Abstract
At a nontoxic growth inhibitory concentration benzyloxyacyclouridine (BAU), a potent and specific inhibitor of uridine phosphorylase (UrdPase), enhanced 5-fluorouracil (5-FU) cytotoxic activity against human prostate cancer PC-3 and DU-145 cell lines. The BAU/5-FU combination exhibited greater antitumor activity in vivo using PC-3 human xenografts compared to 5-FU alone, with no associated increase in animal host toxicity. The mechanism(s) responsible for the enhanced in vitro and in vivo activity of this combination may involve enhanced formation of the 5-FU nucleotide metabolites FdUMP, FdUTP, and FUTP resulting in enhanced inhibition of thymidylate synthase (TS) and increased incorporation of fluoropyrimidine metabolites into tumoral RNA and DNA.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antimetabolites, Antineoplastic / therapeutic use*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Drug Interactions
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / therapeutic use*
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Fluorouracil / administration & dosage
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Fluorouracil / metabolism
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Fluorouracil / therapeutic use*
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Humans
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Male
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Mice
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Mice, Nude
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / metabolism
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Thymidylate Synthase / antagonists & inhibitors
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Tumor Cells, Cultured
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Uracil / administration & dosage
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Uracil / analogs & derivatives*
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Uracil / pharmacology
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Uridine Phosphorylase / antagonists & inhibitors
Substances
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Antimetabolites, Antineoplastic
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Enzyme Inhibitors
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5-benzylacyclouridine
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Uracil
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Thymidylate Synthase
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Uridine Phosphorylase
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Fluorouracil