Cytokines induce uridine phosphorylase in mouse colon 26 carcinoma cells and make the cells more susceptible to 5'-deoxy-5-fluorouridine.
The antiproliferative activity of 5-fluorouracil (5-FUra) and 5'-deoxy-5-fluorouridine (5'-dFUrd), used in combination with typical cytokines and growth factors, was investigated in mouse colon 26 carcinoma cells. Tumor necrosis factor alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha), and interferon gamma (IFN gamma) at low doses showing < 50% inhibition of cell growth by themselves enhanced the susceptibility of the cells to the activity of 5'-dFUrd. In particular, a mixture of these cytokines greatly enhanced the activity of 5'-dFUrd and 5-FUra by up to 12.4- and 2.7-fold, respectively, whereas the activity of other cytostatics was only slightly changed (< 1.5-fold). Basic fibroblast growth factor also increased the susceptibility, but only to 5'-dFUrd. This preferential enhancement of the activity of 5'-dFUrd would be due to induction by the cytokines of uridine phosphorylase (Urd Pase), by which 5'-dFUrd is converted to 5-FUra. TNF alpha, IL-1 alpha, IFN gamma, and a mixture of these factors increased the enzyme activity by up to 3.7-fold in colon 26 cells. Consequently, the anabolism of 5'-dFUrd to fluoronucleotides and the incorporation of 5-FUra into RNA in colon 26 cells were increased by TNF alpha treatment. In addition, the increase by the cytokine mixture in the susceptibility to 5'-dFUrd was abolished by an inhibitor of Urd Pase, 2,2'-anhydro-5-ethyluridine. These results indicate that induction of Urd Pase activity by cytokines is a critical event that increases the susceptibility to 5'-dFUrd.
Eda
H
H
Department of Oncology, Nippon Roche Research Center, Kanagawa.
Fujimoto
K
K
Watanabe
S
S
Ishikawa
T
T
Ohiwa
T
T
Tatsuno
K
K
Tanaka
Y
Y
Ishitsuka
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology; D016207:Cytokines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004790:Enzyme Induction; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005467:Floxuridine / Q000633:toxicity*; D005472:Fluorouracil / Q000633:toxicity; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D051379:Mice; D012334:RNA, Neoplasm / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014529:Uridine / Q000031:analogs & derivatives / Q000494:pharmacology; D014543:Uridine Phosphorylase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
C054825:5-ethyl-2,2'-anhydrouridine; D000970:Antineoplastic Agents; D016207:Cytokines; D007375:Interleukin-1; D012334:RNA, Neoplasm; D014409:Tumor Necrosis Factor-alpha; D005467:Floxuridine; D016222:Fibroblast Growth Factor 2; D007371:Interferon-gamma; D014543:Uridine Phosphorylase; D005472:Fluorouracil; C025034:doxifluridine; D014529:Uridine