[Estimation of pathways of 5-fluorouracil anabolism in human cancer cells in vitro and in vivo].
Possible pathways of intracellular phosphorylation of 5-fluorouracil (5-FU) in human cancer cells were investigated in vitro and in vivo. We used two inhibitors which regulate the anabolism of 5-FU for the purpose of elucidation of its pathways; one is oxonic acid (Oxo), an inhibitor of orotate phosphoribosyltransferase (OPRTase), catalizing a formation of FUMP from 5-FU, and another is 2, 6-dihydroxypyridine (DP), an inhibitor of uracil ribosyltransferase which catalizes a conversion of 5-FU to 5-fluorouridine. Although the pathway of 5-FU phosphorylation in murine tumor cells was varied, about 80% of human cancer cells tested were found to utilize the first pathway in which 5-FU was converted to FUMP by OPRTase. Thus, the phosphorylation of 5-FU via the first pathway was markedly inhibited by Oxo in 4 strains of 5 gastric cancer cells, 7 of 8 colorectal cancer cells and 3 of 4 lung cancer cells. In xenografts of human gastric and colorectal adenocarcinoma in which 5-FU phosphorylation is regulated by Oxo in vitro, the production of 5-fluoronucleotides and its incorporation into RNA after iv administration of 5-FU significantly decreased by co-administration of Oxo, suggesting that the nature of an anabolic pathway of 5-FU in the tumor cells in vitro reflects in vivo behavior. We also confirmed that the phosphoribosylpyrophosphate level in tumor cells was importantly related to determination of the metabolic pathway of 5-FU. These results would suggest that possible modulation of 5-FU lies on the augmentation of 5-FU efficacy.
Fukushima
M
M
Second Cancer Research Laboratory, Taiho Pharmaceutical Co., Ltd., Japan.
Nomura
H
H
Murakami
Y
Y
Shirasaka
T
T
Aiba
K
K
D000818:Animals; D015179:Colorectal Neoplasms / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005472:Fluorouracil / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008813:Mice, Inbred ICR; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism*; D009962:Orotate Phosphoribosyltransferase / Q000037:antagonists & inhibitors; D010094:Oxonic Acid / Q000494:pharmacology; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000201:enzymology / Q000378:metabolism
D004791:Enzyme Inhibitors; D011725:Pyridines; D010094:Oxonic Acid; C089431:2,6-dihydroxypyridine; D010430:Pentosyltransferases; D009962:Orotate Phosphoribosyltransferase; C023269:uracil phosphoribosyltransferase; D005472:Fluorouracil