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Antitumor Activity, Pharmacology and Clinical Trials of Elliptinium (NSC 264-137)

  • Anette Kragh Larsen
  • Claude Paoletti
Part of the NATO ASI Series book series (NSSA, volume 120)

Abstract

Ellipticine and some of its derivatives are naturally occuring alkaloids found in plants of the Apocynaceae family. The antitumoral activities were described in 1967 by Dalton et al.(1) and later confirmed by Mathe et al. who reported the antitumor activity of 9-methoxy-ellipticine in patients with acute myeloblastic leukemia. The finding of drug-related side-effects such as hemolysis and nervous toxicity (3,4) prompted an intensive search for new derivatives at the Institut Gustave-Roussy in Villejuif, France.

Keywords

Antitumor Drug Acute Myeloblastic Leukemia Glutathione Conjugate Mixed Function Oxygenase Hyperplastic Alveolar Nodule 
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.

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References

  1. 1.
    L. K. Dalton, S. Demerac, B. C. Elmes, I. W. Loder, J. M. Swan, and T. Teitei, Synthesis of the tumor inhibitory alkaloids ellipticine 9-methoxyellipticine and related pyrido 4,3-b-carbazols. Austr. J., 20: 2715 (1967).CrossRefGoogle Scholar
  2. 2.
    G. Mathe, M. Hayat, F. de Vassal, L. Schwartzenberg, M. Schneider, J. R. Schlumberger, C. Jasmin, and C. Rosenfeld, Methoxy-9ellipticine lactate III. Clinical screening: its action in acute myeloblastic leukemia, Rev. Eur. Etud. Clin. Biol., 15: 541 (1970).PubMedGoogle Scholar
  3. 3.
    E. H. Herman, D. P. Chadwick, and R. M. Mhatre, Comparison of the acute hemolytic and cardiovascular action of ellipticine (NSC 71795) and some ellipticine analogs, Cancer Chemother., 58: 637 (1974).Google Scholar
  4. 4.
    R. H. Liss, and C. J. Kensler, Radioautographic methods for physiologic, disposition and toxicology studies, in: “Advances in modern toxicology; new concepts in safety evaluation”. Hemisphere Publishing Corp., Washington D.C. (1976).Google Scholar
  5. 5.
    J. B. LePecq, N. Dat-Xuong, C. Gosse, and C. Paoletti, A new anti-tumoral agent: 9-hydroxy ellipticine. Possibility of a rational design of anticancerous drugs in the series of DNA intercalating drugs, Proc. Nat. Acad. Sci. USA, 71: 5078 (1974).CrossRefGoogle Scholar
  6. 6.
    J. B. LePecq, C. Gosse, N. Dat-Xuong, S. Cros, and C. Paoletti, Anti-tumoral activity of 9-hydroxy ellipticine (NSC 210717) on L1210 mice leukemia, Cancer Res., 36: 3067 (1976).Google Scholar
  7. 7.
    C. Paoletti, J. B. LePecq, N. Dat-Xuong, P. Lesca, and P. Lecointe, New anticancer derivatives in the ellipticine series, Curr. Chemother., 1195 (1978).Google Scholar
  8. 8.
    N. Van-Bac, C. Moisand, A. Gouyette, G. Muzard, N. Dat-Xuong, J. B. LePecq, and C. Paoletti, Metabolism and disposition studies of 9-hydroxyellipticinium acetate in animals, Cancer Treat. Rep., 64: 879 (1980).PubMedGoogle Scholar
  9. 9.
    P. Juret, A. Tanguy, J.Y. Le Talaer, J. S. Abbatucci, N. Dat-Xuong, J. B. LePecq, and C. Paoletti, Preliminary trials of 9-hydroxy2-methyl ellipticinium (NSC 264137) in advanced human cancers, Eur. J. Cancer, 14: 205 (1978).PubMedCrossRefGoogle Scholar
  10. 10.
    J. Y. Charcosset, A. Jacquemin-Sablon, and J. B. LePecq, Effect of membrane potential on the cellular uptake of 2-N-methyl-ellipticinium by L1210 cells, Biochem. Pharmacol., 33: 2271 (1984).PubMedCrossRefGoogle Scholar
  11. 11.
    L. V. Johnson, M. L. Walsh, B. J. Bockus, and L. B. Chen, Monitoring of relative mitochondrial membrane potential in living cells by fluorescence microscopy, J. Cell. Biol., 88: 526 (1981).PubMedCrossRefGoogle Scholar
  12. 12.
    P. Harikumar, and J. P. Reeves, The lysosomal proton pump is electrogenic, J. Biol. Chem., 258: 10403 (1983).PubMedGoogle Scholar
  13. 13.
    J. Y. Charcosset, B. Salles, and A. Jacquemin-Sablon, Uptake and cytofluorescence localization of ellipticine derivatives in sensitive and resistant chinese hamster lung cells, Biochem. Pharmacol., 32: 1037 (1983).PubMedCrossRefGoogle Scholar
  14. 14.
    C. Paoletti, S. Cros, W. Dat-Xuong, P. Lecointe, and A. Moisand, Comparative cytotoxic and antitumoral effects of ellipticine derivatives on mouse L1210 leukemia, Chem. Biol. Interact., 25: 45 (1979).PubMedCrossRefGoogle Scholar
  15. 15.
    E. Garcia-Giralt, and A. Macieira-Coelho, Methoxy-9-ellipticine. Analysis in vitro of the mechanism of action, Eur. J. Clin. Biol. Res., 15: 539 (1970).Google Scholar
  16. 16.
    C. Paoletti, J. B. LePecq, N. Dat-Xuong, P. Juret, H. Garnier, J.L. Amiel, and J. Rouesse, Antitumor activity, pharmacology and toxicity of ellipticines, ellipticinium and 9-hydroxy derivatives: preliminary clinical trials of 2-methyl-9-hydroxy ellipticinium (NSC 264–137). Recent Results, Cancer Res., 74: 107 (1984).CrossRefGoogle Scholar
  17. 17.
    H. Nasagawa, M. Nomma, H. Namidi, and K. Niki, Inhibition by hydroxyN-methyl Elliptinium of precancerous mammary hyperplastic alveolar module formation in mice, Eur. J. Cancer Clin. Oncol., 20: 273 (1984).CrossRefGoogle Scholar
  18. 18.
    J. Bernadou, B. Meunier, G. Meunier, C. Auclair, and C. Paoletti, Regioselective arylation of ribose in adenosine and guanosine with the antitumor drug 2-N-methyl-9-hydroxyellipticinium acetate Proc. Nat. Acad. Sci. USA, 81: 1297 (1984).CrossRefGoogle Scholar
  19. 19.
    L. A. Zwelling, S. Michaels, L. C. Ericson, L. C. Ungerleider, R.S. Nichols, and K. W. Kohn, Protein-associated DNA strand breaks in L1210 cells treated with the DNA intercalating agents, 4’(9-acridinylamino) methanesulfon-m-anisidine (m-AMSA) and adriamycin, Biochemistry, 20: 6553 (1981).PubMedCrossRefGoogle Scholar
  20. 20.
    K. M. Tewey, G. L. Chen, E. M. Nelson, and L. F. Liu, Intercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II, J. Biol. Chem., 259: 9182 (1984).PubMedGoogle Scholar
  21. 21.
    C. Paoletti, C. Auclair, P. Lesca, J. F. Tocanne, C. Malvy, and M. Pinto, Ellipticine, 9-hydroxyellipticine, and 9-hydroxy-ellipticinium: some biochemical properties of possible pharmacologic significance, Cancer Treat. Rep., 65 (suppl. 3): 107 (1981).PubMedGoogle Scholar
  22. 22.
    B. Salles, J. Y. Charcosset, and A. Jacquemin-Sablon, Isolation and properties of chinese hamster lung cells resistant to ellipticine derivatives, Cancer Treat. Rep., 66: 327 (1982).PubMedGoogle Scholar
  23. 23.
    J. Y. Charcosset, J. P. Bendirdjian, M. F. Lantieri, and A. Jacquemin-Sablon, Effects of 9-OH-ellipticine on cell survival, macro-molecular synthesis and cell cycle progression in sensitive and resistant cells, Cancer Res., 45: 4229 (1985).PubMedGoogle Scholar
  24. 24.
    N. Van-Bac, C. Moisand, A. Gouyette, G. Muzard, N. Dat-Xuong, J.B. LePecq, and C. Paoletti, Metabolism and disposition studies of 9-hydroxyellipticine and 2-methyl-9-hydroxyellipticinium acetate in animals, Cancer Treat. Rep., 64: 879 (1980).PubMedGoogle Scholar
  25. 25.
    M. Majetouh, B. Montsarrat, R. C. Rao, B. Meunier, and C. Paoletti, Identification of the glucuronide and glutathione conjugates of the antitumor drug 2N-methyl-9-hydroxyelliptinium acetate (Celiptium), Drug Metab. Dise., 12: 111 (1984).Google Scholar
  26. 26.
    L. W. Oberley, and C. R. Buettner, Role of superoxide dismutase in cancer, Cancer Res., 39: 1141 (1980).Google Scholar
  27. 27.
    J. M. McCord, B. B. Keele, and I. Fridovich, An enzyme based theory of obligate anaerobiosis: the physiological function of superoxide dismutase, Proc. Nat. Acad. Sci. USA, 68: 1024 (1971).PubMedCrossRefGoogle Scholar
  28. 28.
    A. Clarysse, A. Brugarolas, P. Siegenthaler, R. Abele, F. Cavalli, R. De Jager, R. Grenard, M. Rozencweig, and H. Hansen, Phase II study of 9-hydroxy-2N-methylellipticinium acetate, Eur. J. Cancer Clin. Oncol., 20: 243 (1984).PubMedCrossRefGoogle Scholar
  29. 29.
    P. Juret, J. F. Heron, J. E. Couette, T. Delozier, and J. Y. Le Talaer, Hydroxy-9-methyl-2-ellipticinium for osseous metastases from breast cancer: a 5-year experience, Cancer Treat. Rep., 66: 1909 (1982).PubMedGoogle Scholar
  30. 30.
    J. L. Amiel, J. Rouesse, J. P. Droz, P. Caille, J. P. Travagli, C. Theodore, T. Le Chevalier, J. P. Ducret, J. M. Bidard, H. Garnier, and C. Paoletti, Chimotherapie des cancers du rein, metastases par le N-methylhydroxyellipticinium (NHME), Nouv. Presse Med., 10: 1504 (1981).Google Scholar
  31. 31.
    J. G. Rouesse, T. Le Chevalier, P. Caille, J. M. Mondesir, H. SanchoGranier, F. May-Levin, M. Spielmann, R. de Jager, and J. L. Amiel, Phase II study of Elliptinium in advanced breast cancer, Cancer Treat. Rep., 69: 707 (1985).PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • Anette Kragh Larsen
    • 1
  • Claude Paoletti
    • 1
  1. 1.Unite de Biochimie et Enzymologie, INSERM U 140CNRS LA 147, Institut Gustave-RoussyVillejuifFrance

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