TY - JOUR
T1 - Intracellular metabolism of CycloSaligenyl 3'-azido-2',3'- dideoxythymidine monophosphate, a prodrug of 3'-azido-2',3'-dideoxythymidine (zidovudine)
AU - Balzarini, Jan
AU - Naesens, Lieve
AU - Aquaro, S.
AU - Knispel, T.
AU - Perno, C. F.
AU - De Clercq, E.
AU - Meier, C.
PY - 1999
Y1 - 1999
N2 - 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 intracellular T( 1/2 ) 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 of CycloSal-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.
AB - 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 intracellular T( 1/2 ) 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 of CycloSal-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.
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M3 - Article
C2 - 10570065
AN - SCOPUS:0032731244
VL - 56
SP - 1354
EP - 1136
JO - Molecular Pharmacology
JF - Molecular Pharmacology
SN - 0026-895X
IS - 6
ER -