Abstract
A gemcitabine (2',2'-difluorodeoxycytidine, dFdC) phosphoramidate prodrug designed for the intracellular delivery of gemcitabine 5'-monophosphate was synthesized. The prodrug was about an order of magnitude less active than gemcitabine against wild-type cells, and the nucleoside transport inhibitor dipyridamole reduced prodrug activity. The prodrug was more active than gemcitabine against two deoxycytidine kinase-deficient cell lines. The results suggest that the prodrug is a potent growth inhibitor that can bypass dCK deficiency at higher drug concentrations.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Antimetabolites, Antineoplastic / chemical synthesis
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Antimetabolites, Antineoplastic / chemistry
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Antimetabolites, Antineoplastic / pharmacology*
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Cell Line, Tumor
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Cytidine Monophosphate / analogs & derivatives*
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Cytidine Monophosphate / chemical synthesis
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Cytidine Monophosphate / chemistry
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Cytidine Monophosphate / pharmacology
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Deoxycytidine / analogs & derivatives*
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Deoxycytidine / pharmacology
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Deoxycytidine Kinase / genetics
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Dipyridamole / pharmacology
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Drug Screening Assays, Antitumor
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Gemcitabine
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Humans
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Nucleoside Transport Proteins / antagonists & inhibitors
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Prodrugs / chemical synthesis
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Prodrugs / chemistry
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Prodrugs / pharmacology*
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Structure-Activity Relationship
Substances
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5'-(2'-deoxy-2',2'-difluorocytidyl) 5-nitrofurfuryl N-methyl-N-(4-chlorobutyl) phosphoramidate
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Antimetabolites, Antineoplastic
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Nucleoside Transport Proteins
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Prodrugs
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Deoxycytidine
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Dipyridamole
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Deoxycytidine Kinase
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Cytidine Monophosphate
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Gemcitabine