Yeast as a Model for Studying DNA-Alterations and Biological Response Induced by Alkylating Anti-Cancer Drugs: Effects of Cyclophosphamide

  • Reinhard Fleer
  • Martin Brendel
Part of the NATO Advanced Study Institutes Series book series (NSSA, volume 40)


Activated cyclophosphamide (CP) induces DNA interstrand cross-links and DNA strand-breakage in the chromosomes of yeast. In contrast to the post-incubation reaction of other polyfunctional alkylating agents, a further increase of cross-links after treatment with activated CP was hardly detectable. This is possibly due to the observed continued DNA fragmentation which decreases the sensitivity of the cross-link assay. Cell killing by non-activated CP depends on the function of DNA repair as well as on the mode of cellular energy metabolism. At concentrations 1000-fold higher than those used for activated CP it induces DNA single- as well as double-strand breaks. In contrast, no induction of interstrand cross-links could be detected.


Nitrogen Mustard Cellular Energy Metabolism Yeast Chromosome Phosphoramide Mustard Neutral Sucrose Gradient 
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  1. 1.
    A. Ruhland, R. Fleer, and M. Brendel, Genetic activity of chemicals in yeast: DNA alterations and mutations induced by alkylating anti-cancer agents, Mutat.Res., 58: 241 (1978)PubMedCrossRefGoogle Scholar
  2. 2.
    R. Fleer and M.Brendel, Formation and fate of cross-links induced by polyfunctional anticancer drugs in yeast, Molec.gen.Genet., 176: 41 (1979)PubMedCrossRefGoogle Scholar
  3. 3.
    R. H. Haynes, B. J. Barclay, F. Eckhardt, O. Landman, B. Kunz, and J. G. Little, Genetic control of DNA repair in yeast, in: “Proc.XIV.Internat.Congr.Genetics”, Moscow (USSR)(1978)in pressGoogle Scholar
  4. 4.
    A. Ruhland and M. Brendel, Mutagenesis by cytostatic alkylating agents in yeast strains of differing repair capacities, Genetics, 92: 83 (1979)PubMedGoogle Scholar
  5. 5.
    M. Kircher, R. Fleer, A. Ruhland, and M. Brendel, Biological and chemical effects of mustard gas in yeast, Mutat.Res., 63: 273 (1979)PubMedCrossRefGoogle Scholar
  6. 6.
    D. L. Hill,“A review of cyclophosphamide”,Charles C. Thomas, Springfield (1975)Google Scholar
  7. 7.
    O. M. Friedman, A. Myles, and M. Colvin, Cyclophosphamide and related phosphoramide mustards, in: “Advances in Cancer Chemotherapy”, A. Rosowsky, ed., Dekker, New York, Basel (. 1979 )Google Scholar
  8. 8.
    N. Brock, and H. J. Hohorst, Ober die Aktivierung von Cyclophosphamid in vivo und vitro, Arzneim.Forsch.(Drug Res.), 13: 1021 (1963)Google Scholar
  9. 9.
    H. J. Hohorst, U. Draeger, G. Peter, and G. Voelcker: The problem of oncostatic specificity of cyclophosphamide (NSC-26271): Studies on reactions that control the alkylating and cytotoxic activity, Cancer Treat.Rep., 60: 309 (1976)PubMedGoogle Scholar
  10. 10.
    G. P. Wheeler, and J. A. Alexander, Studies with mustards. V. In vivo fixation of C14 of labeled alkylating agents by bilaterally grown sensitive and resistant tumors, Cancer Res., 24:1331 (1964)Google Scholar
  11. 11.
    E. G. Trams, M. V. Nadkarni, and P. K. Smith, On the mechanisms of action of the alkylating agents. I. Interaction of alkylating agents with nucleic acids, Cancer Res., 21: 560 (1961)Google Scholar
  12. 12.
    E. Liss, H. Schmidt, E. Schaumlöffel, and G. Palme, Alkylierung der DNA verschiedener Tumorzellarten nach in vivo Gabe von Cyclophosphamid, Z. Krebsforsch.Klin.Onkol., 80: 239 (1973)Google Scholar
  13. 13.
    P. D. Lawley, J. H. Lethbridge, P. A. Edwards, and K. V. Shooter, Inactivation of bacteriophage T7 by mono-and difunctional sulphur mustards in relation to cross-linking and depurination of bacteriophage DNA, J.Mol.Biol., 39: 181 (1969)PubMedCrossRefGoogle Scholar
  14. 14.
    P. J. Cox, B. J. Phillips, and P. Thomas, Studies on the selective action of cyclophosphamide (NSC-26271): Inactivation of the hydroxylated metabolite by tissue-soluble enzymes, Cancer Treat.Rep., 60: 321 (1976)PubMedGoogle Scholar
  15. 15.
    R. S. Cole, Inactivation of E.coli and bacteriophage lambda by psoralen plus 360 nm-light. Significance of DNA-crosslinks, J.Bacteriol., 107: 846 (1971)PubMedGoogle Scholar
  16. 16.
    G. Voelcker, U. Dräger, G. Peter, and H. J. Hohorst: Studien zum Spontanzerfall von 4-Hydroxycyclophosphamid und 4-Hydroperoxycyclophosphamid mit Hilfe der Dünnschichtchromatographie, Arzneim.Forsch.(Drug Res.), 24: 1172 (1974)Google Scholar
  17. 17.
    I. Jardine, C. Feselau, M. Appler, M.-N. Kan, R. B. Brundrett, and M. Colvin, Quantitation by gas chromatography - chemical ionization mass spectrometry of cyclophosphamide, phosphor-amide mustard, and nor-nitrogen mustard in the plasma and urine of patients receiving cyclophosphamide therapy, Cancer Res., 38: 408 (1978)Google Scholar
  18. 18.
    W. E. Ross, R. A. G. Ewig, and K. W. Kohn, Differences between melphalan and nitrogen mustard in the formation and removal of DNA cross-links, Cancer Res., 38: 1502 (1978)PubMedGoogle Scholar
  19. 19.
    R. J. Rutman, E. H. L. Chun, and J. Jones, Observations on the mechanism of the alkylation reaction between nitrogen mustard and DNA, Biochim.Biophys.Acta, 174: 663 (1969)PubMedGoogle Scholar
  20. 20.
    K. R. Harrap and E. W. Gascoigne, The interaction of bifunctional alkylating agents with the DNA of tumour cells, Eur.J. Cancer, 12: 53 (1976)PubMedCrossRefGoogle Scholar
  21. 21.
    G. R. Mohn and J. Ellenberger, Genetic effects of cyclophosphamide, ifosfamide and trofosfamide, Mutat.Res., 32: 331 (1976)PubMedGoogle Scholar
  22. 22.
    D. Gatehouse, Detection of mutagenic derivatives of cyclophosphamide and a variety of other mutagens in a “microtitre” fluctuation test, without microsomal activation, Mutat.Res., 53: 289 (1978)PubMedGoogle Scholar
  23. 23.
    V. W. Mayer, C. J. Hybner, and D. J. Brusick, Genetic effects induces in Saccharomyces cerevisiae by cyclophosphamide in vitro without liver enzyme preparations, Mutat.Res., 37: 201 (1976)PubMedCrossRefGoogle Scholar
  24. 24.
    H. Arnold and H. Klose, Ober den hydrolytischen Abbau des hexacyclischen N-Lost-phosphamidesters B518 unter physiologischen Bedingungen, Arneim.Forsch.(Drug Res.), 11: 159 (1961)Google Scholar

Copyright information

© Plenum Press, New York 1981

Authors and Affiliations

  • Reinhard Fleer
    • 1
  • Martin Brendel
    • 1
  1. 1.Institut für MikrobiologieJ.W.Goethe-UniversitätFrankfurt/M.Germany

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