Benzylacyclouridine enhances 5-fluorouracil cytotoxicity against human prostate cancer cell lines.
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.
Yee
L K
LK
Department of Medicine and Clinical Pharmacology, Brown University, Rhode Island Hospital, Providence 02903, USA.
Chu
E
E
Pan
B C
BC
Chu
S H
SH
Chen
T M
TM
Lipsky
M H
MH
Chu
M Y
MY
Calabresi
P
P
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005472:Fluorouracil / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D014543:Uridine Phosphorylase / Q000037:antagonists & inhibitors
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; C034753:5-benzylacyclouridine; D014498:Uracil; D013940:Thymidylate Synthase; D014543:Uridine Phosphorylase; D005472:Fluorouracil