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Antitumor Activity, Pharmacology, and Toxicity of Ellipticines, Ellipticinium, and 9-Hydroxy Derivatives: Preliminary Clinical Trials of 2-Methyl-9-Hydroxy Ellipticinium (NSC 264-137)

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Cancer Chemo- and Immunopharmacology

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 74))

Summary

Ellipticine and some derivatives are highly cytotoxic substances which kill L1210 cells at concentrations ranging form 10-8 to 10-6 M. Some compounds in this series bind with high affinity to DNA (affinity constant between 107 M -1 and 105 M -1) by intercalation between base pairs. The antitumoral properties of these derivatives are thought to be related to their DNA-binding ability. Both 9-hydroxylation of ellipticine and quaternarization of 2-pyridinic nitrogen tend to increase DNA binding and antitumor activity.

2-Methyl-9-hydroxyellipticine (NSC 264-137) was selected for a phase I and later for a phase II trial in human cancer. This drug does not affect blood cell counts in animals or in man. It is not mutagenic in the Ames’ test nor teratogenic in mice, but is endowed with anti-inflammatory properties and induces a marked decrease of motoricity in mice. Transient bradycardia and decrease of blood pressure are the most noticeable cardiovascular effects in dogs.

This compound administered at 80–100 mg/m2/week in 1-h intravenous (IV) infusion induces objective remissions in about 25% of patients suffering from advanced breast cancer refractory to all other treatment. These remissions, which occurred after 3–4 weeks, lasted for 1–18 months. This drug seems particularly to improve the condition of patients suffering from oesteolytic breast cancer metastasis. Activity against anaplastic thyroid carcinoma and ovarian carcinoma has also been observed in some cases.

Toxic side effects are nausea and vomiting (one-third of the patients), hypertension (less than 10% of the patients), muscular cramp (one-third of the patients), fatigue which can be very pronounced (in most patients after 3 months of treatment), mouth dryness, and mycosis of the tongue and esophagus (less than 20% of the patients).

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References

  1. Ansari BM, Thompson EN (1975) Methoxy 9 ellipticine lactate in refractory acute myeloid leukemia. Postgrad Med J 51:103–105

    Article  PubMed  CAS  Google Scholar 

  2. Auclair C, Gouyette A, Paoletti C (1978) Peroxydases catalyzed oxidation of the antitumor drug 9-hydroxy ellipticine. Abstract Coordination Chem and Cancer Chemother Meeting, Toulouse, July 24–26, 1978. Biochimie 60:1073

    Article  Google Scholar 

  3. Bachur NR, Gordon SL, Gee MV (1978) A general mechanism for microsomal activation of quinone anticancer agents to free radicals. Cancer Res 38:1745–1750

    PubMed  CAS  Google Scholar 

  4. Bachur NR, Gordon SL, Gee MV, Kon H (1979) NADPH cytochrome P450 reductase activation of quinone anticancer agents to free radicals. Proc Natl Acad Sci USA 76:954–957

    Article  PubMed  CAS  Google Scholar 

  5. Branfman AR, Bruni RJ, Reinhold VN, Silveira DM, Chadwick M, Yesair DW (1978) Characterization of the metabolites of ellipticine in rat bile. Drug Metab Dispos 6:542–548

    PubMed  CAS  Google Scholar 

  6. Brugarolas A, Gracia M, De Jager R, Mallarmen M, Clarysse A (1979) Hydroxy methyl ellipticinium (9 HME, NSC 264137). Phase I clinical study. Proc 17th Annu Meet Am Assoc Cancer Res 20: C77

    Google Scholar 

  7. Chadwick M, Silveira DM, Platz BB, Hayes D (1978) Comparative physiological disposition of ellipticine in several animal species after intravenous administration. Drug Metab Dipos 6:528–541

    CAS  Google Scholar 

  8. Cros J, Thibault A, Dat-Xuong N (1975) Action anti-inflammatoire de l’hydroxy 9 ellipticine. CR Acad Sci [D] Paris 281:1139–1142

    CAS  Google Scholar 

  9. Dalton LK, Demerac S, Elmes BC, Loder JW, Swan JM, Teitei T (1967) Synthesis of the tumour-inhibitory alkaloids ellipticine 9-methoxy ellipticine and related pyrido (4,3-6) carbazoles. Aust J Chem 20:2715–2727

    Article  CAS  Google Scholar 

  10. Dufer J, Desplaces A, Aurousseau M (1973) Etude cytochimique des leucocytes de rats traites par la methoxy 9 ellipticine. Ann Pharm Fr 31:441–450

    PubMed  CAS  Google Scholar 

  11. Festy B, Poisson J, Paoletti C (1971) A new intercalating drug: Methoxy 9 ellipticine. FEBS Lett 17:321–323

    Article  PubMed  CAS  Google Scholar 

  12. Garcia-Giralt E, Macieira-Coelho A (1970) Methoxy 9 ellipticine. II. Analysis in vitro of the mechanism of action. Eur J Clin Biol Res 15:539–544

    CAS  Google Scholar 

  13. Goldin A, Johnson RK (1974) Evaluation of actinomycin in experimental systems. Cancer Chemother Rep 58:63–77

    PubMed  CAS  Google Scholar 

  14. Handa K, Sato S (1976) Stimulation of microsomal NADPH oxidation by quinone group containing anticancer chemicals. Gann 67:523–528

    PubMed  CAS  Google Scholar 

  15. Hardesty CT, Chaney NA, Mead JAR (1972) The effect of route of administration of the distribution of ellipticine in mice. Cancer Res 32:1884–1889

    PubMed  CAS  Google Scholar 

  16. Hartwell JL, Abbotth BJ (1969) Antineoplastic principles in plants: Recent development in the field. In: Garrattini S, Goldin A, Hawking F, Kopin IJ (eds) Advances in pharmacology and chemotherapy, vol 7. Academic, New York, pp 117–209

    Google Scholar 

  17. Hayat M, Mathe G, Janot MM, Potier P, Dat-Xuong N, Cave A, Sevenet T, Kan-Fan C, Poisson J, Miet J, Le Men J, Le Goffic F, Gouyette A, Ahond A, Dalton LK, Connors TA (1974) Experimental screening of 3 forms and 19 derivatives of analogs of ellipticine: Oncostatic effect on L1210 leukemia and immunosuppressive effect of 4 of them. Biomedicine 21:101–106

    PubMed  CAS  Google Scholar 

  18. Herman EH, Chadwick DP, Mhatre RM (1974) Comparison of the acute hemolytic and cardiovascular actions of ellipticine (NSC 71795) and some ellipticine analogs. Cancer Chemother 58:637–643

    CAS  Google Scholar 

  19. Herman EH, Lee IP, Mhatre RM, Chadwick DP (1974) Prevention of hemolysis induced by ellipticine (NSC 71795) in rhesus monkeys. Cancer Chemother Rep 58:171–179

    PubMed  CAS  Google Scholar 

  20. Herman E, Vick J, Burka B (1971) The cardiovascular actions of ellipticine. Toxicol Appl Pharmacol 18:743–751

    Article  PubMed  CAS  Google Scholar 

  21. Juret P, Tanguy A, Le Talaer JY, Abbatucci JS, Dat-Xuong N, Le Pecq J-B, Paoletti C (1978) Preliminary trial of 9-hydroxy 2-methyl ellipticinium (NSC 264137) in advanced human cancers. Eur J Cancer 14:205–206

    PubMed  CAS  Google Scholar 

  22. Juret P, Tanguy A, Le Talaer JY, Abbatucci JS, Dat-Xuong N, Le Pecq J-B, Paoletti C (1979) L’acétate d’hydroxy 9-methyl 2-ellipticinium (NSC 264137). Etude toxicologique et thérapeutique chez 100 cancéreux. Nouv Presse Med 8:1495–1498

    PubMed  CAS  Google Scholar 

  23. Lecointe P, Lesca P, Cros S, Paoletti C (1978) Some antitumor derivatives of ellipticine deprived of mutagenic properties. Chem Biol Interact 20:113–121

    Article  PubMed  CAS  Google Scholar 

  24. Lee IP (1976) A possible mechanism of ellipticine induced hemolysis. J Pharmacol Exp Ther 196:525–535

    CAS  Google Scholar 

  25. Le Men J, Hayat M, Mathé G, Guillon JC, Chenu E, Humbolt M, Masson Y (1970) Methoxy-9-ellipticine lactate. Experimental study (oncostatic and immunosuppressive actions: preclinical pharmacology). Rev Eur Etud Clin Biol 15:534–538

    PubMed  Google Scholar 

  26. Le Pecq J-B, Dat-Xuong N, Gosse C, Paoletti C (1974) A new antitumoral agent: 9-Hydroxy ellipticine. Possibility of a rational design of anticancerous drugs in the series of DNA intercalating drugs. Proc Natl Acad Sci USA 71:5078–5082

    Article  PubMed  Google Scholar 

  27. Le Pecq J-B, Gosse C, Dat-Xuong N, Cros S, Paoletti C (1976) Antitumoral activity of 9 hydroxy ellipticine (NSC 210717) on L1210 mice leukemia. Effect of the route of injection. Cancer Res 36:3067–3076

    PubMed  Google Scholar 

  28. Le Pecq J-B, Gosse C, Dat-Xuong N, Paoletti C (1975) Deux nouveaux derives antitumoraux: l’hydroxy-9 methyl-2 ellipticinium et l’hydroxy 9 dimethyl 2,6-ellipticinium. Action sur la leucemie L1210 de la souris. CR Acad Sci [D] Paris 281:1365–1367

    Google Scholar 

  29. Lesca P, Lecointe P, Paoletti C, Mansuy D (1976) Induction des monooxygenases hepatiques par Tellipticine chez le rat: formation de cytochrome P448. Activité hydroxylante. CR Acad Sci [D] Paris 282:1457–1460

    CAS  Google Scholar 

  30. Lesca P, Lecointe P, Paoletti C, Mansuy D (1977) The hydroxylation of the antitumor agent ellipticine by liver microsomes from differently pretreated rats. Biochem Pharmacol 26:2169–2173

    Article  PubMed  CAS  Google Scholar 

  31. Lesca P, Lecointe P, Paoletti C, Mansuy D (1978) Ellipticine as potent inhibitors of aryl hydrocarbon hydroxylase: Their binding to microsomal cytochrome P450 and protective effect against benzo(a)pyrene mutagenicity. Biochem Pharmacol 27:1203–1209

    Article  PubMed  CAS  Google Scholar 

  32. Lesca P, Lecointe P, Paoletti C, Mansuy D (1978) Ellipticines as potent inhibitors of drug metabolism. Protective effect against chemical mutagenesis and carcinogenesis. Biochimie 60:1011–1018

    Article  CAS  Google Scholar 

  33. Lesca P, Rafidinarivo E, Lecointe P, Mansuy D (1978) A class of strong inhibitors of microsomal monooxygenases: The ellipticines. Chem Biol Interact 24:189–198

    Article  Google Scholar 

  34. Mathé G, Hayat M, De Vassal F, Schwarzenberg L, Schneider M, Schlumberger JR, Jasmin C, Rosenfeld C (1970) Methoxy 9 ellipticine lactate. III. Clinical screening: Its action in acute myeloblasts leukemia. Rev Eur Etud Clin Biol 15:541–545

    PubMed  Google Scholar 

  35. Muller W, Crothers DM (1968) Studies of the binding of actinomycin and related compounds to DNA. J Mol Biol 35:251–290

    Article  PubMed  CAS  Google Scholar 

  36. Paoletti C, Cros S, Dat-Xuong N, Lecointe P, Moisand A (1979) Comparative cytotoxic and antitumoral effects of ellipticine derivatives on mouse L1210 leukemia. Chem Biol Interact 25:45–58

    Article  PubMed  CAS  Google Scholar 

  37. Paoletti C, Le Pecq J-B, Dat-Xuong N, Lesca P, Lecointe P (1978) New anticancer derivatives in the ellipticine series. Curr Chemother 1195–1197

    Google Scholar 

  38. Paoletti C, Lesca C, Cros S, Malvy C, Auclair C (1978) Ellipticine and derivatives induce breakage of L1210 cells DNA in vitro. Biochem Pharmacol 28:345–350

    Article  Google Scholar 

  39. Pham-Huu-Chanh, Dat-Xuong N, Le Pecq J-B, Paoletti C (1976) Cardiovascular activity of 9 hydroxy ellipticine. Pharmacology 14:490–498

    Article  CAS  Google Scholar 

  40. Pham-Huu-Chanh, Sorbara R, Dat-Xuong N, Paoletti C, Le Pecq J-B (1974) Actions cardiovasculaires et toxicites de l’hydroxy 9 ellipticine chez le chien. CR Acad Sci [D] Paris 279:1039–1042

    CAS  Google Scholar 

  41. Rakieten N, Cooney D, Davis R (1970) Acute toxicity of ellipticine (NSC 71795) following i.v. and p.o. administration to beagle dogs with special emphasis on its hypotensive action. US Dep Commer Natl Tech Inf Serv, PB 174–743

    Google Scholar 

  42. Reinhold VN, Bruni RJ (1976) Aromatic hydroxylation of ellipticine in rats: Lack of an NIH shift. Biomed Mass Spectrom 3:335–339

    Article  PubMed  CAS  Google Scholar 

  43. Sainsbury M (1977) The synthesis of 6H-pyrido (4,3-b) carbazoles. Synthesis 7:437–448

    Article  Google Scholar 

  44. Svoboda GH, Poore GA, Montfort M (1968) Alkaloids of ochrosia maculate {Ochrosia borbonica G mel). Isolation of the alkaloids and study of the antitumor properties of 9-methoxy ellipticine. J Pharm Sci 57:1720–1725

    Article  PubMed  CAS  Google Scholar 

  45. Tomasz M, Mercado C, Olson J, Catterjie N (1974) The mode of interaction of mitomycin C with deoxyribonucleic acid and other polynucleotides in vitro. Biochemistry 13:4878–4887

    Article  PubMed  CAS  Google Scholar 

  46. Van-Bac N, Moisand C, Gouyette A, Muzard G, Dat-Xuong N, Le Pecq J-B, Paoletti C (to be published) Metabolic and diposition studies of 9-hydroxy ellipticine and 2-methyl 9-hydroxy ellipticinium acetate in animals

    Google Scholar 

  47. White HL, White JR (1968) Lethal action and metabolic effects of streptonigrin on Escherichia coli. Mol Pharmacol 4:549–565

    PubMed  CAS  Google Scholar 

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Authors
  1. C. Paoletti
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  2. J.-B. Le Pecq
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  3. N. Dat-Xuong
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  4. P. Juret
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  5. H. Garnier
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  6. J.-L. Amiel
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  7. J. Rouesse
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Editor information

Editors and Affiliations

  1. Institut de Cancérologie et Immunogénétique, Hôpital Paul-Brousse, 14 - 16 Avenue Paul-Vaillant-Couturier, F-94800, Villejuif, France

    Georges Mathé

  2. Medical Center, Division of Oncology, Department of Internal Medicine, Institute of Environmental Medicine, New York University, 550 First Avenue, 10016, New York, NY, USA

    Franco M. Muggia

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© 1980 Springer-Verlag Berlin Heidelberg

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Paoletti, C. et al. (1980). Antitumor Activity, Pharmacology, and Toxicity of Ellipticines, Ellipticinium, and 9-Hydroxy Derivatives: Preliminary Clinical Trials of 2-Methyl-9-Hydroxy Ellipticinium (NSC 264-137). In: Mathé, G., Muggia, F.M. (eds) Cancer Chemo- and Immunopharmacology. Recent Results in Cancer Research, vol 74. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-81488-4_15

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  • DOI: https://doi.org/10.1007/978-3-642-81488-4_15

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-81490-7

  • Online ISBN: 978-3-642-81488-4

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