Summary
Mitoxantrone (MIT) has recently been introduced into cancer therapy as a possible substitute for the structurally related drug, adriamycin (ADR), because it causes less cardiotoxicity and fewer gastrointestinal side effects. However, the dose-limiting toxicity of MIT is pronounced neutropenia. The in vitro hematoxicity of both drugs in granulocyte-macrophage precursor cells (GM-CFCs) was analyzed using drug-exposure schedules analogous to the principles of the in vivo pharmacokinetics of MIT. Bone-marrow and peripheral-blood cells were exposed to 0.075–20 ng/ml MIT or ADR for 5, 20, 60, and 120 min, and for 14 days. The 14-day exposure resulted in Do values of 0.95 and 0.68 ng/ml for bone-marrow and peripheral-blood GM-CFCs subjected to MIT. Exposure to ADR resulted in Do values of 5.43 and 5.13 ng/ml, respectively. As was the case after 14-day exposure to MIT or ADR, short-term exposure again revealed that peripheral-blood GM-CFCs were more sensitive to both drugs. Moreover, at low concentrations, ADR was less toxic than MIT in both types of GM-CFCs, but was more toxic than MIT when a concentration of 20 ng/ml was used. The intracellular concentration of MIT, as measured by high-performance liquid chromatography, was constantly below 1 ng per 2×107 cells, even when it was applied at a concentration of 20 ng/ml for an exposure time of 2 h. The fact that such low concentrations of MIT are toxic for hemopoietic precursor cells may explain the myelotoxicity of this drug. However, the difference between the precursor-cell toxicity of MIT and that of ADR was small when their respective therapeutic doses were taken into consideration. Further analyses of their toxicity in stem cells and/or the microenvironment would appear to be needed.
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Alberts DS, Griffith KS, Goodman GE, Herman TS, Murray E (1980) Phase I clinical trial of mitoxantrone: A new anthracenedione anticancer drug. Cancer Chemother Pharmacol 5: 11
Alberts DS, Peng YP, Leigh S, Davis TP, Woodward DL (1983) Disposition of mitoxantrone in patients. Cancer Treat Rev 10 (Suppl B): 23
Andersson KC, Garnick MB, Meshad MW, Cohen GI, Pegg WJ, Frei E, Israel M, Modest E, Canellas GP (1983) Phase I trial of mitoxantrone by 24-h continuous infusion Cancer Treat Rep 67: 435
Benjamin RS, Keating MJ, Valdivieso M, McCredie KB, Livingston RA, Burgess MA, Rodriguez V, Bodey GP, Gottlieb JA (1979) Phase I–II study of piperazinedione in adults with solid tumors and acute leukemia. Cancer Treat Rep 63: 939
Chikkappa G, Phillips PG, Brinson P (1982) Differences in the sensitivity of normal human peripheral blood and bone marrow granulocytic-macrophagic and eosinophilic colony forming cells (CFC) to a source of colony stimulating factor. Exp Hematol 10: 852
Coltman CA, McDaniel TM, Balcerzak SP, Morrison FS, von Hoff DD (1983) Mitoxantrone hydrochloride (NSC-310739) in lymphoma. Invest New Drugs 1: 65
Creaven PJ, Madajewicz S, Pendyala L, Mittelman A, Pontis E, Spaulding M, Arbuck S, Solomon J (1983) Phase I clinical trial of cis-dichloro-trans-dihydroxy-bis-isopropylamine platinum (IV) (CHIP). Cancer Treat Rep 67: 795
DiPersio JF, Brennan JK, Lichtman MA, Speiser BL (1978) Human cell lines that elaborate colony-stimulating activity for marrow cells of man and other species. Blood 51: 507
DiPersio JF, Brennan JK, Lichtman MA, Abboud CN, Kirkpatrick FH (1980) The fractionation, characterization, and subcellular localization of colony-stimulating activities released by the human monocyte-like cell line, GCT. Blood 56: 717
Egorin MJ, van Echo DA, Tipping SJ, Olman EA, Whitacre MY, Thompson BW, Aisner J (1984) Pharmacokinetics and damage reduction of cis-diamine(1,1-cyclobutanedicarboxylato)platinum in patients with impaired renal function. Cancer Res 44: 5432
Ehninger G, Weible KH, heidemann EG, Waller HD (1984) Mitoxantrone and cyclophosphamide in patients with advanced breast cancer. Cancer Treat Rep 68: 1283
Ehninger G, Proksch B, Schiller E (1985) Detection and separation of mitoxantrone and its metabolites in plasma and urine by high performance liquid chromatography. J Chromatogr 342: 119
Ehninger G, Proksch B, Heinzel G, Weible KH, Woodward DL (1985) The pharmacokinetics and metabolism of mitoxantrone in man. Invest New Drugs 3: 109
Ehninger G, Ho AD, Meyer P, Mjaaland I, Ostendorf P, Seither E (1985) Mitoxantrone in the treatment of relapsed and refractory acute leukemia. Onkologie 8: 146
Ehninger G, Proksch B, Heinzel G, Woodward DL (1987) Clinical pharmacology of mitoxantrone. Cancer Treat Rep 70: 1373
Estey EH, Keating MJ, McCredie KB, Bodey GP, Freireich EJ (1983) Phase II trial of mitoxantrone in refractory acute leukemia. Cancer Treat Rep 67: 389
Ferrero D, Broxmeyer HE, Pagliardi GL, Venuta S, Lange B, Pessano S, Rovera G (1983) Antigenically distinct subpopulations of myeloid progenitor cells (CFU-GM) in human peripheral blood and marrow. Proc Natl Acid Sci USA 80: 4114
Ho AD, Lipp T, Ehninger, G, Meyer P, Freund M, Hunstein W (1986) Combination therapy with mitoxantrone and etopoxide in refractory acute myelogenous leukemia. Cancer Treat Rep 70: 1025
Johnson RK, Zee-Chung RK-Y, Lee WW, Acton EM, Henry DN, Chen CC (1979) Experimental antitumor activity of aminoanthraquinones. Cancer Treat Rep 63: 425
Mergenthaler HG (1985) Myelolymphopoiesis in long-term bone marrow culture. Klin Wochenschr 63: 337
Metcalf D (1984) Clonal culture of hemopoietic cells: Techniques and applications. Elsevier, Amsterdam
Nathanson L (1984) Mitoxantrone. Cancer Treat Rev 11: 289
OKunewick JP, Buffo MJ, Kociban DL (1985) Comparative toxicity of mitoxantrone and doxorubicin on hematopoietic stem cells. Exp Hematol (Suppl 16) 13: 23
Paciucci PA, Ohnuma T, Cuttner J, Silvers RT, Holland JF (1983) Mitoxantrone in patients with acute leukemia in relapse. Cancer Res 42: 3919
Schabel FM, Corbett TH, Griswold DP, Laster WR, Trader MW (1983) Therapeutic activity of mitoxantrone and ametantrone against murine tumors. Cancer Treat Rep 10 (Suppl B): 13
Shenkenberg TD, von Hoff DD (1986) Mitoxantrone: A new anticancer drug with significant clinical activity. Ann Int Med 105: 67
Stewart JA, McCormack JJ, Karkoff IH (1982) Clinical and clinical pharmacologic studies of mitoxantrone. Cancer Treat Rep 66: 1327
Stuart-Harris RC, Bozek T, Pavlidis NA, Smith IE (1984) Mitoxantrone: An active new agent in the treatment of advanced breast cancer. Cancer Chemother Pharmacol 12: 1
Tebbi K, Rubin S, Cowan DH, McCulloch EA (1976) A comparison of granulopoiesis in culture from blood and marrow cells of nonleukemic individuals and patients with acute leukemia. Blood 48: 235
Von Hoff DD, Pollard E, Kuhn J, Murray E, Coltman CA Jr (1980) Phase I clinical investigation of 1,4-dihydroxy-5,8-bis (((2-((2-hydroxyethyl)amino)ethyl)amino))-9,10-anthracenedione dihydrochloride (NSC 301739), a new anthracenedione. Cancer Res 40: 1516
Wynert WR, Harvey HA, Lipton A, Schweitzer J, White DS (1982) Phase I study of a 5-day schedule of mitoxantrone (dihydroxyanthracenedione). Cancer Treat Rep 66: 1303
Yap HY, Esparza L, Blumenschein GR, Hortobagyi GN, Bodey GP (1983) Combination chemotherapy with cyclophosphamide, mitoxantrone, and 5-fluorouracil in patients with metastatic breast cancer. Cancer Treat Rep 10 (Suppl B): 53
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Mergenthaler, HG., Brühl, P., Ehninger, G. et al. Comparative in vitro toxicity of mitoxanatrone and adriamycin in human granulocyte-macrophage progenitor cells. Cancer Chemother. Pharmacol. 20, 8–12 (1987). https://doi.org/10.1007/BF00252951
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DOI: https://doi.org/10.1007/BF00252951