Advertisement

Inhibitory effects of potent inhibitors of human immunodeficiency virus and cytomegalovirus on the growth of human granulocyte-macrophage progenitor cells in vitro

  • R. Snoeck
  • L. Lagneaux
  • A. Delforge
  • D. Bron
  • P. Van der Auwera
  • P. Stryckmans
  • J. Balzarini
  • E. De Clercq
New Antimicrobial Agents

Abstract

Phosphonoformate, ganciclovir, zidovudine and the novel acyclic nucleotide analogues (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA] and (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine [(S)-HPMPC] were evaluated for their inhibitory effect on colony forming unit formation by human granulocyte-macrophage progenitor cells (obtained from 11 healthy volunteers) in vitro. The 50 % inhibitory dose of zidovudine, (S)-HPMPA, (S)-HPMPC, ganciclovir and phosphonoformate were 10.61, 16.55, 80.88, 41.02 and 668.64 µM, respectively, when the median-effect principle was applied. The bone marrow toxicity of zidovudine used at a low concentration (3.74 µM) was significantly decreased if the drug was combined with (S)-HPMPA, (S)-HPMPC or ganciclovir. If used at higher concentrations (74.90 µM), zidovudine showed increased myelotoxicity in the presence of (S)-HPMPA and ganciclovir, but not (S)-HPMPC.

Keywords

Nucleotide Bone Marrow Human Immunodeficiency Virus Healthy Volunteer Adenine 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Mitsuya H, Weinhold KJ, Furman PA, St. Clair MH, Nusinoff-Lehrman S, Gallo RC, Bolognesi D, Barry DW, Broder S: 3′-azido-3′-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proceedings of the National Academy of Sciences of the USA 1985, 82: 7096–7100.PubMedGoogle Scholar
  2. 2.
    Matthews T, Boehme R: Antiviral activity and mechanism of action of ganciclovir. Reviews of Infectious Diseases 1988, 10, Supplement 3: 490–494.Google Scholar
  3. 3.
    Dainiak N, Worthington M, Riordan MA, Kreczko S, Goldman L: 3′-azido-3′-deoxythymidine (AZT) inhibits proliferation in vitro of human haematopoietic progenitor cells. British Journal of Haematology 1988, 69: 299–304.PubMedGoogle Scholar
  4. 4.
    Sommadossi J-P, Carlisle R: Toxicity of 3′-azido-3′-deoxythymidine and 9-(1,3-dihydroxy-2-propoxy-methyl)-guanine for normal human hematopoietic progenitor cells in vitro. Antimicrobial Agents and Chemotherapy 1987, 31: 452–454.PubMedGoogle Scholar
  5. 5.
    Sommadossi J-P, Carlisle R, Schinazi RF, Zhou Z: Uridine reverses the toxicity of 3′-azido-3′-deoxythymidine in normal human granulocyte-macrophage progenitor cells in vitro without impairment of antiretroviral activity. Antimicrobial Agents and Chemotherapy 1988, 32: 997–1001.PubMedGoogle Scholar
  6. 6.
    Buhles WC, Mastre BJ, Tinker AJ, Strand V, Koretz SH, the Syntex Collaborative Ganciclovir Treatment Group: Ganciclovir treatment of life-or sight-threatening cytomegalovirus infection: experience in 314 immunocompromised patients. Reviews of Infectious Diseases 1988, 10, Supplement, 3: 495–506.Google Scholar
  7. 7.
    Winston DJ, Ho WG, Bartoni K, Holland GN, Mitsuya RT, Gale RP, Busuttil RW, Champlin RE: Ganciclovir therapy for cytomegalovirus infections in recipients of bone marrow transplants and other immunosuppressed patients. Reviews of Infectious Diseases 1988, 10, Supplement 3: 547–553.Google Scholar
  8. 8.
    De Clercq E, Sakuma T, Baba M, Pauwels R, Balzarini J, Rosenberg I, Holy A: Antiviral activity of phosponylmethoxyalkyl derivatives of purine and pyrimidines. Antiviral Research 1987, 8: 261–272.CrossRefPubMedGoogle Scholar
  9. 9.
    De Clercq E, Holy A, Rosenberg I, Sakuma T, Balzarini J, Maudgal PC: A novel selective broad-spectrum anti-DNA virus agent. Nature 1986, 323: 464–467.PubMedGoogle Scholar
  10. 10.
    Snoeck R, Sakuma T, De Clercq E, Rosenberg I, Holy A: (S)-1-(3-hydroxy-2-phosponylmethoxypropyl) cytosine, a potent and selective inhibitor of human cytomegalovirus replication. Antimicrobial Agents and Chemotherapy 1988, 32: 1839–1844.PubMedGoogle Scholar
  11. 11.
    Pike BL, Robinson WA: Human bone marrow colony growth in agar-gel. Journal of Cellular Physiology 1970, 76: 77–84.CrossRefPubMedGoogle Scholar
  12. 12.
    delforge A, de Caluwe JP, Rongé-Collard E, Mattelaer MA, Spino T, Van den Heule B, Stryckmans PA: Increased levels of myeloid progenitor cells in the blood of patients with metastatic invasion of the marrow. Scandinavian Journal of Haematology 1983, 31: 275–279.PubMedGoogle Scholar
  13. 13.
    Moore M, Metcalf D, McCullock E, Robinson W, Dicke K, Chewenick P, Wu A, Goldman J, Testa N: Report of a workshop on standardization of selective cultures for normal and leukaemic cells. British Journal of Cancer 1977, 35: 500–508.PubMedGoogle Scholar
  14. 14.
    Chou T, Talalay P: Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Advances in Enzyme Regulation 1984, 22: 27–55.CrossRefPubMedGoogle Scholar
  15. 15.
    Parker LM, Lipton JM, Binder N, Crawford EL, Kudisch M, Levin MJ: Effect of acyclovir and interferon on human hematopoietic progenitor cells. Antimicrobial Agents and Chemotherapy 1982, 21: 146–150.PubMedGoogle Scholar
  16. 16.
    Bhalla K, Birkhofer M, Grant S, Graham G: The effect of recombinant human granulocyte-macrophage colony-stimulating factor (rGM-CSF) on 3′-azido-3′-deoxythymidine (AZT)-mediated biochemical and cytotoxic effects on normal human myeloid progenitor cells. Experimental Hematology 1989, 17: 17–20.PubMedGoogle Scholar

Copyright information

© Friedr. Vieweg & Sohn Verlagsgesellschaft mbH 1990

Authors and Affiliations

  • R. Snoeck
    • 1
  • L. Lagneaux
    • 2
  • A. Delforge
    • 2
  • D. Bron
    • 2
  • P. Van der Auwera
    • 2
  • P. Stryckmans
    • 2
  • J. Balzarini
    • 1
  • E. De Clercq
    • 1
  1. 1.Rega Institute for Medical ResearchKatholieke Universiteit LeuvenLeuvenBelgium
  2. 2.Service de Médecine Interne, Institut Jules BordetCentre des Tumeurs de l'Université Libre de BruxellesBrusselsBelgium

Personalised recommendations