A pro-drug of zidovudine with enhanced efficacy against human immunodeficiency virus

In a attempt to alleviate the drug-related toxicity of zidovudine in patients with AIDS, a pro-drug of zidovudine, 5′-{(1,4-dihydro-1-methyl-3-pyridinylcarbonyl)oxy}-3′-azido-2′,3′-dideoxythymidine (DP-AZT), has been evaluated. Cellular uptake by H9 cells and peripheral blood lymphocytes (PBL) with...

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Veröffentlicht in:	Biochemical and biophysical research communications 1989-04, Vol.160 (2), p.656-661
Hauptverfasser:	Gogu, Sudhir R., Aggarwal, Sunil K., Rangan, S.R.S., Agrawal, Krishna C.
Format:	Artikel
Sprache:	eng
Schlagworte:	5′-{(1,4-dihydro-1-methyl-3-pyridinyl-carbonyl)oxy}-3′-azido-2′,3′-dideoxythymidine Animals Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Biological and medical sciences Bone Marrow Cell Line, Transformed Cell Membrane Permeability - drug effects cerebrospinal fluid Colony-Forming Units Assay CSF Cytoplasm - metabolism DP-AZT Hematopoietic Stem Cells - drug effects HIV-1 - drug effects Humans Hydrolysis Lymphocytes - drug effects Medical sciences Mice PBL PBS peripheral blood lymphocytes Pharmacology. Drug treatments phosphate-buffered saline Prodrugs - metabolism Prodrugs - pharmacology Prodrugs - toxicity Virus Replication - drug effects Zidovudine - metabolism Zidovudine - pharmacology Zidovudine - toxicity
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Zusammenfassung:	In a attempt to alleviate the drug-related toxicity of zidovudine in patients with AIDS, a pro-drug of zidovudine, 5′-{(1,4-dihydro-1-methyl-3-pyridinylcarbonyl)oxy}-3′-azido-2′,3′-dideoxythymidine (DP-AZT), has been evaluated. Cellular uptake by H9 cells and peripheral blood lymphocytes (PBL) with zidovudine and DP-AZT showed at least a 50% greater intracellular concentration of DP-AZT with-in 2 hr. DP-AZT was significantly less toxic to murine bone marrow cells as measured by CFU-E assay. The ED 50 concentration to inhibit the production of HIV specific p24 antigen was 0.05 μM for DP-AZT whereas zidovudine required 0.125 μM. These results demonstrated that DP-AZT has a higher therapeutic ratio than zidovudine as an anti-HIV-1 agent.
ISSN:	0006-291X 1090-2104
DOI:	10.1016/0006-291X(89)92483-2