Serum factors attenuating the anti-tumor activity of 5-fluorouracil.
In sera of cachectic patients bearing advanced cancers, the concentration of interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrotizing factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) have been reported to elevate. In this study, we investigated whether those cytokines influenced in vitro anti-tumor effect of 5-fluorouracil (5-FU) on a human colon tumor cell line, HCT-15. Pretreatment of HCT-15 cells with IL-1 beta, IL-6 or TNF-alpha did not affect the anti-tumor effect of 5-FU at various concentrations. However, IFN-gamma attenuated the anti-tumor effect of 5-FU at the concentrations of 0.1-10 IU/ml. An experiment with tritium thymidine showed that 0.1 IU/ml of IFN-gamma did not suppress the growth of HCT-15 cells. As low as 0.1 IU/ml of IFN-gamma attenuated the anti-tumor effect of 5-FU in another experimental system where HCT-15 cells were exposed to 0.1 IU/ml of IFN-gamma before and during the treatment with 5-FU. This system mimicked the clinical condition around in situ cancer cells. Treatment of HCT-15 cells with 0.1-10 IU/ml of IFN-gamma did not change their DNA histogram pattern. An immunoblotting with the antibodies to thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in HCT-15 cells revealed that 0.1-10 IU/ml of IFN-gamma enhanced their TS and DPD expressions. Results of the immunoblotting gave some explanation to attenuation in the sensitivity of HCT-15 cells to 5-FU.
Miwa
M
M
First Department of Surgery, Aichi Medical University, 21 Karimata-Yazako, Nagakute-cho, Aichi 480-1195, Japan.
Kojima
T
T
Naruse
T
T
D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D016207:Cytokines / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000187:drug effects; D004347:Drug Interactions; D004351:Drug Resistance; D005472:Fluorouracil / Q000633:toxicity*; D006801:Humans; D015151:Immunoblotting; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D013940:Thymidylate Synthase / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D016207:Cytokines; D004273:DNA, Neoplasm; D007375:Interleukin-1; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D013940:Thymidylate Synthase; D005472:Fluorouracil; D013936:Thymidine