The Polyamine Metabolism of Filarial Worms as Chemotherapeutic Target

  • Sylke Müller
  • R.-M. Wittich
  • R. D. Walter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 250)


Parasite-specific putrescine-N-acetyltransferase and polyamine oxidase, both involved in the reversed pathway of polyamine metabolism, were demonstrated for Ascaris suum and Onchocerca volvulus. Berenil-treatment was found to be correlated with accumulation of polyamines, especially spermine, obviously due to blockaded polyamine interconversion. Furthermore it was shown that added spermine to the culture medium led to the death of worms. These specificities might be exploited for chemotherapy of filarial infections.

Polyamines are widely distributed in the nature. They are found in higher and lower eucaryotes and in procaryotes as well as in viruses (Tabor and Tabor, 1984). During the last years there have been many approaches to examine the role of polyamines in cell growth and differentiation in vertebrates (Tabor and Tabor, 1984; Pegg, 1986). The polyamine metabolism of parasites also has attracted increasing interest, e. g. in African trypanosomes the initial enzyme of polyamine synthesis — ornithine decarboxylase — has been exploited as a target for chemotherapy by using DFMO (DLα-difluoro-methylornithine) (Bacchi et al., 1980; Bacchi et al., 1983; Fairlamb et al., 1985; Giffin et al., 1986).

The polyamine metabolism of filaria and other helminths is still a neglected area of research, although there are reports about distribution pattern of polyamines and some peculiarities of polyamine metabolism in filarial worms (Srivastava et al., 1980; Wittich et al., 1987; Walter, 1988). DFMO and MGBG (methylglyoxal bis-(guanylhydrazone)), both of which are potent inhibitors of polyamine synthesis in mammals, do not significantly effect the viability of filarial worms (Wittich et al., 1987). If synthesis via ornithine as well as arginine decarboxylase could finally be denied, the absolute dependence of filarial worms on their host for a supply with polyamines would offer some leads for chemotherapy of river blindness and lymphatic fila-riasis. It should be demonstrated for filaria and other helminths that blockade and disturbance of polyamine synthesis and distribution leads to death of worms. Furthermore the enzymes involved in the interconversion pathway should be identified and their potential as targets for design and developement of enzyme inhibitors to antifilarial drugs should be studied.


Trypanosoma Brucei Diamine Oxidase Polyamine Metabolism Polyamine Synthesis Arginine Decarboxylase 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bacchi, C. J., Nathan, H. C., Hunter, S. H., 1980, Polyamine metabolism: A potential therapeutic target in trypanosomes, Science, 210: 332–334.PubMedCrossRefGoogle Scholar
  2. Bacchi, C. J., Garofalo, J., Mockenhaupt, D., McCann, P. P., Diekema, K. A., Pegg, A. E., Nathan, H. C., Mullany, E. A., Chunosoff, L., Sjoerdsma, A., Hunter, S. H., 1983, In vivo effects of-D, L-difluoromethyl-ornithine on the metabolism and morphology of trypanosoma brucei brucei, Mol. Biochem., Parasitol., 7: 209–225.CrossRefGoogle Scholar
  3. Balana-Fouce, R., Garzon-Pulido, T., Ordonez-Escudero, D., and Garrido-Pertierra, A., 1986, Inhibition of diamine oxidase and S-adenosyl-methionine decarboxylase by diminaceneaceturate (berenil), Biochem.Pharmacol., 35(9): 1597–1600.PubMedCrossRefGoogle Scholar
  4. Bey, P., Bolkenius, F. N., Seiler, N., and Casara, P., 1985, N-2, 3-butadienyl-1, 4-butanediamine derivatives: Potent irreversible inactivators of mammalian polyamine oxidase, J. Med. Chem., 28(l): 1–2.PubMedCrossRefGoogle Scholar
  5. Bitonti, A. J., Dumont, J. A., and McCann, P. P., 1986, Characterisation of trypanosoma brucei brucei S-adenosyl-L-metnionine decarboxylase and its inhibition by berenil, pentamidine and methylglyoxal bis(guanyl-hydrazone), Biochem. J., 237: 685–689.PubMedGoogle Scholar
  6. Bolkenius, F. N., and Seiler, N., 1987, The role of polyamine reutilization in depletion of cellular stores of polyamines in non-proliferating tissues, Biochem. Biophys. Acta, 923: 125–135.PubMedCrossRefGoogle Scholar
  7. Fairlamb, A. H., Blackburn, P., Ulrich, P., Chait, B. F., and Cerami, A., 1985, Trypanothione. A novel bis(glutathionyl)spermidine cofactor for glutathione reductase in trypanosomatids, Science, 227: 1485–1487.PubMedCrossRefGoogle Scholar
  8. Ferrante, A., Ljungstrom, I., Rzepzyk, C. M., and Morgan, D. M. L., 1986, Differences in sensitivity of Schistosoma mansoni schistosomula, Dirofilaria immitis microfilariae and Nematospiroides dubius third-stage larvae to damage by polyamine oxidase-polyamine system, Infect.Immun., 53(3): 606–610.PubMedGoogle Scholar
  9. Franke, E. D., and Weinstein, P. P., 1983, Dipetalonema vitae (Nematoda: Filarioidea): Culture of third-stage larvae to young adults in vitro, Science, 221: 161–163.PubMedCrossRefGoogle Scholar
  10. Giffin, B. F., McCann, P. P., Bitonti, A. J., and Bacchi, C. J., 1986, Polyamine depletion following exposure to DL-difluoromethylornithine both in vivo and in vitro initiates morphological alterations and mitochondrial activation in a monomorphic strain of trypanosoma brucei brucei, J. Protozool., 33(2): 238–243.PubMedGoogle Scholar
  11. Karvonen, E., Kauppinen, L., Partanen, T., and Pösö, H., 1985, Irreversible inhibition of putrescine-stimulated S-adenosyl-L-methionine decarboxylase by berenil and pentamidine, Biochem. J., 231: 165–169.PubMedGoogle Scholar
  12. Libby, P. R., 1978, Calf liver nuclear N-acetyltransferase, J. Biol. Chem., 253: 233–237.PubMedGoogle Scholar
  13. Libby, P. R., 1980, Rat liver nuclear N-acetyltransferase: Seperation of two enzymes with both histone and spermidine acetyltransferase activity, Arch. Biochem. Biophys., 203: 384–389.PubMedCrossRefGoogle Scholar
  14. McCann, P. P., Bacchi, C. J., Nathan, H. C, and Sjoerdsma, A., 1983, in “Mechanism of Drug Action”, T. P. Singer and R. N. Ordarza, eds., Academic Press, New York.Google Scholar
  15. Morgan, D. M. L., Bachrach, U., Assaraf, Y. G., Harari, E., and Golenser, J., 1986, The effect of purified aminoaldehydes produced by polyamine oxidation on developement in vitro of Plasmodium falciparum in normal and glucose-6-phosphate-dehydrogenase-deficient erythrocytes, Biochem. J., 236: 97–101.PubMedGoogle Scholar
  16. Müller, S., and Walter, R. D., 1988, Effect of berenil and spermine on viability and polyamine metabolism of filarial worms in vitro, International Symposium on Polyamines in Biochemistry and Clinical research, Sorrento, Naples, Italy, 13-17 June 1988 (Abstract).Google Scholar
  17. Müller, S., Wittich, R.-M., and Walter, R. D., Characteristics and function of polyamine oxidase in nematodes, Zbl. Bakt. Hyg., in press.Google Scholar
  18. Pegg, A. E., 1986, Recent advances in the biochemistry of polyamines in eukaryotes, Biochem. J., 234: 249–262.PubMedGoogle Scholar
  19. Rathauer, S., Wittich, R.-M., and Walter, R. D., 1988, Ascaris suum and Onchocerca volvulus: S-adenosylmethionine decarboxylase, Exp. Parasitol., 65: 277–281.CrossRefGoogle Scholar
  20. Seiler, N., and Al-Therib, M. J., 1974, Putrescine catabolism in mammalian brain, Biochem. J., 144: 29–35.PubMedGoogle Scholar
  21. Srivastava, D. K., Roy, T. K., and Shukla, O. P., 1980, Polyamines of helminths, Ind. J. Parasitol., 4(2): 187–189.Google Scholar
  22. Tabor, C. W., and Tabor, H., 1984, Polyamines, Annu. Rev. Biochem., 53: 749–790.PubMedCrossRefGoogle Scholar
  23. Walter R. D., 1988, Polyamine metabolism in filaria and allied parasites, Parasitol. Today, 4(4): 18–20.PubMedCrossRefGoogle Scholar
  24. Williams-Ashman, H. G., and Seidenfeld, J., 1986, Aspects of the biochemical pharmacology of methylglyoxal bis(guanylhydrazone), Biochem. Pharmacol., 35(8): 1217–1225.PubMedCrossRefGoogle Scholar
  25. Wittich, R.-M., Kilian, H.-D., and Walter, R. D., 1987, Polyamine metabolism in filarial worms, Mol. Biochem. Parasitol., 24: 155–162.PubMedCrossRefGoogle Scholar
  26. Wittich, R.-M., and Walter, R. D., 1988, A novel putrescine (diamine) N-acetyltransferase from Onchocerca volvulus and Ascaris suum, International Symposium on Polyamines in Biochemistry and Clinical Research, Sorrento, Naples, Italy, 13-17 June 1988 (Abstract).Google Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Sylke Müller
    • 1
  • R.-M. Wittich
    • 1
  • R. D. Walter
    • 1
  1. 1.Abteilung für BiochemieBernhard-Nocht-Institut für TropenmedizinHamburg 4F. R. Germany

Personalised recommendations