Role of Oxygen and of Superoxide Radical in the Mechanisms of Monoelectronic Activation of Various Xenobiotics : A Radiolysis Study

  • Monique Gardès-Albert
  • Chantal Houée-Levin
  • Abdelhafid Sekaki
  • Christiane Ferradini
Part of the NATO ASI Series book series (NSSA, volume 189)


Many xenobiotics need a free-radical mediated metabolism activation to exhibit their biological properties. Among them, antitumor drugs such as anthracycline or ellipticine derivatives are known to be enzymically activated by one-electron transfer. We present here two anticancer agents: an ellipticine substituted derivative, EH2 (scheme 1) which has a paraaminophenol structure and daunorubicin, DOS (scheme 2) which is an anthra-cycline antibiotic with a quinone group. Both these anticancer agents possess a resonant plane structure which allows their intercalation in DNA and each drug has a side group which enhances this intercalation ability (an amino side chain for EH2 and a sugar for DOS). During the metabolism of these antitumor agents, oxygen and/or reactive oxygen species are required forthe development of their cytotoxic properties. Hence we have investigated the interaction of 02 and/or 02 with the radical transient of each drug. In both cases pulse radiolysis combined with kinetic spectroscopy is well appropriated for such studies of model in vitro systems. Indeed this technique gives free radicals in homogeneous solution in a determined amount and allows the direct observation of the free radical reactions with substrates.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    B.Monsarrat, M.Maftouh, G.Meunier, B.Dugué, J.Bernadou, J.P.Armand, C.Picard-Fraire, B.Meunier and C.Paoletti, Human and rat urinary metabolites of the antitumor drug celiptium (N2-methyl –9- hydroxyellipticinium acetate, NSC 264 137). Identification of cysteine conjugates supporting the “bioxidative alkylation” hypothesis, Biochem. Pharmacol. 32: 3887 (1983).Google Scholar
  2. 2.
    J.Bernadou, B.Monsarrat, H.Roche, J.P.Armand, C.Paoletti and B.Meunier, Evidence for electrophilic properties of N2 — methyl — 9 — hydroxyellipticinium acetate (celiptium) from human biliary metabolites, Cancer Chemother. Pharmacol. 15: 63 (1985).Google Scholar
  3. 3.
    T.Ha, J.Bernadou, E.Voisin, C.Auclair and B.Meunier, Hemoglobin — catalyzed transformation of ellipticinium acetate into electrophilic species. Evidences for oxidative activation of the drug in human red blood cells, Chem. Biol. Interactions 65: 73 (1988).CrossRefGoogle Scholar
  4. 4.
    C.Auclair and C.Paoletti, Bioactivation of the antitumor drugs 9 — hydroxyellipticine and derivatives by a peroxidase — hydrogen peroxide system, J. Med. Chem. 24: 289 (1981).CrossRefGoogle Scholar
  5. 5.
    C.Auclair, K.Hyland and C.Paoletti, Autoxidation of the antitumor drug 9 — hydroxyellipticine and its derivatives J. Med. Chem. 26: 1438 (1983).CrossRefGoogle Scholar
  6. 6.
    E.Bisagni, C.Ducrocq, J.M.Lhoste, C.Rivalle and A.Civier, Synthesis of 1 — substituted ellipticines by a new route to pyrido (4,3-b)- carbazoles, J. Chem. Soc. Perkin Trans. I, 1706 (1979).Google Scholar
  7. 7.
    A.Sekaki, M.Gardès-Albert, C.Houée-Levin, C.Ferradini, C.Rivalle, E.Bisagni and B.Hickel, Influence of oxygen and superoxide free radicals on the oxidative activation of several antitumor drugs. In “Medical, Biochemical and chemical aspects of free radicals” Elsevier Science Publishes. In Press (1988).Google Scholar
  8. 8.
    C.Houée-Levin, M.Gardès-Albert, and C.Ferradini. Reduction of daunorubicin aqueous solutions by C00- free radicals. Reactions of reduced transients with H202. FEBS Lett. 173: 27 (1984).Google Scholar
  9. 9.
    C.Houée-Levin, M.Gardès-Albert, C.Ferradini, M.Faraggi, and M.Klapper. Pulse-radiolysis study of daunorubicin redox cycles. Reduction by eaq- and C00- free radicals. FEBS Lett. 179: 46 (1985).CrossRefGoogle Scholar
  10. C.Houée-Levin, M.Gardès-Albert, and C.Ferradini. Daunorubicin redox cycles and glycosidic cleavage. J. Free Rad. Biol. Med. 2: 89 (1986).Google Scholar
  11. 11.
    A.Arcamone, Doxorubicin anticancer antibiotics, Academic Press (1981).Google Scholar
  12. 12.
    J.Fischer, B.R.J.Abdella, and K.E.McLIne. Anthracycline antibiotics reduction by spinach ferredoxin, NADP+ reductase and ferredoxin. Biochemistry 24: 3562 (1985).CrossRefGoogle Scholar
  13. 13.
    N.R.Bachur, S.L.Gordon, and M.V.Gee. A general mechanism for microsomal activation of quinone anticancer agents to free radicals. Cancer Res. 38: 1745 (1978).Google Scholar
  14. 14.
    N.R.Bachur, M.V.Gee and R.D.Friedman, Nuclear catalyzed antibiotic free radical formation. Cancer Res. 42: 1078 (1982).Google Scholar
  15. 15.
    J.H.Doroshow. Effect of anthracycline antibiotics on oxygen radical formation in rat heart. Cancer Res. 43: 460 (1983).Google Scholar
  16. 16.
    J.W.Lown, H.H.Chen, J.A.Plambeck, and E.M.Acton. Diminished superoxide anion generation by reduced 5-iminodaunorubicin relative to daunorubicin and the relationship to cardiotoxicity of the anthracycline antitumour agents. Biochem. Pharmacol. 28: 2563–2568 (1979).CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1990

Authors and Affiliations

  • Monique Gardès-Albert
    • 1
  • Chantal Houée-Levin
    • 1
  • Abdelhafid Sekaki
    • 1
  • Christiane Ferradini
    • 1
  1. 1.Laboratoire de Chimie Physique UA 400Université Paris VParis Cedex 06France

Personalised recommendations