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.