Mitoxantrone: A Promising New Agent for the Treatment of Human Cancer

  • Colin P. Turnbull
  • David Jackson
Part of the Developments in Oncology book series (DION, volume 23)

Abstract

Mitoxantrone (1,4-dihydroxy-5,8-bis((2-(2-hydroxyethyl)amino)ethyl- amino)-9, 10-anthracenedione hydrochloride NOVANTRONE*) was first synthesized by Murdoch. Based on its antitumor activity in mice and the observation that it did not cause progressive irreversible cardiotoxicity in animals, mitoxantrone was selected for clinical evaluation. An independent effort at the University of Kansas2 also identified mitoxantrone and confirmed the observations of the Lederle investigators in transplantable murine tumors.

Keywords

Lymphoma Leukemia NADPH Neutropenia Cyclophosphamide 

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References

  1. 1.
    Murdock, K. C., Wallace, R. E., Durr, F. E., Child, R. G., Citarella, R. V., Fabio, P. F., Angier, R. B. Antitumor Agents I. 1,4-bis-(aminoalky1 amino)-9,10-anthracenediones. J. Med. Chem. 22, 1024–1030, 1979.PubMedCrossRefGoogle Scholar
  2. 2.
    Zee-Cheng, R. K. Y., Cheng, C. C. Antineoplastic Agents: Structure-Activity Relationship Study of bis(substituted aminoalkylamino)anthraquinones. J. Med. Chem. 21, 291–294, 1978.PubMedCrossRefGoogle Scholar
  3. 3.
    Johson R. K., Broome, M. G., Howard, W. S., Evans, S. F., Pritchard, D. F. Experimental Therapeutic and Biochemical Studies of Anthracenedione Derivatives, in “New Anticancer Drugs: Mitoxantrone and Bisantrene,” edited by M. Rozencweig et al, Raven Press, New York, 1983.Google Scholar
  4. 4.
    Mimnaugh, E. G., Trush, M. A., Ginsburg, E., Gram, T. E. Differential Effects of Anthracycline Drugs on Rat Heart and Liver Microsomal Reduced Nicotinamide Adenine Dinucleotide Phosphate Dependent Lipid Peroxidation. Cancer Res., 42, 3574–3548, 1982.PubMedGoogle Scholar
  5. 5.
    Doroshow, J. H. Comparative Cardiac Oxygen Radical Production by Anthracycline Antiobiotics, Mitoxantrone, Bisantrene, m-AMSA, and Neocarcinostatin. Clinical Res., 31, 67A, 1983.Google Scholar
  6. 6.
    Kharasch, E. D., Novak, R. F. Biochemical Pharmacoloy, 20, 2881–2884, 1981.CrossRefGoogle Scholar
  7. 7.
    Sinha, B. K., Motten, A. G., Hanck, K. W. The Electrochemical Reduction of 1,4-bis (2-(2-hydroxyethyl)amino)ethylamino) anthracenedione and daunomycin: Biochemical Significance in Superoxide Formation. Chem. Biol Interactions, 43, 371–377, 1983.CrossRefGoogle Scholar
  8. 8.
    Kharasch, E. D., Novak, R. F. Inhibition of Adriamycin- Stimulated Microsomal Lipid Peroxidation by Mitoxantrone and Ametantrone, two New Anthracenedione Antineoplastic Agents. Biochemical and Biophysical Research Communications, 108 (3), 1346–1352, 1982.PubMedCrossRefGoogle Scholar
  9. 9.
    Fujimoto, S, Ogawa, M. Antitumor Activity of Mitoxantrone Against Murine Experimental Tumors: Comparative Analysis Against Various Antitumor Antibiotics. Cancer Chemother. Pharmacol, 8, 157–162, 1982.Google Scholar
  10. 10.
    Neidhart, J. A., Gochnour, D., Roach, R. W., Young, D. C. Mitoxantrone Versus Doxorubicin in Advanced Breast Cancer: a Randomized Cross-Over Trial. Abstracts 13th ICC, 1983. Cancer Treatment Reviews, in Press.Google Scholar
  11. 11.
    Stuart-Harris, R. C., Smith, I. E. Mitoxantrone: A Phase II Study in the Treatment of Patients with Advanced Breast Carcinoma and Other Solid Tumors. Cancer Chemotherapy and Pharmacology 8, 179–182, 1982.PubMedCrossRefGoogle Scholar
  12. 12.
    Yap, H. Y, Blumenschein, G. R., Schell, F. C., Buzdar, A. U., Valdivieso, M., Bodey G. P. Dihydroxyanthracenedione: a Promising New drug in the Treatment of Metastatic Breast Cancer. Ann. Int. Med., 95, 694–697.Google Scholar
  13. 13.
    Johnson, R. K., Zee-Cheng, R. K. Y., Lee, W. W., Acton, E. M., Henry, E. W., Cheng, C. C. Experimental Antitumor Activity of Aminoanthraquinones. Cancer Treatment Reports 63, 425–439, 1979.PubMedGoogle Scholar
  14. 14.
    Foye, W. O., Vajragupta, O. P. A., Sengupta, S. K. DNA-Binding Specificity and RNA Polymerase Inhibitory Activity of bis-(aminoalkyl)anthraquinones and bis(methylthio)vinylquinone iodides. J. Pharm. Sci., 71 (2), 253–257, 1982.PubMedCrossRefGoogle Scholar
  15. 15.
    Kapuschinski, J., Darzynkiewicz, Z., Traganos, F., Malamed, M. R. Interactions of a New Antitumor Agent, 1,4-dihydroxy-5, 8-bis ((2-(2-hydroxyethyl)amino)ethylamino)-9,10-anthracenedione with nucleic acids. Biochem. Pharmacol., 30, 231–240, 1981.CrossRefGoogle Scholar
  16. 16.
    Hsu, T. C., Cherry, L. M., Pathak, S. Induction of Chromatid Breakage by Clastogens in Cells in G£ Phase. Mutation Research, 93, 185–193, 1982.PubMedCrossRefGoogle Scholar
  17. 17.
    Nishio, A., DeFeo, F., Cheng, C. C., Uyeki, E. M. Sister-Chromatid Exchange and Chromasomal Aberrations by DHAQ and Related Anthraquinone Derivatives in Chinese Hamster Ovary Cells. Mutation Research, 101, 77–86, 1982.PubMedCrossRefGoogle Scholar
  18. 18.
    Traganos, F., Evenson, D. P., Staiano-Coico, L., Darzynkiewicz, Z., Melamed, M. R. Action of Dihydroxyanthraquinone on Cell Cycle Progression and Survival of a Variety of Cultured Mammalian Cells. Cancer Res., 40, 671–681, 1980.PubMedGoogle Scholar
  19. 19.
    Reynolds, D. L., Ulrich, K. K. Patton, T. F., Repta, A. J., Sternson, L. A., Myron, M. C., Taylor, S. A. Plasma Levels of l,4-dihydroxy-5,8-bis ((2-((2-hydroxyethyl)amino)ethyl)amino)-9, 10-anthracenedione dihydrochloride (DHAD) in Humans. Int. J. Pharmaceutics, 67–71, 1981.Google Scholar
  20. 20.
    Savaraj, N., Lu, K., Valdivieso, M., Burgess, M., Umsawasdi, T., Benjamin, R. S., Loo, T. L. Clinical Kinetics of 1,4-dihydroxy-5,8-bis ((2-hydroxyethyl)amino)ethyl)amino)-9 10-anthracenedione. Clin. Pharmacol Ther. 312–316, 1982.Google Scholar
  21. 21.
    Stewart, J. A., McCormack, J. J., Krakoff, I. H., Clinical and Clinical Pharmacologic Studies of Mitoxantrone. Cancer Treat. Rep. 66, 1327–1331, 1982.PubMedGoogle Scholar
  22. 22.
    Alberts, D. S., Peng, Y. M., Leigh, S., Davis, T.P., Woodward, D. L. Pharmacokinetics of Mitoxantrone in Patients. Abstracts 13th ICC. Cancer Treatment Reviews in Press.Google Scholar
  23. 23.
    Neidhart, J. A., Malspeis, L. Pharmacokinetics of Mitoxantrone Following Administration of a Single Intravenous Dose. Data on file, Lederle Laboratories.Google Scholar
  24. 24.
    Smith, I. E., Mitoxantrone (NOVANTRONE): A Review of Experimental and Early Clinical Studies. Cancer Treatment Reviews, 10, 103–115, 1983.PubMedCrossRefGoogle Scholar
  25. 25.
    Mouridson, H. T., Van Oosterom, A. T., Rose, C., Nooi, M. A. A Phase II Study of Mitoxantrone as First Line Cytotoxic Therapy in Advanced Breast Cancer. 13th ICC Abstracts. Cancer Treatment Reviews, in Press.Google Scholar
  26. 26.
    Yap, H. Y., Esparza, L., Blumenschein, G. R., Hortobagyi, G. N., Bodey, G. P. Combination Chemotherapy with Cyclophosphamide, Mitoxantrone, 5-Fluorouracil in Patients with Metastatic Breast Cancer. 13th ICC Abstracts. Cancer Treatment Reviews, in Press.Google Scholar
  27. 27.
    Prentice, H. G., Robbins, G., Hulhoven, R., Michaux, J. L., Therapeutic Activity, Toxicity, and Pharmacokinetics of Mitoxantrone. A Phase I/II Study in Patients with Acute Leukemia. 13th ICC Abstracts. Cancer Treatment Reviews, in Press.Google Scholar
  28. 28.
    Paciucci, P. A., Ohnuma, T., Cuttner, J., Holland, J. F. Mitoxantrone in Refractory Acute Leukemia. 13th ICC Abstracts Cancer Treatment Reviews, in Press.Google Scholar
  29. 29.
    Arlin, Z., Silver, R., Cassileth, P., Armentrout, S., Gams, R., Ersler, A., Amare, M., Brown, G., Schoch, I., and Dukart, G. Phase I/II Trial of Mitoxantrone in Adult Acute Leukemia (AL) Abstracts. 2nd European Congress of Clinical Oncology, 1983.Google Scholar
  30. 30.
    Data on file, Lederle Laboratories.Google Scholar
  31. 31.
    Gams, R. A., Keller, J., Colomb, H. M., Steinberg, J., Dukart, G. Mitoxantrone in Malignant Lymphoma. 13th ICC Abstracts. Cancer Treatment Reviews, in Press.Google Scholar
  32. 32.
    Coltman, C. A., Jr., McDaniel, T. M., Balcerzk, S. P., Morrison, F. S., Von Hoff, D. D. Mitoxantrone Hydrochloride in Lymphoma. 13th ICC Abstracts. Cancer Treatment Reviews, in Press.Google Scholar
  33. 33.
    Data on file, Lederle Laboratories.Google Scholar
  34. 34.
    Data on file, Lederle Laboratories.Google Scholar
  35. 35.
    Holland, J. F., Chairman’s Summary on the 13th ICC Symposium on Mitoxantrone. Cancer Treatment Reviews, in Press.Google Scholar
  36. 36.
    Crossley, R. J. Clinical Safety and Tolerance of Mitoxantrone 13th ICC Abstracts, Cancer Treatment Reviews, in Press.Google Scholar

Copyright information

© Martinus Nijhoff Publishing, Boston 1984

Authors and Affiliations

  • Colin P. Turnbull
    • 1
  • David Jackson
    • 2
  1. 1.American Cyanamid CompanyWayneUSA
  2. 2.Division of American Cyanamid CompanyLederle LaboratoriesPearl RiverUSA

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