Skip to main content

Implications of Free Radical Activation for Improved Anthracycline Therapy

  • Chapter
Anthracycline Antibiotics in Cancer Therapy

Part of the book series: Developments in Oncology ((DION,volume 10))

  • 125 Accesses

Abstract

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 (ADMĀ·) in these toxicities. This interest has been fueled by the realizations that ADM is activated to ADMĀ· throughout biologic systems, that ADM side toxicities can be inhibited by a number of antioxidants, and that ADM-stimulated radical formation produces DNA damage.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  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: 405ā€“414, 1979.

    PubMedĀ  CASĀ  Google ScholarĀ 

  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 ScholarĀ 

  3. Del Maestro RF. An approach to free radicals in medicine and biology. Acta Physiol. Scand. Suppl. 492: 153ā€“168, 1980.

    PubMedĀ  Google ScholarĀ 

  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 ScholarĀ 

  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: 189ā€“192, 1981.

    CASĀ  Google ScholarĀ 

  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: 603ā€“608, 1977.

    PubMedĀ  CASĀ  Google ScholarĀ 

  7. Bachur NR, Gordon SL, Gee MV. Anthracycline antibiotic auqmentation of microsomal electron transport and free radical formation. Mol. Pharm. 13: 901ā€“910, 1977.

    CASĀ  Google ScholarĀ 

  8. Bachur NR, Gordon SL, Gee MV. A general mechanism for microsomal activation of quinone antiCancer agents to free radicals. Ca Res. 38: 1745ā€“1750, 1978.

    CASĀ  Google ScholarĀ 

  9. Goodman J, Hochstein P. Generation of free radicals and lipid peroxidation by redox cycling of adriamycin and daunomycin. Biochem. Biophys. Res. Comm. 77: 797ā€“803, 1977.

    ArticleĀ  PubMedĀ  CASĀ  Google ScholarĀ 

  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: 613ā€“615, 1977.

    PubMedĀ  CASĀ  Google ScholarĀ 

  11. Handa K, Sato S. Stimulation of microsomal NADPH oxidation by quinone group-containing antiCancer chemicals. Gann 67: 523ā€“528, 1976.

    PubMedĀ  CASĀ  Google ScholarĀ 

  12. Lai CS, Grover TA, Piette LH. Hydroxyl radical production in a purified NADPH-cytochrome c (P-450) reductase system. Arch. Biochem. Biophys. 193: 373ā€“378, 1979.

    ArticleĀ  PubMedĀ  CASĀ  Google ScholarĀ 

  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: 798ā€“803, 1978.

    ArticleĀ  CASĀ  Google ScholarĀ 

  14. Bachur NR, Gee MV. Microsomal reductive glycosidase. J. Pharmacol. Exp. Ther. 197: 681ā€“686, 1976.

    PubMedĀ  CASĀ  Google ScholarĀ 

  15. Zimmerman JJ, Kasper CB. Immunological and biochemical characterization of nuclear envelope reduced nicotinamide adenine dinucleotide phosphatecytochrome c oxidoreductase. Arch. Biochem. Biophys. 190: 726ā€“735, 1978.

    ArticleĀ  PubMedĀ  CASĀ  Google ScholarĀ 

  16. Pietronigro DD, Jones WBG, Kalty K, Demopoulos HB. Interaction of DNA and liposomes as a model for membrane-mediated DNA damage. Nature 267: 78ā€“79, 1977.

    ArticleĀ  PubMedĀ  CASĀ  Google ScholarĀ 

  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: 282ā€“294, 1970.

    ArticleĀ  PubMedĀ  CASĀ  Google ScholarĀ 

  18. Doroshow JH. Mitomycin C-enhanced superoxide and hydrogen peroxide formation in rat heart. J. Pharm. Exp. Therap. 218: 206ā€“211, 1981.

    CASĀ  Google ScholarĀ 

  19. Thayer WS. Adriamycin stimulated superoxide formation in submitochondrial particles. Chem. Biol. Interact. 19: 265ā€“278, 1977.

    ArticleĀ  PubMedĀ  CASĀ  Google ScholarĀ 

  20. Henderson CA, Metz EN, Balcerzak SP, Sagone AL. Adriamycin and daunomycin generate reactive oxygen compounds in erythrocytes. Blood 52: 878ā€“885, 1970

    Google ScholarĀ 

  21. Doroshow JH, Locker GY, Myers CE. Enzymatic defenses of themouse heart against reactive oxygen metabolites. Alterations produced by doxorubicin. J. Clin. Invest. 65: 128ā€“135, 1980.

    ArticleĀ  PubMedĀ  CASĀ  Google ScholarĀ 

  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: 746ā€“754, 1980.

    ArticleĀ  PubMedĀ  CASĀ  Google ScholarĀ 

  23. Slater TF. Free radical mechanisms in tissue injury. Pion Limited, London, 1972.

    Google ScholarĀ 

  24. Fitzsimons OW (ed.). Oxygen free radicals and tissue damage. Ciba Foundation symposium 65, Excerpta Medica, New York, 1979.

    Google ScholarĀ 

  25. Demopoulos HB. Control of free radicals in biologic systems. Fed. Proc. 32: 1903ā€“1908, 1973.

    PubMedĀ  CASĀ  Google ScholarĀ 

  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: 223ā€“227, 1979.

    CASĀ  Google ScholarĀ 

  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: 165ā€“167, 1977.

    ArticleĀ  PubMedĀ  CASĀ  Google ScholarĀ 

  28. Myers CE, McGuire WP, Young R. Adriamycin: Amelioration of toxicity by a-tocopherol. Ca. Treat. Rep. 60: 961ā€“962, 1976.

    CASĀ  Google ScholarĀ 

  29. Lubawy WC, Dallam RA, Hurley LH. Protection against anthramycininduced toxicity in mice by coenzyme Q10. J. Natl. Ca. Inst. 64: 105ā€“109, 1980.

    CASĀ  Google ScholarĀ 

  30. Bertazoli C, Ghione M. Adriamycin associated cardiotoxicity: Research on prevention with coenzyme O. Pharm. Res. Comm. 9: 235ā€“250, 1977.

    ArticleĀ  Google ScholarĀ 

  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: 79ā€“91, 1981.

    CASĀ  Google ScholarĀ 

  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: 887ā€“891, 1978.

    Google ScholarĀ 

  33. Sonneveld P. Effect of a-tocopherol on the cardiotoxicity of adriamycin in the rat. Ca. Treat. Rep. 62: 1033ā€“1036, 1978.

    CASĀ  Google ScholarĀ 

  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: 997ā€“1010, 1978.

    PubMedĀ  Google ScholarĀ 

  35. Van Vleet JF, Ferrans VJ. Evaluation of vitamin E and selenium protection against chronic adriamycin toxicity in rabbits. Ca. Treat. Rep. 64: 315ā€“317, 1980.

    Google ScholarĀ 

  36. Doroshow JH, Locker GY, Ifrim I, Myers CE, Prevention of doxorubicin cardiac toxicity in the mouse by n-acetylcysteine. J. Clin. Invest. 68: 1053ā€“1064, 1981.

    ArticleĀ  PubMedĀ  CASĀ  Google ScholarĀ 

  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, 1977

    Google ScholarĀ 

  38. Revis NW, Marusic N. Glutathione peroxidase activity and selenium concentration in the hearts of doxorubicin-treated rabbits. J. Mol. Cell. Card. 10: 945ā€“951, 1978.

    ArticleĀ  CASĀ  Google ScholarĀ 

  39. Umezawa K, Sawamura M, Matsushima T, Sugimura T. Mutagenicity ofaclacinomycin A and daunomycin derivatives. Ca. Res. 38: 1782ā€“1784, 1978.

    CASĀ  Google ScholarĀ 

  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: 2148ā€“2156, 1978.

    CASĀ  Google ScholarĀ 

  41. Marquardt H. This volume.

    Google ScholarĀ 

  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: 2065ā€“2069, 1976.

    CASĀ  Google ScholarĀ 

  43. Bertazzoli C, Chieli T, Solcia E. Different incidence of breast carcinomas or fibroadenomas in daunomycin or adriamycin treated rats. Experientia 27: 1209ā€“1210, 1971.

    ArticleĀ  PubMedĀ  CASĀ  Google ScholarĀ 

  44. Demopoulos HB, Pietronigro DO, Flamm ES, Seligman ML. The possible role of pathologic free radical reactions in carcinogenesis. J. Environ. Path. Tox. 3: 273ā€“303, 1980.

    CASĀ  Google ScholarĀ 

  45. Chan JT, Black HS. The mitigating effect of dietary antioxidants on chemically-induced carcinogenesis. Experientia 34: 110ā€“111, 1978.

    Google ScholarĀ 

  46. Daoud AH, Griffin AC. Effect of retinoic acid, butylated hydroxy toluene, selenium and sorbic acid on azo-dye hepatocarcinogenesis. Ca. Lett. 9: 299ā€“304, 1980.

    ArticleĀ  CASĀ  Google ScholarĀ 

  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: 349ā€“355, 1979.

    CASĀ  Google ScholarĀ 

  48. Jacobs MM, Griffin AC. Effects of selenium on chemical carcinogenesis. Comparative effects of antioxidants. Biol. Trace Elem. Res. 1: 1ā€“13, 1979.

    ArticleĀ  CASĀ  Google ScholarĀ 

  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 ScholarĀ 

  50. Carroll KK. Lipids and carcinogenesis. J. Environ. Path. Tox. 3: 253ā€“271, 1980.

    CASĀ  Google ScholarĀ 

  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: 657ā€“663, 1979.

    CASĀ  Google ScholarĀ 

  52. Bachur N. Antracycline antibiotic pharmacology and metabolism. Ca. Treat. Rep. 63: 817ā€“820, 1979.

    CASĀ  Google ScholarĀ 

  53. Sinha BK. Binding specificity of chemically and enzymatically activated anthracycline antiCancer agents to nucleic acids. Chem.-Biol. Interact. 30: 66ā€“77, 1980.

    ArticleĀ  Google ScholarĀ 

  54. Sinha BK, Chignell CF. Binding mode of chemically activated semiquinone free radicals from quinone antiCancer agents to DNA. Chem.-Biol. Interac 28: 301ā€“308, 1979.

    ArticleĀ  CASĀ  Google ScholarĀ 

  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: 4747ā€“4756, 1981.

    PubMedĀ  CASĀ  Google ScholarĀ 

  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: 705ā€“710, 1977.

    ArticleĀ  Google ScholarĀ 

  57. Tomasz M. H202 generation during the redox cycle of mitomycin C and DNA-bound mitomycin. C. Chem. Biol. Interact. 13: 89ā€“97, 1976

    ArticleĀ  CASĀ  Google ScholarĀ 

  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: 119ā€“130, 1980.

    ArticleĀ  Google ScholarĀ 

  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: 110ā€“119, 1976.

    ArticleĀ  PubMedĀ  CASĀ  Google ScholarĀ 

  60. Lown JW, Sim SK. The mechanism of bleomycin-induced cleavage of DNA. Biochem. Biophys. Res. Comm. 77: 1150ā€“1157, 1977.

    CASĀ  Google ScholarĀ 

  61. Oberley LH, Buettner GR. The production of hydroxyl radical by bleomycin and iron (II). FEBS Lett. 97: 47ā€“49, 1979.

    ArticleĀ  CASĀ  Google ScholarĀ 

  62. Sugiura Y. Production of free radicaTS from phenol and tocopherol by bleomycin-iron (II) complex. Biochem. Biophys. Res. Comm. 87: 649ā€“653, 1979.

    ArticleĀ  PubMedĀ  CASĀ  Google ScholarĀ 

  63. Cone R, Hasan SK, Lown JW, Morgan AR. The mechanism of the degradation of DNA by streptonigrin. Can. J. Biochem. 54: 219ā€“223, 1976.

    ArticleĀ  PubMedĀ  CASĀ  Google ScholarĀ 

  64. Sinha BK, Cox MG. Stimulation of superoxideformation by actinomycin D and its N2_substituted spin-labeled derivatives. Mol. Pharm. 17: 432ā€“434, 1980.

    CASĀ  Google ScholarĀ 

  65. Teicher BA, Lazo JS, Sartorelli AC. Classification of antineoplastic agents by their selective toxicities towards oxygenated and hypoxic tumor cells. Ca. Res. 41: 73ā€“81, 1981.

    CASĀ  Google ScholarĀ 

  66. Smith E, Stratford IJ, Adams GE. The resistance of hypoxic mammalian cells to chemotherapeutic agents. Br. J. Can. 40: 316, 1979.

    Google ScholarĀ 

  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: 1245ā€“1248, 1979.

    PubMedĀ  CASĀ  Google ScholarĀ 

  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: 532ā€“540, 1977.

    ArticleĀ  PubMedĀ  CASĀ  Google ScholarĀ 

  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: 613ā€“615, 1977.

    PubMedĀ  CASĀ  Google ScholarĀ 

  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. 151ā€“200.

    Google ScholarĀ 

  71. Bielski BJ, Shiue GG, Bajuk S, Reduction of nitroblue tetrazolium by CO2-and O2-radicals. J. Phys. Chem. 84: 830ā€“833, 1980.

    ArticleĀ  CASĀ  Google ScholarĀ 

  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: 633ā€“638, 1974.

    ArticleĀ  CASĀ  Google ScholarĀ 

  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: 4653ā€“4656, 1976.

    ArticleĀ  PubMedĀ  CASĀ  Google ScholarĀ 

Download references

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

Ā© 1982 Martinus Nijhoff Publishers, The Hague

About this chapter

Cite this chapter

Pietronigro, D.D. (1982). Implications of Free Radical Activation for Improved Anthracycline Therapy. In: Muggia, F.M., Young, C.W., Carter, S.K. (eds) Anthracycline Antibiotics in Cancer Therapy. Developments in Oncology, vol 10. Springer, Dordrecht. https://doi.org/10.1007/978-94-009-7630-6_20

Download citation

  • DOI: https://doi.org/10.1007/978-94-009-7630-6_20

  • Publisher Name: Springer, Dordrecht

  • Print ISBN: 978-94-009-7632-0

  • Online ISBN: 978-94-009-7630-6

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics