New Strategies for the Improvement of Alkylating Antitumor Agents

  • H. Grunicke
  • W. Doppler
  • J. Hofmann
  • H. Lindner
  • K. Maly
  • H. Oberhuber
  • B. Puschendorf
  • H. Ringsdorf


Concepts for an improvement of alkylating antitumor agents are generally based on the assumption that alkylation of DNA, especially the formation of DNA-interstrand cross-links, is the essential mechanism which causes growth inhibition of tumor cells. However, although most authors agree that alkylation of DNA may be important, definite proof that this is the one and only mechanism by which alkylating drugs inhibit cell proliferation is still lacking. For review see Wilman and Connors (1).


Alkylating Agent Combination Index Amino Acid Uptake Ehrlich Ascites Tumor Cell Calmodulin Antagonist 
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  1. 1.
    D. E. V. Wilman and T. A. Connors, Molecular Structure and Antitumor Activity of Alkylating Agents, in: “Molecular Aspects of Anticancer Drug Action,” S. T. Neidle and N. J. Waring, eds., Verlag Chemie, Weinhein, Deerfield Beach (1983).Google Scholar
  2. 2.
    H. Grunicke, A. Csordas, W. Heiliger, S. Hauptlorenz, A. Loidl, I. Multhaup, H. Zwierzina, and B. Puschendorf, Depression of Histone Acetylation by Alkylating Antitumor Agents: Significance for Antitumor Activity and Possible Biological Consequences, Adv. Enz. Reg. 22: 433 (1984).CrossRefGoogle Scholar
  3. 3.
    H. Zwierzina, A. Loidl, L. C. Fuith, W. Heiliger, B. Puschendorf, and H. Grunicke, Depression of Histone Acetylation by Alkylating Antitumor Agents in Murine Cells, Cancer Res. 44: 3336 (1984).PubMedGoogle Scholar
  4. 4.
    H. Grunicke, W. Heiliger, B. J. Hermann, W. Hoeck, J. Hofmann, and B. Puschendorf, Alkylating Agents Reduce Histone Acetyl Transferase Activity, Adv. Enz. Reg., in press (1986).Google Scholar
  5. 5.
    H. Grunicke, F. Hirsch, H. Wolf, U. Bauer, and G. Kiefer, Selective Inhibition of Thymidine Transport at Low Doses of the Alkylating Agent Trisethyleneiminobenzoquinone (Trenimon), Exptl. Cell. Res. 90: 357 (1975).PubMedCrossRefGoogle Scholar
  6. 6.
    M. Ihlenfeldt, G. Gantner, H. Harrer, B. Puschendorf, H. Putzer, and H. Grunicke, Interaction of the Alkylating Antitumor Agent 2,3,5-tris(ethyleneimino)benzoquinone with the Plasma Membrane of Ehrlich Ascites Tumor Cells, Cancer Res. 41: 289 (1981).PubMedGoogle Scholar
  7. 7.
    H. Grunicke, K. Gruenewald, W. Heiliger, F. Scheidl, E. Wolff-Schreiner, and B. Puschendorf, Inhibition of Tumor Growth by an Alkylation of the Plasma Membrane, Adv. Enz. Reg. 21: 21 (1983).CrossRefGoogle Scholar
  8. 8.
    H. Grunicke, W. Doppler, S. A. E. Finch, R. Greinert, K. Gruenewald, J. Hoffmann, K. Maly, A. Stier, F. Scheidl, and J. K. Thomas, Effects of N-mustard on Potassium Transport Systems and Membrane Structure of Ehrlich Ascites Tumor Cells, Adv. Enz. Reg. 23: 277 (1985).CrossRefGoogle Scholar
  9. 9.
    W. Doppler, J. Hofmann, H. Oberhuber, K. Maly, and H. Grunicke, N-mustard Interference with Potassium Transport Systems in Ehrlich Ascites Tumor Cells, J. Cancer Res. Clin. Oncol. 110: 35 (1985).PubMedCrossRefGoogle Scholar
  10. 10.
    H. Grunicke, W. Doppler, J. Hofmann, H. Lindner, K. Maly, H. Oberhuber, H. Ringsdorf, and J. J. Roberts, Plasma Membrane as Target of Alkylating Agents, Adv. Enz. Reg. 24: 247 (1986).CrossRefGoogle Scholar
  11. 11.
    L. A. Zwelling, S. Michaels, H. Schwartz, P. P. Dobson, and K. W. Kohn, DNA Cross-linking as Indicator of Sensitivity and Resistance of Mouse-L1210 Leukemia to Cancer (II) and L- Phenylalanine Mustard, Cancer Res. 41:640 (1983). + + Google Scholar
  12. 12.
    S. Paris and J. PouyssAgur, Growth Factors Activate the Na /H -anti-porter in Quiescent Fibroblasts by Increasing its Affinity for Intracellular H, J. Biol. Chem. 259: 10989 (1984).PubMedGoogle Scholar
  13. 13.
    M. A. Bexter, S. W. Chawala, J. A. Hickman, and G. E. Spurgin, The Effect of N-mustard (HN2) on Activities of the Plasma Membrane of PC6A Mouse Plasmacytoma Cells, Biochem. Pharm. 31: 1773 (1982).CrossRefGoogle Scholar
  14. 14.
    V. Ling, Genetic Bases of Drug Resistance in Mammalian Cells, in: “Drug and Hormone Resistance in Neoplasia,” Vol. 1, N. Bruchovsky and J. A. Goldie, eds., C.R.C. Press, Boca Raton (1982).Google Scholar
  15. 15.
    P. E. Thorpe and W. C. J. Rosse, The Preparation and Cytotoxic Properties of Antibody Toxin Conjugats, Immunol. Rev. 62: 119 (1982).Google Scholar
  16. 16.
    S. Schuldiner and A. Rozengurt, Na /H -antiport in Swiss 3T3 Cells: Mi.togenic Stimulation Leads to Cytoplasmic Al.kalinization, Proc. Natl. Acad. Sci. U.S.A. 79: 7778 (1982).PubMedCrossRefGoogle Scholar
  17. 17.
    G. L’Allemain, S. Paris, and J. Pouyssé.gur, Growth Factor Action and Intracellular pH Regulation in Fibroblasts, J. Biol. Chem. 259: 5809 (1984).PubMedGoogle Scholar
  18. 18.
    W. H. Moolenaar, L. G. J. Tertoolen, and S. W. deLaat, Phorbol Ester and Diatyiglyteroi Mimick Growth Factors in Raising Cytoplasmic pH, Nature 312: 371 (1984).PubMedCrossRefGoogle Scholar
  19. 19.
    R. Panet, J. Fromer, and H. Atlan, Differentiation between Serum Stimulation. of Ouabain Resistant and Sensitive Rb Influx in Quiescent NIH 3T3 Cells, J. Membrane Biol. 70: 165 (1982).CrossRefGoogle Scholar
  20. 20.
    E. Rozengurt, Early Events in Growth Stimulation, in: “Surface of Normal and Malignant Cells,” R. 0. Heynes, ed., John Wiley and Sons, New York (1979).Google Scholar
  21. 21.
    M. J. Berridge and R. F. Irvin, Inositol Triphosphate, a Novel Second Messenger in Cellular Signal Transduction, Nature 312: 315 (1984).PubMedCrossRefGoogle Scholar
  22. 22.
    M. M. Winkler and J. L. Grainger, Mechanisms of Action of NH4C1 and Other Weak Bases in the Activation of Sea Urchin Eggs, Nature 273: 536 (1978).PubMedCrossRefGoogle Scholar
  23. 23.
    J. Pouyss6gur, C. Sardet, A. Franchi,G. L’Allemain, and S. Paris, A Specific Mutation Abolishing Na /H+ -antiport Activity in Hamster Fibroblasts Precludes Growth at Neutral and Acidic pH, Proc. Natl. Acad. Sci. U.S.A. 81: 4833 (1984).CrossRefGoogle Scholar
  24. 24.
    T. R. Hesketh, J. P. Moore, J. D. H. Morris, M. V. Taylor, J. Rogers, G. A. Smith, and J. C. Metcalfe, A Common Sequence of Calcium and pH Signals in the Mitogenic Stimulation of Eukaryotic Cells, Nature 313: 481 (1985).PubMedCrossRefGoogle Scholar
  25. 25.
    L. M. Vicentini, R. J. Miller, and M. Villereal, Evidence for a Role of Phospholipase Activity in the Serum Stimulation of Na -influx in Human Fibroblasts, J. Biol. Chem. 259: 6912 (1984).PubMedGoogle Scholar
  26. 26.
    N. E. Owen and M. L. Villereal, Evidence for a Role of Calmodulin in Serum Stimulation of Na -influx in Human Fibroblasts, Proc. Natl. Acad. Sci. U.S.A. 79: 3537 (1982).PubMedCrossRefGoogle Scholar
  27. 27.
    H. Ito and H. Hidaka, Antitumor Effect of a Calmodulin Antagonist on the Growth of Solid Sarkoma-]80, Cancer Lett. 19: 215 (1983).PubMedCrossRefGoogle Scholar
  28. 28.
    T. Matsui, Y. Nakao, N. Kobayashi, T. Koizumi, T. Nakagawa, M. Kishihara, and T. Fujita, Effects of Calmodulin Antagonists and Cytochalasins on Proliferation and Differentiation of Human Promyelocytic Leukemia Cell Line HL-60, Cancer Res. 45: 311 (1985).PubMedGoogle Scholar
  29. 29.
    M. L. Sezzi, G. Zupi, G. de Luca, M. Materazzi, and L. Bellelli, Effects of a Calcium-antagonist (Flunarizine) on the In Vitro Growth of B16 Mouse Melanoma Cells, Anticancer Res. 4: 229 (1984).PubMedGoogle Scholar
  30. 30.
    D. P. Wallach and V. J. R. Brown, Studies on the Arachidonis Acid Cascade. I. Inhibitors of Phospholipase A In Vitro and In Vivo by Several Novel Series of Inhibitor Compounds, Biochem. Pharm. 30: 1315 (1981).PubMedCrossRefGoogle Scholar
  31. 31.
    Y. Nishizuka, Turnover of Phospholipids and Signal Transduction, Science 225: 1365 (1984).PubMedCrossRefGoogle Scholar
  32. 32.
    J. M. Besterman, S. J. Trey, E. J. Cragoe, Jr., and P. Cuatrecasas, Inhibition of Epidermal Growth Factor Induced Mitogenesis by Fell-oxide and an Analogue: Evidence Against a Requirement for Na /H - exchange, Proc. Natl. Acad. Sci. U.S.A. 81: 6762 (1984).PubMedCrossRefGoogle Scholar
  33. 33.
    G. L. L’Allemain, A. rachi, E. J. Cragoe, Jr., and J. Pouyss6gur., Blockade of the Na /H -antiport Abolishes Growth Factor Induced DNA-synthesis in Fibroblasts. Structure Activity Relationships in the Amiloride Series, J. Biol. Chem. 259: 4313 (1984).PubMedGoogle Scholar
  34. 34.
    T. C. Chou and P. Talalay, Quantitative Analysis of Dose-effect Relationships: The Combined Effects of Multiple Drugs or Enzyme Inhibitors, Adv. Enz. Reg. 22: 27 (1984).CrossRefGoogle Scholar
  35. 35.
    P. A. Charp and J. D. Regan, Inhibition of DNA-repair by Trifluoperazine, Biochim. Biophys. Acta 824: 34 (1984).Google Scholar
  36. 36.
    H. Grunicke, G. Gantner, F. Holzweber, M. Ih]enfeldt, and B. Puschendorf, New Aspects on the Interference of Alkylating Anti-tumor Agents with the Regulation of Cell Division, Adv. Enz. Reg. 17: 291 (1979).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1987

Authors and Affiliations

  • H. Grunicke
    • 1
  • W. Doppler
    • 1
  • J. Hofmann
    • 1
  • H. Lindner
    • 1
  • K. Maly
    • 1
  • H. Oberhuber
    • 1
  • B. Puschendorf
    • 1
  • H. Ringsdorf
    • 1
  1. 1.Institut fur Medizinische Chemie and BiochemieUniversitat InnsbruckInnsbruckAustria

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