1887

Abstract

Glutamine depletion strongly inhibits the replication of Rauscher murine leukaemia retrovirus (RLV) glutaminase-asparaginase (PGA), capable of depleting glutamine and asparagine for prolonged periods, was used to determine the therapeutic effectiveness of glutamine depletion in mice infected with RLV or Friend virus. During PGA treatment of viraemic animals, serum reverse transcriptase activity fell to control levels and infected animals did not develop splenomegaly. The therapeutic results obtained with PGA compared favourably with those of azidothymidine given intraperitoneally at 30 mg/kg/day. Western blots performed on splenic tissue from control and treated animals indicated that glutamine depletion prevented readthrough of an amber codon at the junction, stopping translation of viral mRNA at that point. Treatment of RLV-infected animals with PGA resulted in nearly a 200% increase in mean survival time even when therapy was initiated late in the course of the disease. To our knowledge, this is the first demonstration that a nutrient required for viral replication can be enzymically depleted to inhibit viral replication.

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1991-02-01
2024-12-07
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References

  1. Anderson-Berg W. T., Squire R. A., Strand M. 1987; Specific radioimmunotherapy using 90Y-labeled monoclonal antibody in erythroleukemic mice. Cancer Research 47:1905–1912
    [Google Scholar]
  2. Boiron M., Levy J. P., Lasneret J., Oppenheim S., Bernard J. 1965; Pathogenesis of Rauscher leukemia. Journal of the National Cancer Institute 35:865–884
    [Google Scholar]
  3. Chirigos M. A. 1964; Studies with the murine leukemogenic Rauscher virus. III. An in vivo assay for anti-viral agents. Cancer Research 24:1035–1041
    [Google Scholar]
  4. Falk L. A., Paul D., Landay A., Kessler H. 1987; HIV isolation from plasma of HIV-infected persons. New England Journal of Medicine 316:1547–1548
    [Google Scholar]
  5. Feng Y. -X., Hatfield D. L., Rein A., Levin J. 1989; Translational readthrough of the murine leukemia virus gag gene amber codon does not require virus-induced alteration of tRNA. Journal of Virology 63:2405–2410
    [Google Scholar]
  6. Gloger I., Panet A. 1986; Glutamine starvation of murine leukaemia virus-infected cells inhibits read through of the gag-pol genes and proteolytic processing of the gag polyprotein. Journal of General Virology 67:2207–2213
    [Google Scholar]
  7. Gloger I., Arad G., Panet A. 1985; Regulation of Moloney murine leukemia virus replication in chronically infected cells arrested at the G0/G1 phase. Journal of Virology 54:844–850
    [Google Scholar]
  8. Gregerson J. P., Wege H., Preiss L., Jentsch K. D. 1988; Detection of human immunodeficiency virus and other retroviruses in cell culture supernatants by a reverse transcriptase microassay. Journal of Virological Methods 19:161–168
    [Google Scholar]
  9. Hartley J. W., Fredrickson T. N., Yetter R. A., Makino M., Morse H. C. 1989; Retrovirus-induced murine acquired immunodeficiency syndrome: natural history of infection and differing susceptibility of inbred mouse strains. Journal of Virology 63:1223–1231
    [Google Scholar]
  10. Hershfield M. S., Buckley R. H., Greenberg M. L., Melton A. L., Schiff R., Hatem C., Kurtzberg J., Markert M. L., Kobayashi R. H., Kobayashi A. L., Abuchowski A. 1987; Treatment of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase. New England Journal of Medicine 310:589–596
    [Google Scholar]
  11. Holcenberg J. S. 1981; Therapy of neoplasia with other nonessential amino acid degrading enzymes. In Enzymes as Drugs pp. 25–61 Edited by Holcenberg J. S., Roberts J. New York: John Wiley;
    [Google Scholar]
  12. Jacks T., Power M. D., Masiarz F. R., Lucin P. A., Barr P. J., Varmus H. E. 1988; Characterization of ribosomal frameshifting in HIV-1 gag-pol expression. Nature, London 331:280–283
    [Google Scholar]
  13. Kuchino Y., Nishimura S., Schröder H. Z., Rottmann M., Müller W. E. G. 1988; Selective inhibition of formation of suppressor glutamine tRNA in Moloney murine leukemia virus-infected NIH-3T3 cells by avarol. Virology 165:518–526
    [Google Scholar]
  14. Kurtzberg J., Moore J. O., Scudiery D., Franklin A. 1988; A phase II study of polyethylene glycol (PEG) conjugated l-asparaginase in patients with refractory acute leukemias. Proceedings of the American Association for Cancer Research 29:213
    [Google Scholar]
  15. McGregor W. G., Roberts J. 1989; Glutaminase enhances therapeutic effectiveness of glutamine antimetabolites against human and murine solid tumors in vivo . Proceedings of the American Association for Cancer Research 30:578
    [Google Scholar]
  16. Marks P. A., Rifkind R. A. 1978; Erythroleukemic differentiation. Annual Review of Biochemistry 47:419–448
    [Google Scholar]
  17. Mita S., Chou T. C., Roberts J., Steinherz P., Miller D., Tan C. 1980; Phase I trial of succinylated Acinetobacter glutaminase–asparaginase (SAGA) in children. Proceedings of the American Association for Cancer Research 21:143
    [Google Scholar]
  18. Müller W. E. G., Schröder H. C., Reuter P., Sarin P. S., Hess G., Meyer K. H., Zum Büschenfelde M., Kuchino Y., Nishimura S. 1988; Inhibition of expression of natural UAG suppressor glutamine tRNA in HIV-infected human H9 cells in vitro by avarol. Aids Research and Human Retroviruses 4:279–286
    [Google Scholar]
  19. O’Donnell P. V., Stockert E., Obata Y., Old L. J. 1981; Leukemogenic properties of AKR dualtropic (MCF) viruses: amplification of murine leukemia virus-related antigens on thymocytes and acceleration of leukemia development in AKR mice. Virology 112:548–563
    [Google Scholar]
  20. Panganiban A. T. 1988; Retroviral gag gene amber codon suppression is caused by an intrinsic cis-acting component of the viral mRNA. Journal of Virology 62:3574–3580
    [Google Scholar]
  21. Rauscher F. J. 1962; A virus-induced disease of mice characterized by erythropoiesis and lymphoid leukemia. Journal of the National Cancer Institute 29:515–543
    [Google Scholar]
  22. Roberts J. 1976; Purification and properties of a highly potent antitumor glutaminase-asparaginase from Pseudomonas 7A . Journal of Biological Chemistry 251:2119–2123
    [Google Scholar]
  23. Roberts J., McGregor W. G. 1989; Glutaminase has potent antiretroviral activity in vivo . Proceedings of the American Association for Cancer Research 30:454
    [Google Scholar]
  24. Roberts J., Rosenfeld H. 1980; Enhancement of antineoplastic activity of the glutamine antagonists DON and AT-125 by glutaminase–asparaginase. Proceedings of the American Association for Cancer Research 21:283
    [Google Scholar]
  25. Roberts J., Schmid F. A., Rosenfeld H. 1979; Biologic and antineoplastic effects of enzyme-mediated in vivo depletion of l-glutamine, l-tryptophan, and l-histidine. Cancer Treatment Reports 63:1045–1054
    [Google Scholar]
  26. Rosenfeld H., Roberts J. 1981; Enhancement of antitumor activity of glutamine antagonists 6-diazo-5-oxo-l-norleucine and Acivicin in cell culture by glutaminase-asparaginase. Cancer Research 41:1324–1328
    [Google Scholar]
  27. Rowe W. P., Pugh W. E., Hartley J. W. 1970; Plaque assay techniques for murine leukemia viruses. Virology 42:1136–1139
    [Google Scholar]
  28. Ruprecht R. M., O’Brien L. G., Rossoni L. D., Nusinoff-Lehrmann S. 1986; Suppression of mouse viraemia and retroviral disease by 3′-azido-3′-deoxythymidine. Nature, London 323:467–469
    [Google Scholar]
  29. Varmus H. 1989; Lessons from the life cycle of retroviruses. The Harvey Lectures 83:35–56
    [Google Scholar]
  30. Yoshinaka Y., Katoh I., Copeland T. D., Oroszlan S. 1985; Murine leukemia virus protease is encoded by the gag-pol gene and is synthesized through repression of an amber termination codon. Proceedings of the National Academy of Sciences, U.S.A. 82:1618–1622
    [Google Scholar]
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