Antitumor activity of 5'-deoxy-5-fluorouridine in human digestive organ cancer xenografts and pyrimidine nucleoside phosphorylase activity in normal and neoplastic tissues from human digestive organs.
5'-Deoxy-5-fluorouridine (5'-DFUR) is believed to be metabolized to 5-fluorouracil (5-FU) by pyrimidine nucleoside phosphorylase (PyNPase). PyNPase activity is reported to be higher in neoplastic tissues than in normal tissues, and this has been proposed as an explanation for the selective cytotoxicity of 5'-DFUR against tumors. In the present study, PyNPase activity was measured in 95 neoplastic and normal specimens from human digestive organ tissues. In specimens from the esophagus, stomach, intestine and pancreas, PyNPase activity was higher in neoplastic tissues than in normal tissues. However, PyNPase activity in non-malignant liver tissues, especially cirrhotic liver tissues, was much higher than in the normal tissues of the other digestive organs. PyNPase activity in non-malignant liver tissues was a high as in primary liver tumors, and PyNPase activity in metastatic liver tumors was lower than in primary tumors and non-malignant cirrhotic tissues. The in vivo antitumor activities of oral 5'-DFUR and intravenous 5-FU were also assessed in 6 human digestive organ cancer xenograft lines transplanted subcutaneously in nude mice, and the relationship between the in vivo antitumor effects of 5'-DFUR and PyNPase activity in the tumors was assessed. However, there was no statistically significant correlation between them. Although the in vivo antitumor effect of intravenous 5-FU correlated significantly with the in vitro sensitivity of the tumors to 5-FU (assessed by DNA synthesis inhibition assay), the in vivo effects of 5'-DFUR did not correlate with the in vitro sensitivity to 5-FU. It is suggested that: (a) the liver may be the major site for metabolizing 5'-DFUR to 5-FU, and (b) measuring PyNPase activity in the tumor may not be a useful indicator for chemotherapy with 5'-DFUR.
Nio
Y
Y
First Department of Surgery, Kyoto University Faculty of Medicine, Japan.
Kimura
H
H
Tsubono
M
M
Tseng
C C
CC
Kawabata
K
K
Masai
Y
Y
Hayashi
H
H
Meyer
C
C
Fukumoto
M
M
Tobe
T
T
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy* / Q000201:enzymology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004067:Digestive System Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D005467:Floxuridine / Q000627:therapeutic use*; D006801:Humans; D008103:Liver Cirrhosis / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010430:Pentosyltransferases / Q000378:metabolism*; D057845:Pyrimidine Phosphorylases
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D005467:Floxuridine; D010430:Pentosyltransferases; D057845:Pyrimidine Phosphorylases; C025034:doxifluridine