Suppressive effect of TNF-alpha on increased production of FdUMP by IFN-alpha.
Interferon-alpha (IFN-alpha) exhibits synergistic antitumor activity when combined with tumor necrosis factor-alpha (TNF-alpha) in vitro and in vivo and increases the cytotoxicity of 5-fluorouracil (5-FU) in vitro. Using a colon cancer cell line transplanted into nude mice, we examined the effects of pretreatment for 3 days with IFN-alpha (10(6) IU) and/or TNF-alpha (2.9 x 10(3) JRU) on 5-FU metabolism. 5-FU 30 mg/kg was administered after the pretreatment. IFN-alpha increased the tumor level of 5-fluorodeoxuridine monophosphate (FdUMP), and decreased the free level of thymidylate synthetase. Pretreatment with TNT-alpha alone decreased HUMP whereas TNF-alpha plus IFN-alpha abolished the enhancement of FdUMP production by IFN-alpha. TNF-alpha also suppressed thymidine kinase activity. Neither IFN-alpha nor TNF-alpha altered the incorporation of 5-FU into RNA.
Hatano
H
H
First Department of Surgery, Okayama University Medical School, Japan.
Tanaka
N
N
Naomoto
Y
Y
Orita
K
K
D000818:Animals; D002460:Cell Line; D004261:DNA Replication / Q000187:drug effects; D005260:Female; D005468:Fluorodeoxyuridylate / Q000378:metabolism*; D005472:Fluorouracil / Q000378:metabolism*; D016898:Interferon-alpha / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D013937:Thymidine Kinase / Q000187:drug effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016898:Interferon-alpha; D014409:Tumor Necrosis Factor-alpha; D005468:Fluorodeoxyuridylate; D013937:Thymidine Kinase; D005472:Fluorouracil