Cytokines induce thymidine phosphorylase expression in tumor cells and make them more susceptible to 5'-deoxy-5-fluorouridine.
The present study shows that various cytokines such as tumor necrosis factor (TNF alpha), interleukin-1 alpha (IL-1 alpha), and interferon-gamma (IFN gamma) make tumor cells much more susceptible to the cytostatic 5'-deoxy-5-fluorouridine (5'-dFUrd) than to 5-fluorouracil (5-FUra) and other cytostatics. These three cytokines increased the susceptibility of human cancer cell lines (COLO201, MKN45 and WiDr) but did not affect that of normal fibroblast WI38 cells. The cytokine mixture induced a 50-fold increase in the susceptibility of COLO201 to 5'-dFUrd, whereas a 12-fold increase and a less than 5-fold enhancement in the susceptibility to 5-FUra and other cytostatics, respectively, were observed. The increased susceptibility would be a result of the induction of thymidine phosphorylase (TdR Pase), which is the essential enzyme for the conversion of 5'-dFUrd to 5-FUra. The cytokine mixture increased TdR Pase activity by up to 47 times and greatly induced its mRNA expression in the cancer cell lines. These results suggest that the therapeutic benefit of 5'-dFUrd would be improved by its use in combination with the cytokines.
Eda
H
H
Department of Oncology, Nippon Roche Research Center, Kanagawa, Japan.
Fujimoto
K
K
Watanabe
S
S
Ura
M
M
Hino
A
A
Tanaka
Y
Y
Wada
K
K
Ishitsuka
H
H
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology; D016207:Cytokines / Q000494:pharmacology*; D003864:Depression, Chemical; D004357:Drug Synergism; D004790:Enzyme Induction; D005467:Floxuridine / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D013274:Stomach Neoplasms / Q000473:pathology; D013939:Thymidine Phosphorylase / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000970:Antineoplastic Agents; D016207:Cytokines; D007375:Interleukin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D005467:Floxuridine; D007371:Interferon-gamma; D013939:Thymidine Phosphorylase; D005472:Fluorouracil; C025034:doxifluridine