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. 1990 Aug;34(8):1485–1490. doi: 10.1128/aac.34.8.1485

Cure of Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense infections in mice with an irreversible inhibitor of S-adenosylmethionine decarboxylase.

A J Bitonti 1, T L Byers 1, T L Bush 1, P J Casara 1, C J Bacchi 1, A B Clarkson Jr 1, P P McCann 1, A Sjoerdsma 1
PMCID: PMC171857  PMID: 1977366

Abstract

A structural analog, 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxy adenosine (MDL 73811), of decarboxy S-adenosyl-L-methionine, the product of the reaction catalyzed by S-adenosyl-L-methionine (AdoMet) decarboxylase (DC), was found to inhibit Trypanosoma brucei brucei AdoMet DC. The inhibition was time dependent (tau 50, 0.3 min), exhibited pseudo-first-order kinetics (Ki, 1.5 microM), and was apparently irreversible. The natural substrate of the reaction, AdoMet, protected the enzyme from inactivation, suggesting that MDL 73811 was directed at the enzyme active site and was probably catalytically activated. Administration of MDL 73811 to T. b. brucei-infected rats resulted in rapid inhibition of AdoMet DC activity, a decrease in spermidine, and an increase in putrescine in the trypanosomes isolated from treated rats. Treatment of T. b. brucei-infected mice with MDL 73811 (20 mg/kg of body weight intraperitoneally twice daily for 4 days) resulted in cures of the trypanosome infections. Additionally, drug-resistant T. brucei rhodesiense infections in mice were cured by either a combination of MDL 73811 (50 mg/kg intraperitoneally three times per day for 5 days) and relatively low oral doses of alpha-difluoromethylornithine or MDL 73811 (50 mg/kg per day for 7 days) administered alone in implanted miniosmotic pumps. These data suggest that MDL 73811 and, perhaps, other inhibitors of AdoMet DC have potential for therapeutic use in various forms of African trypanosomiasis.

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Selected References

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  1. Bacchi C. J. Content, synthesis, and function of polyamines in trypanosomatids: relationship to chemotherapy. J Protozool. 1981 Feb;28(1):20–27. doi: 10.1111/j.1550-7408.1981.tb02798.x. [DOI] [PubMed] [Google Scholar]
  2. Bitonti A. J., Bacchi C. J., McCann P. P., Sjoerdsma A. Catalytic irreversible inhibition of Trypanosoma brucei brucei ornithine decarboxylase by substrate and product analogs and their effects on murine trypanosomiasis. Biochem Pharmacol. 1985 May 15;34(10):1773–1777. doi: 10.1016/0006-2952(85)90648-3. [DOI] [PubMed] [Google Scholar]
  3. Bitonti A. J., Cross-Doersen D. E., McCann P. P. Effects of alpha-difluoromethylornithine on protein synthesis and synthesis of the variant-specific glycoprotein (VSG) in Trypanosoma brucei brucei. Biochem J. 1988 Feb 15;250(1):295–298. doi: 10.1042/bj2500295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bitonti A. J., Dumont J. A., McCann P. P. Characterization of Trypanosoma brucei brucei S-adenosyl-L-methionine decarboxylase and its inhibition by Berenil, pentamidine and methylglyoxal bis(guanylhydrazone). Biochem J. 1986 Aug 1;237(3):685–689. doi: 10.1042/bj2370685. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bitonti A. J., McCann P. P., Sjoerdsma A. Necessity of antibody response in the treatment of African trypanosomiasis with alpha-difluoromethylornithine. Biochem Pharmacol. 1986 Jan 15;35(2):331–334. doi: 10.1016/0006-2952(86)90534-4. [DOI] [PubMed] [Google Scholar]
  6. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  7. Chang K. P., Steiger R. F., Dave C., Cheng Y. C. Effects of methylglyoxal bis(ganylhydrazone) on trypanosomatid flagellates: inhibition of growth and nucleoside incorporation in Trypanosoma brucei. J Protozool. 1978 Feb;25(1):145–149. doi: 10.1111/j.1550-7408.1978.tb03887.x. [DOI] [PubMed] [Google Scholar]
  8. Fairlamb A. H., Cerami A. Identification of a novel, thiol-containing co-factor essential for glutathione reductase enzyme activity in trypanosomatids. Mol Biochem Parasitol. 1985 Feb;14(2):187–198. doi: 10.1016/0166-6851(85)90037-4. [DOI] [PubMed] [Google Scholar]
  9. Fairlamb A. H., Henderson G. B., Bacchi C. J., Cerami A. In vivo effects of difluoromethylornithine on trypanothione and polyamine levels in bloodstream forms of Trypanosoma brucei. Mol Biochem Parasitol. 1987 Jun;24(2):185–191. doi: 10.1016/0166-6851(87)90105-8. [DOI] [PubMed] [Google Scholar]
  10. Fillingame R. H., Jorstad C. M., Morris D. R. Increased cellular levels of spermidine or spermine are required for optimal DNA synthesis in lymphocytes activated by concanavalin A. Proc Natl Acad Sci U S A. 1975 Oct;72(10):4042–4045. doi: 10.1073/pnas.72.10.4042. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ginoux P. Y., Lancien P., Frezil J. L., Bissadidi N. Les échecs du traitement de la trypanosomiase à T. gambiense au Congo. Med Trop (Mars) 1984 Apr-Jun;44(2):149–154. [PubMed] [Google Scholar]
  12. Kolb M., Danzin C., Barth J., Claverie N. Synthesis and biochemical properties of chemically stable product analogues of the reaction catalyzed by S-adenosyl-L-methionine decarboxylase. J Med Chem. 1982 May;25(5):550–556. doi: 10.1021/jm00347a014. [DOI] [PubMed] [Google Scholar]
  13. Lanham S. M., Godfrey D. G. Isolation of salivarian trypanosomes from man and other mammals using DEAE-cellulose. Exp Parasitol. 1970 Dec;28(3):521–534. doi: 10.1016/0014-4894(70)90120-7. [DOI] [PubMed] [Google Scholar]
  14. Pankaskie M., Abdel-Monem M. M. Inhibitors of polyamine biosynthesis. 8. Irreversible inhibition of mammalian S-adenosyl-L-methionine decarboxylase by substrate analogues. J Med Chem. 1980 Feb;23(2):121–127. doi: 10.1021/jm00176a004. [DOI] [PubMed] [Google Scholar]
  15. Pegg A. E., Jones D. B., Secrist J. A., 3rd Effect of inhibitors of S-adenosylmethionine decarboxylase on polyamine content and growth of L1210 cells. Biochemistry. 1988 Mar 8;27(5):1408–1415. doi: 10.1021/bi00405a003. [DOI] [PubMed] [Google Scholar]
  16. Pegg A. E., McCann P. P. Polyamine metabolism and function. Am J Physiol. 1982 Nov;243(5):C212–C221. doi: 10.1152/ajpcell.1982.243.5.C212. [DOI] [PubMed] [Google Scholar]
  17. Pegg A. E., Pösö H. S-adenosylmethionine decarboxylase (rat liver). Methods Enzymol. 1983;94:234–239. doi: 10.1016/s0076-6879(83)94041-7. [DOI] [PubMed] [Google Scholar]
  18. Seiler N., Knödgen B. High-performance liquid chromatographic procedure for the simultaneous determination of the natural polyamines and their monoacetyl derivatives. J Chromatogr. 1980 Dec 12;221(2):227–235. doi: 10.1016/s0378-4347(00)84307-8. [DOI] [PubMed] [Google Scholar]
  19. Sjoerdsma A., Schechter P. J. Chemotherapeutic implications of polyamine biosynthesis inhibition. Clin Pharmacol Ther. 1984 Mar;35(3):287–300. doi: 10.1038/clpt.1984.33. [DOI] [PubMed] [Google Scholar]
  20. Ulrich P., Cerami A. Trypanocidal 1,3-arylene diketone bis(guanylhydrazone)s. Structure-activity relationships among substituted and heterocyclic analogues. J Med Chem. 1984 Jan;27(1):35–40. doi: 10.1021/jm00367a007. [DOI] [PubMed] [Google Scholar]
  21. Van Nieuwenhove S., Schechter P. J., Declercq J., Boné G., Burke J., Sjoerdsma A. Treatment of gambiense sleeping sickness in the Sudan with oral DFMO (DL-alpha-difluoromethylornithine), an inhibitor of ornithine decarboxylase; first field trial. Trans R Soc Trop Med Hyg. 1985;79(5):692–698. doi: 10.1016/0035-9203(85)90195-6. [DOI] [PubMed] [Google Scholar]
  22. Williams-Ashman H. G., Schenone A. Methyl glyoxal bis(guanylhydrazone) as a potent inhibitor of mammalian and yeast S-adenosylmethionine decarboxylases. Biochem Biophys Res Commun. 1972 Jan 14;46(1):288–295. doi: 10.1016/0006-291x(72)90661-4. [DOI] [PubMed] [Google Scholar]

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