Mafosfamide — A Derivative of 4-Hydroxycyclophosphamide

  • Ulf Niemeyer
  • Jürgen Engel
  • Peter Hilgard
  • Manfred Peukert
  • Jörg Pohl
  • Herbert Sindermann
Part of the Progress in Clinical Biochemistry and Medicine book series (PCBM, volume 9)


The chemical development of mafosfamide (MA)-L-lysine salt as a “stabilized” prodrug of 4-hydroxyCP, i.e. the solid-state unstable primary metabolite of the anticancer drug cyclophosphamide (CP), involved a stereoselective synthesis and an optimized cation exchange with subsequent lyophilization. The stereochemical and physicochemical characterization of MA elucidated further the complex metabolic behavior of oxazaphosphorine cytostatics and confirmed imino-CP as a transient primary intermediate.


Autologous Bone Marrow Transplantation Ehrlich Ascites Tumor Cell Phosphoramide Mustard Subsequent Lyophilization Strong Acid Cation Exchange Resin 
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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  1. 1.
    Brock N (1983) Oxazaphosphorine cytostatics: structure-activity relationships, selectivity and metabolism, regional detoxification. In Reinhoudt DN, Connors TA, Pinedo HM, van de Poll KW (eds) Structure-activity relationships of anti-tumor agents. Developments in pharmacology 3; Martinus Nijhoff, The Hague, p 239CrossRefGoogle Scholar
  2. 2.
    Brock N., Hohorst H-J (1963) Arzneim.-Forsch./Drugs Res. 13: 1021Google Scholar
  3. 3.
    Hohorst H-J, Ziemann A., Brock N (1971) Arzneim.-Forsch./Drug Res. 21: 1254Google Scholar
  4. 4.
    Brock N, Hohorst H-J (1977) Z. Krebsforsch. 88: 185CrossRefGoogle Scholar
  5. 5.
    Brock N, Stekar J, Pohl J, Niemeyer U, Scheffler G (1979) Arzneim.-Forsch./Drug Res. 29: 659Google Scholar
  6. 6.
    Brock N (1980) New experience with the oxazaphosphorines with special reference to the uro-protector Uromitexan. In: Burkert H, Nagel GA (eds) Contributions to Oncology 5; S. Karger, Basel, p 1Google Scholar
  7. 7.
    Borch RF, Hoye TR, Swanson TA (1984) J. Med. Chem. 27: 490CrossRefGoogle Scholar
  8. 8.
    Voelcker G., Draeger U, Peter G, Hohorst H-J (1974) Arzneim.-Forsch./Drug Res. 24: 1172Google Scholar
  9. 9.
    Friedman OM, Myles A, Colvin M (1979) Cyclophosphamide and related phosphoramide mustards: current status and future prospects. In: Rosowsky A (ed) Advances in Cancer Chemother., Dekker, New York, p 143Google Scholar
  10. 10.
    Friedman OM (1967) Cancer Chemother. Rep 51: 347Google Scholar
  11. 11.
    Engle TW, Zon G, Egan W (1979) J. Med. Chem. 22: 897CrossRefGoogle Scholar
  12. 12.
    Grunicke H, Doppler W, Hofmann J, Lindner H, Maly K, Oberhuber H, Ringsdorf H, Roberts JJ (1986) Advances in Enzyme Regul. 24: 247CrossRefGoogle Scholar
  13. 13.
    Wrabetz E, Peter G, Hohorst H-J (1980) J. Cancer Res. Clin. Oncol. 98: 119CrossRefGoogle Scholar
  14. 14.
    Watson E, Phoebe D, Chan KK (1985) J. Pharm. Sci. 74: 1283CrossRefGoogle Scholar
  15. 15.
    Draeger U, Hohorst H-J (1976) Cancer Treat. Rep. 60: 423Google Scholar
  16. 16.
    Lenssen U, Hohorst H-J (1979) J. Cancer Res. Clin. Oncol. 93: 161CrossRefGoogle Scholar
  17. 17.
    Boyd VL, Robbins JD, Egan W, Ludeman SM (1986) J. Med. Chem. 29: 1206CrossRefGoogle Scholar
  18. 18.
    Zon G, Ludeman SM, Sweet EM, Egan W, Phillips LR (1982) J. Pharm. Sci. 71: 443CrossRefGoogle Scholar
  19. 19.
    Sladek NE (1973) Cancer Res. 33: 651Google Scholar
  20. 20.
    Zon G, Ludeman SM, Brandt JA, Boyd VL, Özkan G, Egan W (1984) J. Med. Chem. 27: 466CrossRefGoogle Scholar
  21. 21.
    Borch RF, Gutman KM (1984) J. Med. Chem. 27: 485CrossRefGoogle Scholar
  22. 22.
    Draeger U, Peter G, Hohorst H-J (1976) Cancer Treat. Rep. 60: 355Google Scholar
  23. 23.
    Low JE, Borch RF, Sladek NE (1983) Cancer Res. 43: 4815Google Scholar
  24. 24.
    Bielicki L., Voelcker G, Hohorst H-J (1984) J. Cancer Res. Clin. Oncol. 107: 195CrossRefGoogle Scholar
  25. 25.
    Connors TA, Cox PJ, Farmer PB, Foster AB, Jarman M (1974) Biochem. Pharmacol. 23: 115CrossRefGoogle Scholar
  26. 26.
    Brock N, Stekar J, Pohl J, Scheef W (1979) Naturwissenschaften 66: 60CrossRefGoogle Scholar
  27. 27.
    Scheef W, Klein HO, Brock N, Burkert H, Günther U, Hoefer-Janker H, Mitrenga D, Schnitker J, Voigtmann R (1979) Cancer Treat. Rep. 63: 501Google Scholar
  28. 28.
    Brock N, Hilgard P, Pohl J, Ormstad K, Orrenius S (1984) J. Cancer Res. Clin. Oncol. 108: 87CrossRefGoogle Scholar
  29. 29.
    Cox PJ (1979) Eur. J. Cancer 15: 1071CrossRefGoogle Scholar
  30. 30.
    Brock N (1986) J. Cancer Res. Clin. Oncol. 111: 1CrossRefGoogle Scholar
  31. 31.
    Peter G, Hohorst H-J (1979) Cancer Chemother. Pharmacol. 3: 181Google Scholar
  32. 32.
    Ramonas LM, Erickson LC, Ringsdorf H, Zaharko DS (1980) Cancer Res. 40: 3704Google Scholar
  33. 33.
    Takamizawa A, Matsumoto S, Iwata T, Kentagiri K, Tochino Y, Yamaguchi K (1973) J. Amer. Chem. Soc. 95: 985CrossRefGoogle Scholar
  34. 34.
    Peter G, Wagner T, Hohorst H-J (1976) Cancer Treat. Rep. 60: 429Google Scholar
  35. 35.
    Niemeyer U, Engel J, Scheffler G, Molge K, Sauerbier D, Weigert W (1984) Invest. New Drugs 2: 133CrossRefGoogle Scholar
  36. 36.
    Niemeyer U, Engel J, Scheffler G, Pohl J, Hägele G, Krebs B (1987) Phosphorus and Sulphur 30: 585Google Scholar
  37. 37.
    White DW, Gibbs DE, Verkade JG (1979) J. Amer. Chem. Soc. 101: 1937CrossRefGoogle Scholar
  38. 38.
    Setzer WN, Sopchick AE, Bentrude WG (1985) J. Amer. Chem. Soc. 107: 2083CrossRefGoogle Scholar
  39. 39.
    Domeyer BE, Sladek NE (1980) Biochem. Pharmacol: 29: 2903Google Scholar
  40. 40.
    Molge K (1983) Characterization of the hydrolysis of mafosfamide. ASTA Pharma AG, Research Report no. 53Google Scholar
  41. 41.
    Kwon C-H, Borch RF, Engel J, Niemeyer U (1987) J. Med. Chem. 30: 395CrossRefGoogle Scholar
  42. 42.
    Niemeyer U, Engel J, Meyer zur Heyde M, Molge K, Wolf-Heuss E (1987) International Symposium on pharmaceutical and biomedical analysis, Barcelona, p 244Google Scholar
  43. 43.
    Niemeyer U (1978) TLC-determination of mafosfamide and metabolites in urine samples. ASTA Pharma AGGoogle Scholar
  44. 44.
    Pohl J, Hilgard P, Jahn W, Zechel H-J (1984) Invest. New Drugs 2: 201CrossRefGoogle Scholar
  45. 45.
    Manz I, Dietrich I, Przybylski M, Niemeyer U, Pohl J, Hilgard P, Brock N (1985) Biomed. Mass Spectrometry 12: 545CrossRefGoogle Scholar
  46. 46.
    Ludeman SM (1986) Personal communicationGoogle Scholar
  47. 47.
    Burton LC, Harper PG, James CA, Rogers HJ, Liang R (1985) The clinical trial and pharmacokinetics of 4-hydroxycyclophosphamide and mesna derived from mafosfamide (ASTA Z 7557) and its comparison with other oxazaphosphorines in man. Report to Cancer Research CampaignGoogle Scholar
  48. 48.
    Osieka R, Pannenbächer R, Schmidt CG (1984) Invest. New Drugs 2: 161CrossRefGoogle Scholar
  49. 49.
    Berger MR, Bedford P, Zeller WJ, Kaufmann M (1984) Invest. New Drugs 2: 181CrossRefGoogle Scholar
  50. 50.
    Huang AT, Kremer WB, Laszlo J, Setlow RB (1972) Nature New Biol. 240: 114Google Scholar
  51. 51.
    Grunicke H, Gruenwald K, Heiliger W, Scheidl F, Wolf-Schreiner E, Puschendorf B (1983) Adv. in Enzyme Regul. 21: 21CrossRefGoogle Scholar
  52. 52.
    Askenase PW, Hayden BJ, Gershon RK (1975) J. Exp. Med. 141: 697CrossRefGoogle Scholar
  53. 53.
    L’Age-Stehr J, Diamantstein T (1978) Nature 271: 663CrossRefGoogle Scholar
  54. 54.
    Brock N, Niemeyer U, Pohl J, Scheffler G (1981) Third NCI-EORTC symposium on new drugs in cancer therapy, No. 47, BrusselsGoogle Scholar
  55. 55.
    Pohl J (1984) Mafosfamide - Summary for Investigators. Asta Pharma AGGoogle Scholar
  56. 56.
    Atassi G, Hilgard P, Pohl J (1984) Invest. New Drugs 2: 169CrossRefGoogle Scholar
  57. 57.
    Brock N, Hilgard P, Peukert M, Pohl J, Sindermann H (1989) Cancer Invest.Google Scholar
  58. 58.
    Klein HO, Wickramanayake PD, Christian E, Coerper C (1984) Invest. New Drugs 2: 191CrossRefGoogle Scholar
  59. 59.
    Zeller WJ, Berger MR, Matys R, Schumacher J (1984) Invest. New Drugs 2: 175CrossRefGoogle Scholar
  60. 60.
    Kleine W, Düser B, Runge M, Grezes IR, Kröger H, Klosa J (1984) J. Cancer Res. Clin. Oncol. 107: 80Google Scholar
  61. 61.
    Osieka R, Glatte P, Bamberg M, Scherer E, Schmidt CG (1984) Proc. Am. Ass. Canc. Res. 25: 330Google Scholar
  62. 62.
    Nowrousian MR, Schmidt CG (1984) Invest. New Drugs 2: 207CrossRefGoogle Scholar
  63. 63.
    Hilgard P, Pohl J (1986) Invest. New Drugs 4: 373CrossRefGoogle Scholar
  64. 64.
    Bruntsch U, Groos G, Hiller TA, Wandt H, Tigges FJ, Gallmeier WM (1985) Invest. New Drugs 3: 297CrossRefGoogle Scholar
  65. 65.
    Bruntsch U, Groos U, Hiller TA, Wandt H, Tigges FJ, Gallmeier WM (1984) Cancer Immunol. Immunother. 18: 11Google Scholar
  66. 66.
    Abele R, Aapro MS, Haeflinger JM, Alberto P (1986) Cancer Chemother. Pharmacol. 16: 182Google Scholar
  67. 67.
    Peukert M (1984) Preliminary clinical evaluation of mafosfamide. ASTA Pharma AGGoogle Scholar
  68. 68.
    Peukert M (1985) Phase-I studies with mafosfamide. ASTA Pharma AGGoogle Scholar
  69. 69.
    Voelcker G, Laber P, Rockinger H, Wientzek C, Hohorst HJ (1984) Invest. New Drugs 2: 253CrossRefGoogle Scholar
  70. 70.
    Friedl P, Berger MR, Rozycki-Gerlach W, Schlag P, Schmähl D (1988) J. Cancer Clin. Res. Oncol. 114, Suppl. S 187Google Scholar
  71. 71.
    Bartkowski R, Berger MR, Aguiar JLA, Henne TH, Dörsam J, Geelhaar GH, Schlag P, Herfarth C (1986) J. Cancer Res. Clin. Oncol. 111:.42Google Scholar
  72. 72.
    Wagner T, Walter E, Mittendorf F, Voelcker G (1984) J. Cancer Res. Clin. Oncol. 107: 46Google Scholar
  73. 73.
    Hamburger AW, Salmon SE (1977) Science 197: 461CrossRefGoogle Scholar
  74. 74.
    Alberts DC, Einspahr JG, Struck R, Bignami G, Young L, Surwit EA, Salmon SE (1984) Invest. New Drugs 2: 141CrossRefGoogle Scholar
  75. 75.
    Einspahr J, Alberts DS, Struck R, Salmon SE (1984) Proc. Am. Soc. Clin. Oncol. 25: 38Google Scholar
  76. 76.
    Kaufmann M (1986) Personal communicationGoogle Scholar
  77. 77.
    Buse KD, Kaufmann M, Kubli F (1985) Der biochemische Kurzzeit-Inkubations-Assay zur In-vitro Chemoresistenztestung und als Prognosefaktor bei menschlichen Tumoren. In: Jonat W, Kaufmann M, Kubli F et al. (eds) Aktuelle Onkologie 16, Zuckerschwerdt, MünchenGoogle Scholar
  78. 78.
    Sharkis SJ, Santos GW, Colvin M (1980) Blood 55: 521Google Scholar
  79. 79.
    Körbling M, Hess AD, Tutschka PJ, Kaizer H, Colvin M, Santos GW (1982) Brit. J. Hematol. 52: 89CrossRefGoogle Scholar
  80. 80.
    Kohn FR, Sladek NE (1984) Proc. Am. Ass. Canc. Res. 25: 289Google Scholar
  81. 81.
    Aglietta M, Stacchini A, Sanavio F, Piacibello W, Gavosto F (1987) Bone Marrow Transpl. 2: 56Google Scholar
  82. 82.
    Douay L, Gorin NC, Laporte J-P, Lopez M, Najman A, Duhamel G (1984) Invest. New Drugs 2: 187CrossRefGoogle Scholar
  83. 83.
    Hagenbeek A, Martens ACM (1984) Invest. New Drugs 2: 237CrossRefGoogle Scholar
  84. 84.
    Hervé P, Cahn JY, Plouvier E, Flesch M, Tamayo E, Leconte des Floris R, Peters A (1984) Invest. New Drugs 2: 245Google Scholar
  85. 85.
    Hervé P, Tamayo E, Cahn W, Plouvier E, Flesch M, Peters A (1986) Attempts to eliminate residual acute myeloid leukemia from autologous bone marrow grafts through in vitro chemotherapy - a review. In: Hagenbeck A, Loewenberg B (eds) Minimal residual disease in leukemia, Martinus Nijhoff, Dordrecht, p 248CrossRefGoogle Scholar
  86. 86.
    Hervé P, Plouvier E, Amsallen D, Racadot E, Noir A (1987) Bone Marrow Transpl. 2: 53Google Scholar
  87. 87.
    LeBien TW, Anderson JM, Vallera A, Uckun FM (1986) Leukemia Res. 10: 139CrossRefGoogle Scholar
  88. 88.
    Uckun FM, Ramakrishnan S, Houston LL (1985) Blood 50: 19Google Scholar
  89. 89.
    Uckun FM, Ramakrishnan S, Haag D, Houston LL (1985) Leukemia Res. 9: 83CrossRefGoogle Scholar
  90. 90.
    Uckun FM, Stong RC, Youle RJ, Vallera DA (1985) J. Immunol. 134: 3504Google Scholar
  91. 91.
    Porcellini A, Marchetti Rossi MT, Centis F, Manna A, Talevi N, Agostini A, Pazzaglia C (1987) Bone Marrow Transpl. 2: 52Google Scholar
  92. 92.
    Flesch M, Hervé P (1985) Blood Transfus. Immunohaemat. 28: 489CrossRefGoogle Scholar
  93. 93.
    Rizzoli V, Mangoni L, Carella AM, Torlontano G, Aglietta M, Mozana R, Porcellini A, Cole-selli P (1987) Exp. Hemat. Today (in press)Google Scholar
  94. 94.
    Gorin NC, Aegerter P (1987) Bone Marrow Transpl. 2: 320Google Scholar
  95. 95.
    Körbling M, Ho A, Dörken B, Haas R, Pezzutto A, Martin H, Deboben A, Reichardt P, Tischbirek K, Mende U, Fehrentz D, Hunstein W (1987) Bone Marrow Transpl. 2: 62Google Scholar
  96. 96.
    Laporte JP, Gorin NC, Douay L, Lopez M, Bauters F, Jouet JP, Walter MP, Lemonnier MP, Salmon C, Najman A (1987) Bone Marrow Transpl. 2: 61Google Scholar
  97. 97.
    Gorin NC, Hervé P, Aegerter P, Goldstone A, Linch D, Maraninchi D, Burnett A, Helbig W (1986) Brit. J. Haematol. 64: 385CrossRefGoogle Scholar
  98. 98.
    Potei J, Brock N (1971) Arzneim.-Forsch./Drug Res. 21: 1250Google Scholar
  99. 99.
    Scheper RJ, Vos A, de Groot J, Boerrigter GH (1984) Invest. New Drugs 2: 221CrossRefGoogle Scholar
  100. 100.
    Mitsuoka A, Baba M, Morikawa S (1976) Nature 262: 77CrossRefGoogle Scholar
  101. 101.
    Turk JL, Parker D: The effect of drugs on immunological control mechanisms. In: Turk JL, Parker D (eds) Drugs and immune responsiveness, Macmillan, London, p 73Google Scholar
  102. 102.
    Ozer H, Cowens JW, Nussbaum A, Mihich E, Colvin M (1981) Fed. Proc. 40: 1075Google Scholar
  103. 103.
    Brock N (1978) Pharmakologische Grundlagen der Krebs-Chemotherapie. In: Georgii A (ed) Verhandlungen der Deutschen Krebsgesellschaft. Band 1, 13. Deutscher Krebskongreß Hamburg 1976. Gustav Fischer, Stuttgart, p 15Google Scholar
  104. 104.
    Hilgard P, Pohl J, Stekar J, Voegeli R (1985) Cancer Treatm. Rev. 12, 155Google Scholar
  105. 105.
    Cowens JW, Ozer H, Ehrke J, Colvin M, Mihich E (1981) Fed. Proc. 40: 1086Google Scholar
  106. 106.
    Berd D, Mastrangelo MJ, Engstrom PF, Paul A, Maguire H (1982) Cancer Res. 42: 4862Google Scholar
  107. 107.
    Duclos H, Galanaud P, Devinsky O, Maillot MC, Dormont J (1977) Eur. J. Immunol. 7: 679CrossRefGoogle Scholar
  108. 108.
    Hengst JCD, Mokyr MB, Dray S (1980) Cancer Res. 40: 2135Google Scholar
  109. 109.
    Mokyr MB, Hengst JC, Dray S (1982) Cancer Res. 42: 974Google Scholar
  110. 110.
    Voegeli R, Pohl J, Reissmann T, Stekar J, Hilgard P (1986) Therapeutic efficacy of oxazaphosphorines by immunomodulation. In: Chandra P (ed) New Experimental modalities in the control of neoplasia. Plenum, p 243Google Scholar
  111. 111.
    Mokyr MB, Brundrett RB, Colvin M, Dray S (1986) Cancer Res. 46: 3313Google Scholar
  112. 112.
    Klein HO, Kreysch H-G, Coerper C, Voigt P, Ruff I (1987) Meth. and Find. Exptl. Clin. Pharmacol. 9: 627Google Scholar
  113. 113.
    Klein HO, Kreysch H-G, Coerper C, Voigt P (1988) J. Cancer Res. Clin. Oncol. 114,’Suppl. S 126Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1989

Authors and Affiliations

  • Ulf Niemeyer
    • 1
  • Jürgen Engel
    • 1
  • Peter Hilgard
    • 1
  • Manfred Peukert
    • 1
  • Jörg Pohl
    • 1
  • Herbert Sindermann
    • 1
  1. 1.ASTA Pharma AGBielefeld 14Germany

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