Inhibitory effects of potent inhibitors of human immunodeficiency virus and cytomegalovirus on the growth of human granulocyte-macrophage progenitor cells in vitro.
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 microM, respectively, when the median-effect principle was applied. The bone marrow toxicity of zidovudine used at a low concentration (3.74 microM) was significantly decreased if the drug was combined with (S)-HPMPA, (S)-HPMPC or ganciclovir. If used at higher concentrations (74.90 microM), zidovudine showed increased myelotoxicity in the presence of (S)-HPMPA and ganciclovir, but not (S)-HPMPC.
Snoeck
R
R
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Lagneaux
L
L
Delforge
A
A
Bron
D
D
Van der Auwera
P
P
Stryckmans
P
P
Balzarini
J
J
De Clercq
E
E
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D000077404:Cidofovir; D003587:Cytomegalovirus / Q000187:drug effects*; D003596:Cytosine / Q000031:analogs & derivatives / Q000494:pharmacology; D017245:Foscarnet; D015774:Ganciclovir / Q000494:pharmacology; D006098:Granulocytes / Q000187:drug effects; D006678:HIV / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D015215:Zidovudine / Q000494:pharmacology
D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D017245:Foscarnet; D015215:Zidovudine; D003596:Cytosine; C050127:9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; D000225:Adenine; D000077404:Cidofovir; D010746:Phosphonoacetic Acid; D015774:Ganciclovir