Skip to main content
SpringerLink
Log in

Lymphocyte deactivation by (potential immunosuppressant) alkylating metabolites of cyclophosphamide

  • Immunosuppression and Inflammation
  • Published:
Agents and Actions Aims and scope Submit manuscript

Summary

The potential immunosuppressant activity of the following compounds derived from cyclophosphamide (CPA) was evaluated: 8 known metabolites, oxidation products and hydrolytic products of CPA containing the mustard moiety; the mixture of alkylating products formed from CPA by chemical and biological oxidation in vitro; acrolein. Mechlorethamine (HN2) and mannomustine were included in this survey as reference compounds.

Drug action on lymphoid cells was assayed by ability to block/prevent 2 immunological diseases in rats (GvHR, EAE), GvHR in mice, and the mitogen response of human peripheral lymphocytes. These drug activities of the mustards and CPA derivatives are compared with their toxic/cytostatic and lipophilic properties.

It is proposed that some of the more hydrophilic mustards and CPA metabolites may deactivate lymphocytes through an exoalkylating action upon the cell surface — possibly reacting with membrane-associated DNA —exemplifying the concept of a cell surface poison or ‘ZOG’.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. P.Y. Paterson, M.A. Hanson andE.W. Gerner,Cyclophosphamide Inhibition of Experimental Allergic Encephalomyelitis in Wistar Rats, Proc. Soc. Exp. Biol.124, 928–932 (1967).

    Google Scholar 

  2. M.E. Rosenthale, L.J. Datko, J. Kasserich andF. Schneider,Chemotherapy of Experimental Allergic Encephalomyelitis (EAE), Arch. int. Pharmacodyn. Ther.179, 251–275 (1969).

    PubMed  Google Scholar 

  3. J.H. Brown, N.L. Schwartz, H.L. Mackey andH.L. Murray,Prophylactic Effects of Cyclophosphamide in Adjuvant — Induced Arthritis, Arch. int. Pharmacodyn. Ther.183, 1–11 (1970).

    PubMed  Google Scholar 

  4. P.Y. Paterson andD.G. Drobish,Cyclophosphamide Effect on Experimental Allergic Encephalomyelitis in Lewis Rats, Science165, 191–192 (1969).

    PubMed  Google Scholar 

  5. R.F. Struck, M.C. Kirk, L.B. Mellett, S. ElDareer andD.L. Hill,Urinary Metabolites of the Antitumor Agent Cyclophosphamide, Molec. Pharmac.7, 519–529 (1971).

    Google Scholar 

  6. J.E. Bakke, V.J. Feil, C.E. Fjelstul andE.J. Thacker,Metabolism of Cyclophosphamide by Sheep, Agr. Food Chem.20, 384–388 (1972).

    Article  Google Scholar 

  7. A. Takamizawa, Y. Tochino, Y. Hamashima andT. Iwata,Studies on Cyclophosphamide Metabolites and Their Related Compounds, I., Chem. Pharm. Bull. (Tokyo)20, 1612–1616 (1972).

    Google Scholar 

  8. N.L. Sladek,Evidence for an Aldehyde Possessing Alkylating Activity as a Primary Cytotoxic Metabolite of Cyclophosphamide, Cancer Res.33, 651–658 (1973).

    PubMed  Google Scholar 

  9. D.L. Hill, W.R. Laster, Jr., andR.F. Struck,Enzymatic Metabolism of Cyclophosphamide and Nicotine and Production of a Toxic Cyclophosphamide Metabolite, Cancer Res.32 658–665 (1972).

    PubMed  Google Scholar 

  10. R.F. Struck, unpublished results.

  11. R.A. Alarcon andJ. Meienhofer,Formation of a Cytotoxic Aldehyde Acrolein During ‘in vitro’ Degradation of Cyclophosphamide, Nature New Biol.233, 250–252 (1971).

    Google Scholar 

  12. D.L. Hill, M.C. Kirk andR.F. Struck,Isolation and Identification of 4-Ketocyclophosphamide, a Possible Active Form of the Antitumor Agent Cyclophosphamide, J. Am. Chem. Soc.92, 3207–3208 (1970).

    Article  PubMed  Google Scholar 

  13. O.M. Friedman, H. Sommer andG.E. Foley,Activities of Cytoxan-Related Compounds in vitro and in vivo, Proc. Am. Assoc. Cancer Res.,3, 226 (Abs.) (1961).

    Google Scholar 

  14. H. Arnold andF. Bourseaux,Synthese des N, N-Bis-(2-chloräthyl-0-(3-amino-propyl)-phosphorsäureamidoesters, Arzneimittel-Forsch.13, 927–928 (1963).

    Google Scholar 

  15. H.M. Rauen andU. Dirschka,Bis-(β-chloräthyl)-amin und N-β-Chloräthylaziridin als Folgeprodukte der biologischen Aktivierung von Cyclophosphamid, Arzneimittel.-Forsch.14, 159 (1964).

    Google Scholar 

  16. M.W. Whitehouse, M.M. Dröge andR.F. Struck,Lymphocyte Deactivation by Cyclophosphamide Metabolites and Mammomustine, Proc. W. Pharmacol. Soc.15, 195–199 (1972).

    Google Scholar 

  17. M.W. Whitehouse, M.M. Dröge andR.F. Struck,Potential Immunosuppressant Activity of Cyclophosphamide Metabolites, Abstr. (No. 1506) V. Int. Pharmac. Congr. San Francisco, p. 251 (1972).

  18. M.W. Whitehouse, L. Levy andF.J. Beck,Effect of Cyclophosphamide on a Local Graft versus Host Reaction in the Rat: Influence of Sex, Disease and Different Dosage Regimen, Agents and Actions3, 53–60 (1973).

    PubMed  Google Scholar 

  19. F.J. Beck andM.W. Whitehouse,Effect of Adjuvant Disease in Rats on Cyclophosphamide and Isophosphamide Metabolism, Biochem. Pharmac.22, 2453–2468 (1973).

    Article  Google Scholar 

  20. L. Levy,A Contribution to the Mechanism of Drug Inhibition of the Graft-versus-Host Reaction, RES: J. Reticuloendothel. Soc.13, 1–6 (1973).

    Google Scholar 

  21. B.B. Newbould,Production of Allergic Encephalomyelitis in Rats by Injection of Spinal Chord Adjuvant into Inguinal Lymph Nodes, Immunology9, 613–614 (1965).

    Google Scholar 

  22. D.T.Y. Yu andM.W. Whitehouse,Effect of some Nitrogen Mustards and Thoracic Duct Drainage on Lymphocyte Distribution in Rats, Int. Arch. Allergy Appl. Immunol. (accepted for publication 1973).

  23. M. Morita, Y. Tochino, T. Iwata andT. Miesita,Studies on Cyclophosphamide, Part II, Ann. Rept. Shionogi Res. Lab.17, 114–121 (1967).

    Google Scholar 

  24. S. Udenfriend, C.T. Clark, J. Axelrod andB.B. Brodie,Ascorbic Acid in Aromatic Hydroxylation, J. Biol. Chem.208, 731–739 (1954).

    PubMed  Google Scholar 

  25. G.A. Hamilton, J.W. Hannifin, Jr., andJ.P. Friedman,The Hydroxylation of Aromatic Compounds of Hydrogen Peroxide in the Presence of Catalytic Amounts of Ferric Ion and Catechol. Product Studies, Mechanism, and Relation to some Enzmic Reactions. J. Am. Chem. Soc.88, 5269–5272 (1966).

    Article  Google Scholar 

  26. F.J. Beck, L. Levy andM.W. Whitehouse,The Local Graft versus Host Reaction in the Rat as a Tool for Drug Mechanism Studies, Br. J. Pharmac.49, 293 (1973).

    Google Scholar 

  27. B.B. Newbould, C.M. Pearson andM.W. Whitehouse,Passive Transfer of Allergic Encephalomyelitis (EAE) in Rats as a Tool for Drug Mechanism Studies and Detecting Late-Acting Immunosuppressants, Br. J. Pharmac. (submitted for publication).

  28. A. Takamizawa, S. Matsumato, T. Iwata, K. Katagiri, Y. Tochino andK. Yamaguchi,Studies on Cyclophosphamide Metabolites and Their Related Compounds. II. Preparation of an Active Species of Cyclophosphamide and Some Related Compounds, J. Am. Chem. Soc.95, 985–986 (1973).

    Article  Google Scholar 

  29. E. Sawicki, T.R. Hauser, T.W. Stanley andW. Ebert,The 3-methyl-2-benzothiazolone Hydrazone Test: Sensitive New Methods for Detection, Rapid Estimation and Determination of Aliphatic aldehydes, Anal. Chem.33, 93–96 (1961).

    Article  Google Scholar 

  30. M.w. Whitehouse, F.J. Beck andA. Kacena,Some (Pharmacological) Properties of Chloracetaldehyde, an Oxidation Product and Potential Metabolite of Cyclophosphamide, Agents and Actions,4, 34 (1974).

    Google Scholar 

  31. R.A. Lerner,Association of DNA with Cytoplasmic Membranes, p. 132 in a chapter entitled ‘Relationship of events at the lymphocyte cell surface to gene expression: approaches to the problem’, in:Contemporary Topics in Immunochemistry, 111–142. (Ed. F. P. Inman; Plenum Press, N.Y. 1972), vol. 1.

    Google Scholar 

  32. M.W. Whitehouse,Some Novel Drugs to Regulate Lymphocytes, in:Rheumatoid Arthritis, Pathogenetic Mechanisms and Consequences in Therapeutics (Eds W. Müller, H.-G. Harwerth and K. Fehr; Academic Press, London, N. Y. 1971), p. 205–207.

    Google Scholar 

  33. M.W. Whitehouse andM.M. Dröge,Cell Surface Poisons (ZOG's) as Potential Immunosuppressive Agents, Pharmacologist13, 236 (1971).

    Google Scholar 

Download references

Author information

Author notes

  1. Michael W. Whitehouse

    Present address: Department of Experimental Pathology, John Curtin School of Medical Research, Australian National University, 2600, Canberra, A.C.T., Australia

Authors and Affiliations

  1. Department of Medicine, University of California School of Medicine, 90024, Los Angeles, California, USA

    Michael W. Whitehouse, Frances W. J. Beck & Marlies M. Dröge

  2. Natural Products Section, Kettering-Meyer Laboratory, the Southern Research Institute, 35205, Birmingham, Alabama, USA

    Robert F. Struck

Authors
  1. Michael W. Whitehouse
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Frances W. J. Beck
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marlies M. Dröge
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert F. Struck
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Whitehouse, M.W., Beck, F.W.J., Dröge, M.M. et al. Lymphocyte deactivation by (potential immunosuppressant) alkylating metabolites of cyclophosphamide. Agents and Actions 4, 117–124 (1974). https://doi.org/10.1007/BF01966821

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01966821

Keywords

Search

Navigation