Doxorubicin (adriamycin): A critical review of free radical-dependent mechanisms of cytotoxicity

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Abstract

The antineoplastic drug doxorubicin is capable of generating a variety of free radical species in subcellular systems and this capacity has been considered critical for its antitumor action. However, for most tumor cell lines this mechanism of cytotoxicity does not appear to play a major role. Free radical-independent cytotoxicity mechanisms, taking place in the nuclear compartment of the cell, may more likely be involved in the antitumor effect of doxorubicin.

References (116)

  • R.W. Freeman et al.

    Effect of sulfhydryl-containing compounds on the antitumor effects of adriamycin

    Toxic. appl. Pharmac.

    (1980)
  • L. Gianni et al.

    Characterization of the cycle of iron-mediated electron transfer from adrimycin to molecular oxygen

    J. biol. Chem.

    (1985)
  • M. Gigli et al.

    Quantitative study of doxorubicin in living cell nuclei by microspectrofluorometry

    Biochim. biophys. Acta

    (1988)
  • J. Goodman et al.

    Generation of free radicals and lipid peroxidation by redox cycling of adriamycin and daunomycin

    Biochem. biophys. Res. Commun.

    (1977)
  • M.D. Green et al.

    Cardiotoxicity of anthracyclines

    Eur. J. Cancer clin. Oncol.

    (1984)
  • P.l. Gutiérrez et al.

    Kinetics of anthracycline antibiotic free radical formation and reductive glycosidase activity

    Archs Biochem. Biophys.

    (1983)
  • J.M.C. Gutteridge

    The role of superoxide and hydroxyl radicals in phospholipid peroxidation catalysed by iron salts

    FEBS Lett.

    (1982)
  • J.M.C. Gutteridge

    Adriamycin-iron catalysed phospholipid peroxidation: a reaction not involving reduced adriamycin or hydroxyl radicals

    Biochem. Pharmac.

    (1983)
  • J.M.C. Gutteridge

    Lipid peroxidation and possible hydroxyl radical formation stimulation by the self-reduction of a doxorubicin-iron (III) complex

    Biochem. Pharmac.

    (1984)
  • J.M.C. Gutteridge et al.

    Adriamycin-dependent damage to deoxyribose: a reaction involving iron, hydroxyl and semiquinone free radicals

    FEBS Lett.

    (1982)
  • T.C. Hamilton et al.

    Augmentation of adriamycin, melphalan, and cisplatin cytotoxicity in drug-resistant and -sensitive human ovarian carcinoma cell lines by buthionine sulfoximine mediated glutathione depletion

    Biochem. Pharmac.

    (1985)
  • B. Kalyanaraman et al.

    Spin-trapping and direct electron spin resonance investigations of the redox metabolism of quinone anti-cancer drugs

    Biochem. biophys. Acta

    (1980)
  • H.G. Keizer et al.

    Effect of artificial electron acceptors on the cytotoxicity of mitomycin C and doxorubicin in human lung tumor cells

    Eur. J. Cancer clin. Oncol.

    (1989)
  • T.J. Lampidis et al.

    Effects of adriamycin on rat heart cells in culture: increased accumulation and nucleoli fragmentation in cardiac muscle v. non-muslce cells

    J. molec. cell. Cardiol.

    (1981)
  • L.F. Liu et al.

    Cleavage of DNA by mammalian DNA topoisomerase II

    J. biol. Chem.

    (1983)
  • M.J. Meredith et al.

    Depletion in vitro of mitochondrial glutathione in rat hepatocytes and enhancement of lipid peroxidation by adriamycin and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)

    Biochem. Pharmac.

    (1983)
  • E.G. Mimnaugh

    Potentiation by reduced glutathione of Adriamycin-stimulated lipid peroxidation in kidney microsomes

    Biochem. Pharmac.

    (1986)
  • E.G. Mimnaugh et al.

    Stimulation by adriamycin of rat heart and liver microsomal NADPH-dependent lipid peroxidation

    Biochem. Pharmac.

    (1981)
  • E.G. Mimnaugh et al.

    Enhancement of reactive oxygen-dependent mitochondrial membrane lipid peroxidation by the anticancer drug adriamycin

    Biochem. Pharmac.

    (1985)
  • E.G. Mimnaugh et al.

    A possible role for membrane lipid peroxidation in anthracycline nephrotoxicity

    Biochem. Pharmac.

    (1986)
  • J.R.F. Muindi et al.

    Hydroxyl radical production and DNA damage induced by anthracycline-iron complex

    FEBS Lett.

    (1984)
  • H. Nohl et al.

    OH-generation by adriamycin semiquinone and H2O2: an explanation for the cardiotoxicity of anthracycline antibiotics

    Biochem. biophys. Res. Commun.

    (1983)
  • M. Potmesil et al.

    Two mechanisms of Adriamycin-DNA interaction in L1210 cells

    Biochem. Pharmac.

    (1984)
  • K.E. Rogers et al.

    Novel mode of cytotoxicity obtained by coupling inactive Anthracycline to a polymer

    Biochem. Pharmac.

    (1984)
  • W.E. Ross et al.

    Repair of deoxyribonucleic acid lesions caused by Adriamycin and ellipticine

    Biochem. Pharmac.

    (1982)
  • D.A. Rowley et al.

    DNA damage by superoxide-generating systems in relation to the mechanism of action of the anti-tumur antibiotic Adriamycin

    Biochim. biophys. Acta

    (1983)
  • B.K. Sinha et al.

    Binding mode of chemically activated semiquinone free radicals from quinone anticancer agents to DNA

    Chem. Biol. Interact.

    (1979)
  • B.K. Sinha et al.

    Role of one-electron and two-electron reduction products of adriamycin and daunomycin in deoxyribonucleic acid binding

    Biochem. Pharmac.

    (1981)
  • B.K. Sinha et al.

    Adriamycin-stimulated hydroxyl radical formation in human breast tumor cells

    Biochem. Pharmac.

    (1987)
  • A.E. Alegria et al.

    Free radicals induced by adriamycin-sensitive and adriamycin-resistant cells: A spin-trapping study

    Biochemistry

    (1989)
  • F. Arcamone et al.

    Structure and physicochemical properties of adriamycin (doxorubicin)

  • S.D. Averbuch et al.

    Radical dimer rescue of toxicity and improved therapeutic index of adriamycin in tumor-bearing mice

    Cancer Res.

    (1985)
  • N.R. Bachur et al.

    Anthracycline antibiotic augmentation of microsomal electron transport and free radical formation

    Molec. Pharmac.

    (1977)
  • N.R. Bachur et al.

    A general mechanism for microsomal activation of quinone anticancer agents to free radicals

    Cancer Res.

    (1978)
  • N.R. Bachur et al.

    Nuclear catalyzed antibiotic free radical formation

    Cancer Res.

    (1982)
  • A. Bozzi et al.

    Differential cytotoxicity of daunomycin in tumor cells is related to glutathione dependent hydrogen peroxide metabolism

    Biochem. J.

    (1981)
  • G. Capranico et al.

    Markedly reduced levels of anthracycline-induced DNA strand breaks in resistant P388 leukemia cells and isolated nuclei

    Cancer Res.

    (1987)
  • K.J.A. Davies et al.

    Mitochondrial reduction of anthracyclines: Oxygen radical production at the expense of ATP

  • A.M. Deffie et al.

    Direct correlation between DNA topoisomerase II activity and cytotoxicity in adriamycin-sensitive and -resistant P388 leukemia cell lines

    Cancer Res.

    (1989)
  • J.H. Doroshow

    Effect of anthracycline antibiotics on oxygen radical formation in rat heart

    Cancer Res.

    (1983)
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    Present address: Department of Toxicology, Duphar B.V., P.O. Box 900, 1380 DA Weesp, The Netherlands.

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