Intracellular Metabolism of CycloSaligenyl 3′-Azido-2′,3′-dideoxythymidine Monophosphate, a Prodrug of 3′-Azido-2′,3′-dideoxythymidine (Zidovudine)
- Jan Balzarini1,
- Lieve Naesens1,
- S. Aquaro2,
- T. Knispel3,
- C.-F. Perno2,4,
- E. De Clercq1 and
- C. Meier3
- 1Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium (J.B., L.N., E. De C.); 2Department of Experimental Medicine, University of Rome “Tor Vergata,” Rome, Italy (S.A., C.-F.P.); 3Institut für Organische Chemie, Universität Hamburg, Hamburg, Germany (T.K., C.M.); and 4IRCCS L. Spallanzani, Rome, Italy (C.-F.P.)
Abstract
The administration of CycloSaligenyl 3′-azido-2′,3′-dideoxythymidine monophosphate (CycloSal-AZTMP) to CEM cells resulted in a concentration- and time-dependent conversion to the 5′-monophosphate (AZTMP), 5′-diphosphate (AZTDP), and 5′-triphosphate (AZTTP) derivatives. High ratios of AZTMP/AZTTP were found in the CEM cell cultures treated with CycloSal-AZTMP. The intracellularT1/2 of AZTTP in CEM cell cultures treated with either AZT and CycloSal-AZTMP was approximately 3 h. A variety of human T- and B-lymphocyte cell lines efficiently converted the prodrug to the AZT metabolites, whereas peripheral blood lymphocytes and primary monocyte/macrophages showed at least 10-fold lower metabolic conversion of the prodrug.CycloSal-AZTMP failed to generate marked levels of AZT metabolites in thymidine kinase-deficient CEM/TK− cells, an observation that is in agreement with the substantial loss of antiviral activity of CycloSal-AZTMP in CEM/TK− cells. The inability ofCycloSal-AZTMP to generate AZTMP in CEM/TK−cells is presumably due to a relatively high hydrolysis rate of AZTMP to the parent nucleoside AZT, combined with the inability of CEM/TK− cells to phosphorylate AZT to AZTMP through the cytosolic salvage enzyme thymidine kinase.
Footnotes
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Send reprint requests to: Prof. Dr. J. Balzarini, Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium. E-mail: jan.balzarini{at}rega.kuleuven.ac.be
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This work was supported by Biomedical Research Programme of the European Commission, the Belgian “Geconcerteerde Onderzoeksacties” (Project 95/5), and the “Fonds voor Wetenschappelijk Onderzoek–Vlaanderen” (Project G.0104.98).
- Abbreviations:
- CycloSal-AZTMP
- CycloSaligenyl 3′-azido-2′,3′-dideoxythymidine monophosphate
- AZTMP
- 5′-monophosphate derivative of AZT
- AZTDP
- 5′-diphosphate derivative of AZT
- AZTTP
- 5′-triphosphate derivative of AZT
- TK
- thymidine kinase
- APA
- aryloxyphosphoramidate
- 5′-Nu
- 5′-nucleotidase
- PBL
- peripheral blood lymphocyte
- HIV
- human immunodeficiency virus
- dTMP
- thymidylate
- AZT
- 3′-azido-2′,3′-dideoxythymidine
- M/M
- monocyte/macrophages
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- Received July 2, 1999.
- Accepted September 9, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
