Skip to main content

Alkylphosphocholines: a new class of membrane-active anticancer agents

Conclusion

From the foregoing it is evident that the experimental profile of miltefosine and alkylphosphocholines is different from that of conventional anticancer agents. Much evidence indicated that the mode of action of alkylphosphocholines was related to plasma-membrane-associated phosphoinositide metabolism. Inhibition of phospholipase C and/or PKC is currently thought to be the main biochemical target of alkylphosphocholines. Considering the great importance of both phosphoinositide metabolism and the regulation of a broad spectrum of cellular functions, including differentiation and invasion, miltefosine could become an interesting new drug. In addition, it may be a tool for further studies into the biochemical pathway of signal transduction in malignant cells.

This is a preview of subscription content, access via your institution.

References

  1. Andreesen R, Osterholz J, Luckenbach A, Costabel U, Schulz A, Speth V, Munder PG, Löhr GW (1984) Tumor cytotoxicity of human macrophages after incubation with synthetic analogues of 2-lysophosphatidylcholine. J Natl Cancer Inst 72:53–58

    Google Scholar 

  2. Berdel WE, Himmelmann AW, Danhauser-Riedl S, Steinhauser G, Modest EJ, Rastetter J (1990) In vitro studies in the cross resistance pattern of membrane active lipids (abstract 11.24.03). J Cancer Res Clin Oncol 116:993

    Google Scholar 

  3. Berger MR, Eibl H (1992) Erucylphosphocholine is a second generation alkylphosphocholine (abstract 2483). Proc Am Assoc Cancer Res 33:416

    Google Scholar 

  4. Eibl H, Unger C (1987) Phospholipide als Antitumormittel: Möglichkeiten einer selektiven Therapie. In: Unger C, Eibl H, Nagel GA (eds) Die Zellmembran als Angriffspunkt der Tumortherapie. Zuckerschwerdt, München, pp 1–18

    Google Scholar 

  5. Fleer EAM, Unger C, Kim DJ, Eibl H (1987) Metabolism of ether phospholipids and analogs in neoplastic cells. Lipids 22:856–861

    Google Scholar 

  6. Geilen CC, Haase R, Buchner K, Wieder T, Hucho F, Reutter W (1991) The phospholipid analogue, hexadecylphosphocholine, inhibits protein kinase C in vitro and antagonizes phorbol ester-stimulated cell proliferation. Eur J Cancer 27:1650–1653

    Google Scholar 

  7. Geilen CC, Wieder T, Reutter W (1992) Hexadecylphosphocholine inhibits translocation of CTP: phosphocholine cytidylyltransferase in Madine-Darby canine kidney cells. J Biol Chem (in press)

  8. Grunicke HH, Überall F (1992) Protein kinase C — modulation. Semin Oncol (in press)

  9. Haase R, Geilen CC, Reutter W (1990) Comparison of the effects of the antineoplastic agent hexadecylphosphocholine and of different modulators. of PKC on cell proliferation (abstract). Naunyn-Schmiedeberg's Arch Pharmacol 342:A42

    Google Scholar 

  10. Hilgard P, Stekar J, Voegeli R, Engel J, Schumacher W, Eibl H, Unger C, Berger MR (1988) Characterization of the antitumor activity of hexadecylphosphocholine (D-18506). Eur J Cancer Clin Oncol 24:1457–1461

    Google Scholar 

  11. Hilgard P, Harleman JH, Voegeli R, Maurer HR, Echarti C, Unger C (1989) The antineoplastic activity of hexadecylphosphocholine (HPC) is associated with tumor cell differentiation (abstract 2310). Proc Am Assoc Cancer Res 30:580

    Google Scholar 

  12. Hilgard P, Kampherm E, Nolan L, Pohl J, Reissmann T (1991) Investigation into the immunological effects of miltefosine, a new anticancer agent under development. J Cancer Res Clin Oncol 117:403–408

    Google Scholar 

  13. Hilgard P, Stekar J, Voegeli R, Harleman JH (1992) Experimental therapeutic studies with miltefosine in rats and mice. In: Eibl H, Hilgard P, Unger C (eds) Progress in experimental tumor research, vol 34. S. Karger, Basel, pp 116–130

    Google Scholar 

  14. Hochhuth C, Berkovic D, Eibl H, Unger C, Deonecke D (1990) Effects of antineoplastic phospholipids on parameters of cell differentiation in U937 cells. J Cancer Res Clin Oncol 116:459–466

    Google Scholar 

  15. Hofmann J, Doppler W, Jakob A, Maly K, Posch L, Überall F, Grunicke HH (1988) Enhancement of the antiproliferative effect ofcis-diamminedichloroplatinum(II) and nitrogen mustard by inhibitors of PKC. Int J Cancer 42:382–388

    Google Scholar 

  16. Hofmann J, Überall F, Posch L, Maly K, Herrmann DBJ, Grunicke HH (1989) Synergistic enhancement of the antiproliferative activity ofcis-diamminedichloroplatinum(II) by the ether lipid analogue BM41440, an inhibitor of protein kinase C. Lipids 24:312–317

    Google Scholar 

  17. Lassing I, Lindberg U (1985) Specific interaction between phosphatidylinositol-4,5-bisphosphate and profilactin. Nature 314:472–474

    Google Scholar 

  18. Minana MD, Felipo V, Grisolia S (1990) Inhibition of protein kinase C induces differentiation in Neuro-2a cells. Proc Natl Acad Sci USA 87:4335–4339

    Google Scholar 

  19. Muschiol C, Berger MR, Schuler B, Scherf HR, Garzon FT, Zeller WJ, Unger C, Eibl HJ, Schmähl D (1987) Alkylphosphocholines: toxicity and anticancer properties. Lipids 22:930–934

    Google Scholar 

  20. Nooter K, Vecht B van der, Hogeweg M, Visser J, Hilgard P, Verweij J (1992) The in vitro effects of hexadecylphosphocholine on the murine hemopoietic system (abstract 26). Proceedings, 7th NCI-EORTC Symposium on New Drugs in Cancer Therapy, Amsterdam, March 17–20, p. 65

  21. Parodi MT, Varesio L, Tonini GP (1990) The specific inhibitor of protein kinase C, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7), induces morphological change and cell differentiation of human neural crest-derived cell lineages. FEBS Lett 269:4–6

    Google Scholar 

  22. Pignol B, Coulomb H, Chaumeron S, Maisonnet T, Vandamme B, Broquet C, Mencia-Huerta JM, Braquet P (1990) Effect of synthetic alkyllysophosphatidylcholine (ALP) on IL-1, TNF and IL-2 productions (absstract 126). Anticancer Res 10:1380

    Google Scholar 

  23. Schallier DK, Brunyneel EA, Storme GA, Hilgard P, Mareel MM (1991) Antiinvasive activity of hexadecylphosphocholine in vitro. Anticancer Res 11:1285–1292

    Google Scholar 

  24. Spruß T, Bernhardt G, Reile H, Schönenberger H, Engel J (1989) Combination therapy with platinum complexes and hexadecylphosphocholine of MXT mouse mammary adenocarcinomas (abstract TH10). J Cancer Res Clin Oncol 115:55

    Google Scholar 

  25. Stekar J, Schumacher W, Nößner G, Kutscher B (1992) D-20133, a novel alkylphospholipid with high antineoplastic activity. J Cancer Res Clin Oncol [Suppl] 118:83

    Google Scholar 

  26. Überall F, Oberhuber H, Maly K, Zaknum J, Demuth L, Grunicke HH (1991) Hexadecylphosphocholine inhibits inositol phosphate formation and protein kinase C activity. Cancer Res 51:807–812

    Google Scholar 

  27. Unger C, Eibl H, Nagel GA, Heyden HW von, Breiser A, Engel J, Stekar J, Peukert M, Hilgard P, Berger M (1989) Hexadecylphosphocholine in the topical treatment of skin metastases: a phase I trial. Contrib Oncol 37:219–223

    Google Scholar 

  28. Unger C, Fleer E, Damenz W, Hilgard P, Nagel G, Eibl HJ (1991) Hexadecylphosphocholine: determination of serum concentration in rats. J Lipid Mediators 3:71–78

    Google Scholar 

  29. Vehmeyer K, Scheurich P, Eibl H, Unger C (1991) Hexadecylphosphocholine-mediated enhancement of T-cell responses to interleukin-2. Cell Immunol 137:232–238

    Google Scholar 

  30. Vehmeyer K, Eibl H, Unger C (1992) Hexadecylphosphocholine stimulates the colony-stimulating factor-dependent growth of hemopoietic progenitor cells. Exp Hematol 20:1–5

    Google Scholar 

  31. Verweij J, Planting AST, Stoter G (1992) Increases in leucocyte and platelet counts induced by the ether lipid hexadecylphosphocholine (HePC) (abstract 31). Proceedings, 7th NCI-EORTC Symposium on New Drugs in Cancer Therapy, Amsterdam, March 17–20, p. 66

  32. Yanapirut P, Berger MR, Reinhardt M, Schmähl D (1991) In vitro investigations on the antineoplastic effect of hexadecylphosphocholine. Arzneimittelforschung 41:652–655

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hilgard, P., Klenner, T., Stekar, J. et al. Alkylphosphocholines: a new class of membrane-active anticancer agents. Cancer Chemother. Pharmacol. 32, 90–95 (1993). https://doi.org/10.1007/BF00685608

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00685608

Keywords

  • Signal Transduction
  • Cancer Research
  • Broad Spectrum
  • Malignant Cell
  • Cellular Function