Acyclothymidine alleviates intestinal toxicity of 5'-deoxy-5-fluorouridine without loss of antitumor activity in mice.
To reduce the intestinal toxicity of orally administered 5'-deoxy-5-fluorouridine (5'-DFUR) in mice, we co-administered 5'-DFUR with acyclothymidine [AcyT, 5-methyl-(2'-hydroxyethoxymethyl) uracil], a potent inhibitor of pyrimidine nucleoside phosphorylase (PyNPase). Orally administered 5'-DFUR alone caused intestinal toxicity and severe damage to the intestinal villi, while 5'-DFUR with AcyT reduced the intestinal toxicity, and prevented damage to the intestinal villi. This toxicity arising from orally administered 5'-DFUR could not be reduced by intravenous administration of AcyT, but was alleviated by oral administration. Orally co-administered AcyT showed little effect on antitumor activity of 5'-DFUR toward subcutaneously implanted Lewis lung carcinoma, though the intestinal toxicity was reduced in the tumor-bearing mice. This finding suggests that orally co-administered AcyT may prevent the undesirable conversion of 5'-DFUR to 5-FU by PyNPase during the process of absorption in the intestinal tract.
Hamada
A
A
Department of Pharmacy, Kumamoto University Hospital, Japan.
Fukushima
S
S
Saneyoshi
M
M
Shimizu
S
S
Kawaguchi
T
T
Nakano
M
M
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D001835:Body Weight; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005467:Floxuridine / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D007422:Intestines / Q000187:drug effects*; D007536:Isomerism; D051379:Mice; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors*; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005467:Floxuridine; D014498:Uracil; C046151:N-(2-(hydroxyethoxy)methyl)-5-methyluracil; D013939:Thymidine Phosphorylase; C025034:doxifluridine