Redox Parameters Associated to Cytotoxic and Antitumor Activities in the Series of Antitumor Drugs Ellipticines and Derivatives

  • Christian Auclair
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 264)


Generation of virtual DNA breaks through the alteration of the catalytic activity of topoisomerase II are displayed by the most successful antitumor drugs in clinical use including adriamycin, m-AMSA, hydroxy ellipticine derivatives, raitoxantrone and VP-16 (Nelson et al., 1984; Tewey et al., 1984; Rowe et al., 1986). This feature is thought to be responsible for the selective cytotoxic effect leading to the antitumor activity of these drugs, comparative studies of the physicochemical properties of antitumor topoisomerase inhibitors clearly show that the single parameter that they share in common is the capability to be oxidized to reactive metabolites through one-electron transfer process (Auclair, 1987). Along this line, most of them are able to undergo autoxidation generating oxy-radicals (Dorowshow, 1983; Auclair et al., 1983a; Auclair, 1987; Nakasawa et al., 1985; Kovacic et al., 1986) and are substrate for peroxidases (Auclair & Paoletti, 1981; Auclair et al., 1986; Auclair, 1987; Trush, 1982; Shina et al., 1983, 1984; Reszha et al., 1986; Haim et al., 1987). In view of rational design and screening of new antitumor topoisomerase modifiers, we have attempted to characterize significant parameter(s) in terms of redox properties associated to cytotoxic activity on malignant cells. This study has been made possible in the series of ellipticine in which are available, number of derivatives displaying various cytotoxic activity associated to limited structural modifications.


Methyl Linoleate Phenolic Group Antitumor Drug Bond Dissociation Energy Cleavable Complex 
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. Auclair, C. and Paoletti, C., 1981, Bioactivation of the antitumor drug 9 Hydroxyellipticine and derivatives by a peroxidase-hydrogen peroxide system. J. Med. Chem., 24:289.PubMedCrossRefGoogle Scholar
  2. Auclair, C., Meunier, B. and Paoletti, C., 1983a, The generation of reac tive molecular species during the oxidation of 9-hydroxyellipticine derivatives. Interest of prooxidant compounds in the design of anticancer drugs, In; The control of tumor growth and its biological bases, W. Davis, C. Maltoni and St. Tannenberger, Eds., Akademie Verlag, Berlin.Google Scholar
  3. Auclair, C., Hyland, K. and Paoletti, C., 1983b, Autoxidation of the antitumor drug 9-hydroxyellitpcine and its derivatives. J. Med. Chem., 26:1438.PubMedCrossRefGoogle Scholar
  4. Auclair, C., Dugue, B., Meunier, G., Meunier, B. and Paoletti, C., 1986,Google Scholar
  5. Peroxidase-catalyzed covalent binding of the antitumor drug N2-Methyl 9-Hydroxyellipticinium to DNA in vitro. Biochemistry, 25:1240.Google Scholar
  6. Auclair, C., 1987, Multimodal action of antitumor agents on DNA: The ellipticine series. Arch. Biochem. Biophys., 258:1.CrossRefGoogle Scholar
  7. Auclair, C., Schwaller, M.A., Rene, B., Banoun, H., Saucier, J.M. and Larsen, A.K., 1988, Relationship between physicochemical and biological properties in a series of oxazolopyridocarbazole derivatives (OPCd); comparison with related antitumor agents. Anti-Cancer Drug Design, 3:133.PubMedGoogle Scholar
  8. Bachur, N.R., Gordon, S.L. and Gee, M.V., 1978, A general mechanism forGoogle Scholar
  9. microsomal activation of quinone anticancer agents to free radicals. Cancer Res., 38:1745.Google Scholar
  10. Dorowshow, J.H., 1983, Comparative cardiac oxygen radical production byGoogle Scholar
  11. anthracycline antibiotics, mitoxantrone, bisantrene, m-AMSA and neocarcinostatine. Clin. Res., 31:67.Google Scholar
  12. Haim, N., Nemec, J., Roman, J. and Sinha, B.K., 1987, Peroxidase-catalized oxidation of etoposide (VP-16-213) and covalent binding of reactive intermediates to cellular macromolecules. Cancer Res., 15:5835.Google Scholar
  13. Jurlina, J.L., Lindsay, A., Packer, J.E., Baguley, B.C. and Denny, W.A., 1987, Redox chemistry of the 9-anilinoacridine class of antitumor agents. J. Med. Chem., 30:473.PubMedCrossRefGoogle Scholar
  14. Kovacic, P., Ames, J.R., Lumme, P., Elo, H., Cox, O., Jackson, H., Rivera, L.A., Ramirez, L. and Ryan, M.D., 1986, Charge transfer-oxy radical mechanism for anticancer agents. Anti-Cancer Drug Design, 1:197.PubMedGoogle Scholar
  15. Meunier, G., De Montauzon, D., Bernadou, J., Grassy, G., Bonnafous, M., Cros, S. and Meunier, B., 1987, The biooxidation of cytotoxic ellipticine derivatives: A key to structure-activity relationship studies. Mol. Pharmacol., 33:93.Google Scholar
  16. Moiroux, J. and Ambruster, A.M., 1980, Electrochemical behaviour of ellipticine derivatives Part I. Oxidation of 9-Hydroxy-ellipticine. J. Electroanal. Chem., 114:139.Google Scholar
  17. Nakasawa, H., Andrews, P.A., Callery, P.S. and Bachur, N.R., 1985, Super oxide radical reactions with anthracycline antibiotics. Biochem. Pharmacol., 34:481.CrossRefGoogle Scholar
  18. Nelson, E.M., Tewey, K.M. and Liu, L.F., 1984, Mechanism of antitumor drug action: Poisoning of mammalian topoisomerase II on DNA by 4’-(9-acridinylamino)-methanesulfon-m-anisidine. Proc. Natl. Acad. Sci. USA, 81:1361.PubMedCrossRefGoogle Scholar
  19. Paoletti, C., Cros, S., Dat-Xuong, N., Lecointe, P. and Moisand, A., 1979, Comparative cytotoxic and antitumoral effects of ellipticine derivatives on mouse L1210 leukemia. Chem. Biol. Inter., 25:45.CrossRefGoogle Scholar
  20. Rousseau-Richard, C., Auclair, C., Richard, C. and Martin, R., Free radical scavenging and cytotoxic properties in the ellipticine series. Free Rad. Biol. Med., in press.Google Scholar
  21. Rousseau-Richard, C., Auclair, C., Richard, C. and Martin, R., 1989,Google Scholar
  22. Correlation between the OH bond dissociation energies of ellipticine hydroxylated derivatives and their cytotoxic properties. FEBS Lett., 252:58.Google Scholar
  23. Reszka, K., Kolodziejczyk, P. and Lown, W.J., 1986, Horse radish peroxidase-catalized oxidation of mitoxantrone: spectrophotometric and electron paramagnetic resonance studies. J. Free Rad. Biol. Med., 2:25.CrossRefGoogle Scholar
  24. Rowe, C.T., Chen, G.L., Hsiang, Y.H. and Liu, L.F., 1986, DNA damage by antitumor acridines mediated by mammalian DNA topoisomerase II. Cancer Res., 46:2021.PubMedGoogle Scholar
  25. Searle, A.J.F., Gee, C. and Wilson, R., 1983, Ellipticines and carbazole as antioxidants, In: Oxygen radicals in chemistry and biology, Proc. 3rd. International Conference, Neuherberg. W. Bors, M. Saran and D. Tait, Eds. Walter de Gruyter, Berlin.Google Scholar
  26. Sinha, B.K., 1983, Irreversible binding of quinacrine to nucleic acids during horse radish peroxidaseand prostaglandin synthetase-catalized oxidation. Biochem. Pharmacol., 32:2604.PubMedCrossRefGoogle Scholar
  27. Sinha, B.K. and Myers, C.E., 1984a, Irreversible binding of etoposide (VP- 16-213) to desoxyribonucleic acid and proteins. Biochem. Pharmacol., 33:3725.PubMedCrossRefGoogle Scholar
  28. Sinha, B.K., Trush, M.A., Kennedy, A. and îümmaugh, E.G., 1984b, Enzymatic activation and binding of adriamycin to nuclear DNA. Cancer Res., 44:2892.PubMedGoogle Scholar
  29. Sinha, B.K., Trush, M.A. and Kalyanaraman, 3., 1985, Microsomal inter actions and inhibition of lipid peroxidation by etoposide (VP-16-213) implications for mode of action. Biochem. Pharmacol., 34:2036.PubMedCrossRefGoogle Scholar
  30. Tewey, K.M., Rowe, T.C., Yang, L., Halligan, B.D. and Liu, L.F., 1984, Adriamycin-induced DNA damage mediated by mammalian topoisomerase. Science, 226:466.PubMedCrossRefGoogle Scholar
  31. Trush, M.A., Mimmaugh, E.G. and Gram, T.E., 1982, Activation of pharmacologic agents to radical intermediates. Implication for the role of free radicals in drug action and toxicity. Biochem. Pharmacol., 31:3335.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1990

Authors and Affiliations

  • Christian Auclair
    • 1
  1. 1.Laboratoire de Biochimie-Enzymologie, INSERM U 140, CNRS UA 147Institut Gustave RoussyVillejuif CedexFrance

Personalised recommendations