Differential effects of 2,2'-anhydro-5-ethyluridine, a uridine phosphorylase inhibitor, on the antitumor activity of 5-fluorouridine and 5-fluoro-2'-deoxyuridine.
2,2'-Anhydro-5-ethyluridine (ANEUR), a potent inhibitor of uridine phosphorylase, markedly potentiated the antitumor activity of fluorouridine (FUR) against murine mammary adenocarcinoma 755 in BDF1 mice and human colon adenocarcinoma LS174T in athymic-nude mice. Whereas ANEUR annihilated the antitumor activity of 5-fluoro-2'-deoxyuridine (FUdR) and 5'-deoxy-5-fluorouridine (DFUR) in the murine adenocarcinoma 755 system, it did not alter the antitumor activity of FUdR in the human adenocarcinoma LS174T system. In vitro, ANEUR proved inhibitory to the phosphorolytic cleavage of both FUR and FUdR by uridine phosphorylase, and this could explain why in vivo conversion of FUR and FUdR to 5-fluorouracil was suppressed. FUR can be held directly responsible for the antitumor effects observed in the murine adenocarcinoma 755 system, whereas in the activity against human adenocarcinoma LS174T may be mediated by both FUR and FUdR.
Iigo
M
M
Chemotherapy Division, National Cancer Center Research Institute, Tokyo, Japan.
Nishikata
K
K
Nakajima
Y
Y
Szinai
I
I
Veres
Z
Z
Szabolcs
A
A
De Clercq
E
E
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004347:Drug Interactions; D005467:Floxuridine / Q000097:blood / Q000627:therapeutic use*; D005472:Fluorouracil / Q000097:blood; D006801:Humans; D007700:Kinetics; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors*; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014529:Uridine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D014543:Uridine Phosphorylase / Q000037:antagonists & inhibitors*
C054825:5-ethyl-2,2'-anhydrouridine; D005467:Floxuridine; C001943:5-fluorouridine; D010430:Pentosyltransferases; D014543:Uridine Phosphorylase; D013939:Thymidine Phosphorylase; D005472:Fluorouracil; D014529:Uridine