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Development of mitoxantrone

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Summary

Mitoxantrone (Novantrone®; dihydroxyanthracenedione) belongs to a new structural class of antineoplastic agents, the anthracenediones. It was the outcome of a program in synthetic chemistry, at the Medical Research Division of the American Cyanamid Company, which started from a molecule with structural features predicted to favor intercalation with double stranded DNA.

The initial lead compound had immunomodulatory effects and was subsequently found also to possess significant activity against transplantable murine tumors. A large series of analogues was synthesized and mitoxantrone was selected for clinical trial on the basis of its potency and excellent antitumor activity in mice. It is a cytotoxic agent that will kill both proliferating and non-proliferating cells.

A variety of experiments conducted with both intact cells and cell-free systems have revealed mitoxantrone's ability to bind to single stranded and double stranded RNA and DNA. The drug inhibits cellular RNA and DNA synthesis to about the same extent and causes chromosomal aberrations. In vivo experiments using murine models have demonstrated good activity for mitoxantrone against a variety of transplantable tumors including both leukemias and solid types, in many cases giving putative cures. Surprisingly, it is effective when given up to 30 days before tumor implantation. Combination studies with standard anticancer agents gave evidence of therapeutic synergy in a number of cases.

Preclinical studies in several animal models indicate that mitoxantrone does not have the cumulative cardiotoxic liability associated with anthracycline antibiotics such as doxorubicin.

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References

  1. Murdock KC, Wallace RE, Durr FE, Child RG, Citarella RV, Fabio PF, Angier RB: Antitumor agents I. 1,4-bis-(aminoalkyl-amino)-9, 10-anthracenediones. J Med Chem 22:1024–1030, 1979

    Google Scholar 

  2. Johnson RK, Zee-Cheng RK-Y, Lee WW, Acton EM, Henry DH, Cheng CC: Experimental antitumor activity of aminoanthraquinones. Cancer Treat Rep 63:425–439, 1979

    Google Scholar 

  3. Wallace RE, Citarella RV, Durr FE: The inhibitory effect of 1, 4-dihydroxy-5, 8-bis[[2-[(2-hydroxyethyl)amino]-ethyl] amino)-9, 10-anthracenedione dihydrochloride (CL 232, 315; NSC-301739D) on dividing and non-dividing cells in vitro. Proc Am Assoc Cancer Res 20:12, 1979

    Google Scholar 

  4. Evenson DP, Darzynkiewicz A, Staiaono-Coico L, Traganos F, Melamed MR: Effects of 9,10-anthracenedione, l,4-bis,[[2-[(2-hydroxyethyl)-amino]-ethyl] amino]-diacetate on cell survival and cell cycle progression in cultured mammalian cells. Cancer Res 39:2574–2581, 1979

    Google Scholar 

  5. Drewinko B, Yang L, Barlogie B, Trujillo JM: Comparative cytotoxicity of bisantrene, mitoxantrone, ametantrone, dihydroxyanthracenedione, dihydroxyanthracenedione diacetate, and doxorubicin on human cells in vitro. Cancer Res 43:2648–2653, 1983

    Google Scholar 

  6. Drewinko B, Patchen N, Yang L, Barlogie B: Differential killing efficacy of twenty antitumor drugs on proliferating and non-proliferating human tumor cells. Cancer Res 41:2328–2333, 1981

    Google Scholar 

  7. Traganos F, Evenson DP, Staiano-Coico L, Darzynkiewicz Z, Melamed MR: Action of dihydroxyanthraquinone on cell cycle progression and survival of a variety of cultured mammalian cells. Cancer Res 40:671–681, 1980

    Google Scholar 

  8. Hamburger AW, Salmon SE: Primary bioassay of human tumor stem cells. Science 197:461–463, 1977

    Google Scholar 

  9. Von Hoff DD, Coltman CA, Forseth B: Activity of mitoxantrone in a human tumor cloning assay. Cancer Res 41: 1853–1855, 1981

    Google Scholar 

  10. Murray EF, Wallace RE: CL 232, 315 (NSC-301739) 1,4-dihydroxy-5,. 8-bis[[2-[(2-hydroxyethyl) amino]-ethyl] amino]9, 10-anthracenedione dihydrochloride: A novel antitumor agent. In Anthracyclines: Current Status and New Developments. Academic Press, New York, 1980, pp 397–402

    Google Scholar 

  11. Kapuscinski J, Darzynkiewicz A, Traganos F, Melamed RR: Interactions of a new antitumor agent, 1, 4-dihydroxy-5, 8-bis[[2-[(2-hydroxyethyl) amino]-ethyl]amino] -9, 10-anthracenedione with nucleic acids. Biochem Pharmacol 30: 231–240, 1981.

    Google Scholar 

  12. Rosenberg LJ, Hittelman WM: Direct and indirect clastogenic activity of anthracenedione in Chinese hamster ovary cells. Cancer Res 43:2370–3275, 1983

    Google Scholar 

  13. Nishio A, Defeo F, Cheng CC, Uyeki EM: Sister chromatid exchange and chromosomal aberrations by DHAQ and related anthraquinone derivatives in Chinese hamster ovary cells. Mutat Res 1:77–86, 1982

    Google Scholar 

  14. Nishio A, Uyeki EM: Cellular uptake and inhibition of DNA synthesis by dihydroxyanthraquinone and two analogues. Cancer Res 43:1951–1956, 1983

    Google Scholar 

  15. Cohen LF, Glaubiger DL, Kann HE, Kohn KW: Protein associated DNA single strand breaks and cytotoxicity of dihydroxyanthraquinone (DHAD); NSC-301739, in mouse L1210 leukemia cells. Proc Am Assoc Cancer Res 21:277, 1980

    Google Scholar 

  16. Su RT: Effect of 1, 4-dihydroxy-5, 8-bis(2-(2-hyd-roxyethylamino) ethyl-amino) 9, 10-anthracenedione (dihydroxyanthraquinone) on the replication of simian virus 40 chromosome. Biochem Biophys Res Commun 103:249–255, 1981

    Google Scholar 

  17. Foye WO, Vajaragupta OPA, Sengupta SK: DNA-binding specificity and RNA polymerase inhibitory activity of bis (aminoalkyl) anthraquinones and bis (methylthio) vinylquinone iodides. J Pharm Sci 71:253–257, 1982

    Google Scholar 

  18. Roboz J, Richardson CL, Holland JF: Comparison of the interaction of antineoplastic aminoanthraquinone analogs with DNA using competitive fluorescence polarization. Life Sci 31:25–30, 1982

    Google Scholar 

  19. Lown JW, Hanstock CC, Bradley RD, Scraba DG: Interactions of the antitumor agents mitoxantrone and bisantrene with deoxyribonucleic acids studied by electron microscopy. Molec Pharmacol 25:178–184, 1984

    Google Scholar 

  20. Zee-Cheng RKY, Cheng CC: Antineoplastic agents. Structure-activity relationship study of bis (substituted aminoalkylamino) anthraquinones. J Med Chem 21: 291–294, 1978

    Google Scholar 

  21. Fujimoto S, Ogawa M: Antitumor activity of mitoxantrone against murine experimental tumors: Comparative analysis against various antitumor antibiotics. Cancer Chemother Pharmacol 8:157–162, 1980

    Google Scholar 

  22. Durr FE, Wallace RE: Comparison of the antitumor activity of CL 232, 315, a novel aminoanthraquinone, with standard anticancer agents. Current Chemother and Inf Dis 2:1595–1596, 1980

    Google Scholar 

  23. Corbett TH, Griswold DP: Chemotherapy of transplantable mouse colon tumors. Proc Am Assoc Cancer Res 21:270, 1980

    Google Scholar 

  24. Bailey M, Raghavan D, Shorthouse A: The response to chemotherapy of human breast tumor xenografts. Proc Am Assoc Cancer Res 21:265, 1980

    Google Scholar 

  25. Kharasch ED, Novak RF: Inhibition of Adriamycin-stimulated microsomal lipid peroxidation by mitoxantrone and ametantrone, two new anthracenedione antineoplastic agents. Biochem Biophys Res Commun 108:1346–1352, 1982

    Google Scholar 

  26. Minnaugh EG, Trush MA, Ginsburg E, Gram TE: Differential effects of anthracycline drugs on rat heart and liver microsomal reduced nicotinamide adenine dinucleotide phosphate-dependent lipid peroxidation. Cancer Res 42:3574–3582, 1982

    Google Scholar 

  27. Billingham ME, Mason JW, Bristow MR, Daniels JR: Anthracycline cardiomyopathy monitored by morphologic changes. Cancer Treat Rep 62:865–872, 1978

    Google Scholar 

  28. Henderson BM, Dougherty WJ, James VC, Tilley LP, Noble JF: Safety assessment of a new anticancer compound, mitoxantrone, in beagle dogs: Comparison with doxorubicin. I. Clinical observations. Cancer Treat Rep 66:1139–1143, 1982

    Google Scholar 

  29. Sparano BM, Gordon G, Hall C, Iatropoulos MJ, Noble JF: Safety assessment of a new anticancer compound mitoxantrone, in beagle dogs: Comparison with doxorubicin. II. Histologic and ultrastructural pathology. Cancer Treat Rep 66:1145–1158, 1982

    Google Scholar 

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Authors and Affiliations

  1. Infectious and Neoplastic Disease Research Section, Medical Research Division, Lederle Laboratories, American Cyanamid Company, Pearl River, NY, U.S.A.

    Richard J. White & Frederick E. Durr

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  1. Richard J. White
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  2. Frederick E. Durr
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White, R.J., Durr, F.E. Development of mitoxantrone. Invest New Drugs 3, 85–93 (1985). https://doi.org/10.1007/BF00174154

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