koren MJ, Demopoulos HB. Evidence for both direct and superoxide-mediated reduction of nitroblue tetrazolium by adriamycin radicals. Submitted for publication.Google Scholar
  3. 3.
    Del Maestro RF. An approach to free radicals in medicine and biology. Acta Physiol. Scand. Suppl. 492: 153–168, 1980.PubMedGoogle Scholar
  4. 4.
    McGinness JE, Proctor PH, Demopaulos HB, Hokanson JA, Van NT. In vivo evidence for superoxide and peroxide production by adriamycin and cis platinum. In: Oxygen Induced Pathology, AP Autor (ed.). New York, Academic Press, 1982.Google Scholar
  5. 5.
    Svingen BA, Powis G, Appel PL, Scott M. Protection by a-tocopherol and dimethylsulfoxide (DMSO) against adriamycin induced skin ulcers in the rat. Res. Comm. Chem. Path. Pharm. 32: 189–192, 1981.Google Scholar
  6. 6.
    Sato S, Iwaizumi M, Handa K, Tamura Y. Electron spin resonance study on the mode of generation df free radicals of daunomycin, adriamycin and carboquone in NAD(P)H-microsome system. Gann 68: 603–608, 1977.PubMedGoogle Scholar
  7. 7.
    Bachur NR, Gordon SL, Gee MV. Anthracycline antibiotic auqmentation of microsomal electron transport and free radical formation. Mol. Pharm. 13: 901–910, 1977.Google Scholar
  8. 8.
    Bachur NR, Gordon SL, Gee MV. A general mechanism for microsomal activation of quinone antiCancer agents to free radicals. Ca Res. 38: 1745–1750, 1978.Google Scholar
  9. 9.
    Goodman J, Hochstein P. Generation of free radicals and lipid peroxidation by redox cycling of adriamycin and daunomycin. Biochem. Biophys. Res. Comm. 77: 797–803, 1977.PubMedCrossRefGoogle Scholar
  10. 10.
    Oki T, Komiyama T, Tone H, Inui T, Takeuchi T, Umuzawa H. Reductive cleavage of anthracycline glycosides by microsomal NADPH-cytochrome c reductase. J. Antibiot. 30: 613–615, 1977.PubMedGoogle Scholar
  11. 11.
    Handa K, Sato S. Stimulation of microsomal NADPH oxidation by quinone group-containing antiCancer chemicals. Gann 67: 523–528, 1976.PubMedGoogle Scholar
  12. 12.
    Lai CS, Grover TA, Piette LH. Hydroxyl radical production in a purified NADPH-cytochrome c (P-450) reductase system. Arch. Biochem. Biophys. 193: 373–378, 1979.PubMedCrossRefGoogle Scholar
  13. 13.
    Ohnishi K, Lieber CS. Respective role of superoxide and hydroxyl radical in the activity of the reconstituted microsomal ethanol-oxidizing system. Arch. Biochem. Bionhys. 191: 798–803, 1978.CrossRefGoogle Scholar
  14. 14.
    Bachur NR, Gee MV. Microsomal reductive glycosidase. J. Pharmacol. Exp. Ther. 197: 681–686, 1976.PubMedGoogle Scholar
  15. 15.
    Zimmerman JJ, Kasper CB. Immunological and biochemical characterization of nuclear envelope reduced nicotinamide adenine dinucleotide phosphatecytochrome c oxidoreductase. Arch. Biochem. Biophys. 190: 726–735, 1978.PubMedCrossRefGoogle Scholar
  16. 16.
    Pietronigro DD, Jones WBG, Kalty K, Demopoulos HB. Interaction of DNA and liposomes as a model for membrane-mediated DNA damage. Nature 267: 78–79, 1977.PubMedCrossRefGoogle Scholar
  17. 17.
    Iyanagi T, Yamazaki I. One-electron-transfer reactions in biochemical systems. V. Difference in the mechanism of quinone reduction by the NADH dehydrogenase and the NAD(P)H dehydrogenase (DT-diaphorase). Biochim. Biophys. Acta 216: 282–294, 1970.PubMedCrossRefGoogle Scholar
  18. 18.
    Doroshow JH. Mitomycin C-enhanced superoxide and hydrogen peroxide formation in rat heart. J. Pharm. Exp. Therap. 218: 206–211, 1981.Google Scholar
  19. 19.
    Thayer WS. Adriamycin stimulated superoxide formation in submitochondrial particles. Chem. Biol. Interact. 19: 265–278, 1977.PubMedCrossRefGoogle Scholar
  20. 20.
    Henderson CA, Metz EN, Balcerzak SP, Sagone AL. Adriamycin and daunomycin generate reactive oxygen compounds in erythrocytes. Blood 52: 878–885, 1970Google Scholar
  21. 21.
    Doroshow JH, Locker GY, Myers CE. Enzymatic defenses of themouse heart against reactive oxygen metabolites. Alterations produced by doxorubicin. J. Clin. Invest. 65: 128–135, 1980.PubMedCrossRefGoogle Scholar
  22. 22.
    Crane FL, MacKellar WC, Morre DJ, Ramasarma T, Goldenberg H, Grebing C, Low H. Adriamycin affects plasma membrane redox functions. Biochem. Biophys. Res. Comm. 93: 746–754, 1980.PubMedCrossRefGoogle Scholar
  23. 23.
    Slater TF. Free radical mechanisms in tissue injury. Pion Limited, London, 1972.Google Scholar
  24. 24.
    Fitzsimons OW (ed.). Oxygen free radicals and tissue damage. Ciba Foundation symposium 65, Excerpta Medica, New York, 1979.Google Scholar
  25. 25.
    Demopoulos HB. Control of free radicals in biologic systems. Fed. Proc. 32: 1903–1908, 1973.PubMedGoogle Scholar
  26. 26.
    Yamanaka N, Kato T, Nishida K, Fujikawa T, Fukushima M, Ota K. Elevation of serum lipid peroxide level associated with doxorubicin toxicity and its amelioration by (d)-a-tocopherol acetate or coenzyme Q10 in mouse. Ca. Chemather. Pharmacol. 3: 223–227, 1979.Google Scholar
  27. 27.
    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.PubMedCrossRefGoogle Scholar
  28. 28.
    Myers CE, McGuire WP, Young R. Adriamycin: Amelioration of toxicity by a-tocopherol. Ca. Treat. Rep. 60: 961–962, 1976.Google Scholar
  29. 29.
    Lubawy WC, Dallam RA, Hurley LH. Protection against anthramycininduced toxicity in mice by coenzyme Q10. J. Natl. Ca. Inst. 64: 105–109, 1980.Google Scholar
  30. 30.
    Bertazoli C, Ghione M. Adriamycin associated cardiotoxicity: Research on prevention with coenzyme O. Pharm. Res. Comm. 9: 235–250, 1977.CrossRefGoogle Scholar
  31. 31.
    Domae N, Sawada H, Matsuyama E, Konishi T, Uchino H. Cardiomyopathy and other chronic toxic effects induced in rabbits by doxorubicin and possible prevention by coenzyme Q10. Ca. Treat. Rep. 65: 79–91, 1981.Google Scholar
  32. 32.
    Cortes EP, Gupta M, Chou C, Amin VC, Folkers K: Adriamycin cardiotoxicity: Early detection by systolic time interval and possible prevention by coenzyme Q10. Ca. Treat. Rep. 65: 887–891, 1978.Google Scholar
  33. 33.
    Sonneveld P. Effect of a-tocopherol on the cardiotoxicity of adriamycin in the rat. Ca. Treat. Rep. 62: 1033–1036, 1978.Google Scholar
  34. 34.
    Van Vleet JF, Greenwood L, Ferrans VJ, Rebar AH. Effect of seleniumvitamin E on adriamycin-induced cardiomyopathy in rabbits. Am. J. Vet. Res. 39: 997–1010, 1978.PubMedGoogle Scholar
  35. 35.
    Van Vleet JF, Ferrans VJ. Evaluation of vitamin E and selenium protection against chronic adriamycin toxicity in rabbits. Ca. Treat. Rep. 64: 315–317, 1980.Google Scholar
  36. 36.
    Doroshow JH, Locker GY, Ifrim I, Myers CE, Prevention of doxorubicin cardiac toxicity in the mouse by n-acetylcysteine. J. Clin. Invest. 68: 1053–1064, 1981.PubMedCrossRefGoogle Scholar
  37. 37.
    Olson RD, MacDonald JS, Harbison RD, Van Boxtel CJ, Boerth RC, Slonim AE, Dates JA. Altered myocardial glutathione levels: A possible mechanism of adriamycin toxicity. Fed, Proc. 36: 303, 1977Google Scholar
  38. 38.
    Revis NW, Marusic N. Glutathione peroxidase activity and selenium concentration in the hearts of doxorubicin-treated rabbits. J. Mol. Cell. Card. 10: 945–951, 1978.CrossRefGoogle Scholar
  39. 39.
    Umezawa K, Sawamura M, Matsushima T, Sugimura T. Mutagenicity ofaclacinomycin A and daunomycin derivatives. Ca. Res. 38: 1782–1784, 1978.Google Scholar
  40. 40.
    Seino Y, Nagao M, Yahagi T, Hoshi A, Kawachi T, Sugimura T. Mutagenicity of several classes of antitumor agents to salmonella typhimurium TA98, TA100 and TA92. Ca. Res. 38: 2148–2156, 1978.Google Scholar
  41. 41.
    Marquardt H. This volume.Google Scholar
  42. 42.
    Marquardt H, Philips FS, Sternberg SS. Tumorigenicity in vivo and induction of malignant transformation and mutagenesis in-cerr-cultures by adriamycin and daunomycin. Ca. Res. 36: 2065–2069, 1976.Google Scholar
  43. 43.
    Bertazzoli C, Chieli T, Solcia E. Different incidence of breast carcinomas or fibroadenomas in daunomycin or adriamycin treated rats. Experientia 27: 1209–1210, 1971.PubMedCrossRefGoogle Scholar
  44. 44.
    Demopoulos HB, Pietronigro DO, Flamm ES, Seligman ML. The possible role of pathologic free radical reactions in carcinogenesis. J. Environ. Path. Tox. 3: 273–303, 1980.Google Scholar
  45. 45.
    Chan JT, Black HS. The mitigating effect of dietary antioxidants on chemically-induced carcinogenesis. Experientia 34: 110–111, 1978.Google Scholar
  46. 46.
    Daoud AH, Griffin AC. Effect of retinoic acid, butylated hydroxy toluene, selenium and sorbic acid on azo-dye hepatocarcinogenesis. Ca. Lett. 9: 299–304, 1980.CrossRefGoogle Scholar
  47. 47.
    Shamberger RJ, Corlett CL, Beaman KD, Kasten BL. Antioxidants reduce the mutagenic effect of malondialdehyde and beta-propiolactone. Part IX, Antioxidants and Cancer. Hut. Res. 66: 349–355, 1979.Google Scholar
  48. 48.
    Jacobs MM, Griffin AC. Effects of selenium on chemical carcinogenesis. Comparative effects of antioxidants. Biol. Trace Elem. Res. 1: 1–13, 1979.CrossRefGoogle Scholar
  49. 49.
    Shamberger RJ, Beaman KD, Corlett CL, Kasten BL. Effect of selenium and other antioxidants on the mutagenicity of malonaldehyde. Fed. Proc. 37: 261, 1978.Google Scholar
  50. 50.
    Carroll KK. Lipids and carcinogenesis. J. Environ. Path. Tox. 3: 253–271, 1980.Google Scholar
  51. 51.
    King MM, Bailey DM, Gibson DD, Pitha JV, McCay PB. Incidence and growth of mammary tumors induced by 7,12-dimethylbenzanthracene as related to the dietary content of fat and antioxidant. J. Natl. Ca. Inst. 63: 657–663, 1979.Google Scholar
  52. 52.
    Bachur N. Antracycline antibiotic pharmacology and metabolism. Ca. Treat. Rep. 63: 817–820, 1979.Google Scholar
  53. 53.
    Sinha BK. Binding specificity of chemically and enzymatically activated anthracycline antiCancer agents to nucleic acids. Chem.-Biol. Interact. 30: 66–77, 1980.CrossRefGoogle Scholar
  54. 54.
    Sinha BK, Chignell CF. Binding mode of chemically activated semiquinone free radicals from quinone antiCancer agents to DNA. Chem.-Biol. Interac 28: 301–308, 1979.CrossRefGoogle Scholar
  55. 55.
    Berlin V, Haseltine WAD. Reduction of adriamycin to a semiquinone free radical by NADPH cytochrome P-450 reductase produces DNA cleavage in a reaction mediated by molecular oxygen. J. Biol. Chem. 256: 4747–4756, 1981.PubMedGoogle Scholar
  56. 56.
    Lown JW, Sim SK, Majumdar KC, Chang RY. Strand scission of DNA by bound adriamycin and daunorubicin in the presence of reducing agents. Biochem. Biophys. Res. Comm. 79: 705–710, 1977.CrossRefGoogle Scholar
  57. 57.
    Tomasz M. H202 generation during the redox cycle of mitomycin C and DNA-bound mitomycin. C. Chem. Biol. Interact. 13: 89–97, 1976CrossRefGoogle Scholar
  58. 58.
    Kalyanraman B, Perez-Reyes E, Mason RP. Spin trapping and direct electron spin resonance investigations of the redox metabolism of quinone antiCancer drugs. Biochim. Biophys. Acta 630: 119–130, 1980.CrossRefGoogle Scholar
  59. 59.
    Lown JW, Begleiter A, Johnson O, Morgan R. Studies related to antitumor antibiotics, Part V. Reaction of mitomycin C with DNA examined by ethidium fluorescence assay. Can. J. Biochem. 54: 110–119, 1976.PubMedCrossRefGoogle Scholar
  60. 60.
    Lown JW, Sim SK. The mechanism of bleomycin-induced cleavage of DNA. Biochem. Biophys. Res. Comm. 77: 1150–1157, 1977.Google Scholar
  61. 61.
    Oberley LH, Buettner GR. The production of hydroxyl radical by bleomycin and iron (II). FEBS Lett. 97: 47–49, 1979.CrossRefGoogle Scholar
  62. 62.
    Sugiura Y. Production of free radicaTS from phenol and tocopherol by bleomycin-iron (II) complex. Biochem. Biophys. Res. Comm. 87: 649–653, 1979.PubMedCrossRefGoogle Scholar
  63. 63.
    Cone R, Hasan SK, Lown JW, Morgan AR. The mechanism of the degradation of DNA by streptonigrin. Can. J. Biochem. 54: 219–223, 1976.PubMedCrossRefGoogle Scholar
  64. 64.
    Sinha BK, Cox MG. Stimulation of superoxideformation by actinomycin D and its N2_substituted spin-labeled derivatives. Mol. Pharm. 17: 432–434, 1980.Google Scholar
  65. 65.
    Teicher BA, Lazo JS, Sartorelli AC. Classification of antineoplastic agents by their selective toxicities towards oxygenated and hypoxic tumor cells. Ca. Res. 41: 73–81, 1981.Google Scholar
  66. 66.
    Smith E, Stratford IJ, Adams GE. The resistance of hypoxic mammalian cells to chemotherapeutic agents. Br. J. Can. 40: 316, 1979.Google Scholar
  67. 67.
    Harris JW, Shrieve DC. Effects of adriamycin and X-rays on euoxic and hypoxic EMT6 cells in vitro. Int. J. Radiat. Oncol. Biol. Phys. 5: 1245–1248, 1979.PubMedGoogle Scholar
  68. 68.
    Mason RP, Peterson FJ, Holtzman JL. The formation of an azo anion free radical metabolite during the microsomal azo reduction of sulfonazo III. Biochem. Biophys. Res. Comm. 75: 532–540, 1977.PubMedCrossRefGoogle Scholar
  69. 69.
    Oki T, Komiyama T. Tone H, Inui T, Takeuchi T, Umezawa H. Reductive cleavage of anthracycline glycosides by microsomal NADPH-cytochrome c reductase. J. Antibiot. 30: 613–615, 1977.PubMedGoogle Scholar
  70. 70.
    Mason RP. Free radical metabolites of foreign compounds and their toxicological significance. In: Reviews in Biochemical Toxicolo (Part I), E Hodgson, JR Bend, RM Philpot eds,. Elsevier, NorthHolland, 1979, pp. 151–200.Google Scholar
  71. 71.
    Bielski BJ, Shiue GG, Bajuk S, Reduction of nitroblue tetrazolium by CO2-and O2-radicals. J. Phys. Chem. 84: 830–833, 1980.CrossRefGoogle Scholar
  72. 72.
    Iwamoto Y, Hansen IL, Porter TH, Folkers K,. Inhibition of coenzyme Q10-enzymes, succinoxidase and NADH-oxidase, by adriamycin and other quinones having antitumor activity. Biochem, Biophys. Res. Comm. 58: 633–638, 1974.CrossRefGoogle Scholar
  73. 73.
    Kishi T, Watanabe T, Folkers K. Bioenergetics in clinicar-medicine: Prevention by forms of coenzyme 0 of the inhibition by adriamycin of coenzyme Q10-enzymes in mitochondria of the myocardium. Proc. Natl. Acad. Sci. 73: 4653–4656, 1976.PubMedCrossRefGoogle Scholar

Copyright information

© Martinus Nijhoff Publishers, The Hague 1982

Authors and Affiliations

  • D. D. Pietronigro

There are no affiliations available

Personalised recommendations