Mechanisms underlying apoptosis induced by combination of 5-fluorouracil and interferon-gamma.
Several investigators have reported on the clinical effects of 5-fluorouracil (5-FU) or the combination of 5-FU plus interferon-gamma (IFN-gamma) on patients with advanced colorectal carcinoma. It has also been reported that apoptosis induced by 5-FU is due to the effects on DNA synthesis and functional RNA synthesis. In the present study, we examine the biological mechanisms underlying 5-FU or the combination of 5-FU plus IFN-gamma, using the colorectal carcinoma cell line, COLO 201, 5-FU and IFN-gamma independently or additively induced apoptosis in COLO 201 in a dose- and time-dependent manner, which was correlated with the down-regulation of Bcl-2 and the up-regulation of Bax. An interleukin-1 beta-converting enzyme (ICE)-like protease inhibitor (but not an ICE-inhibitor) blocked apoptosis induced by only 5-FU. These results suggest that 5-FU has the capacity to induce apoptosis in COLO 201, resulting from the up-regulation of Bax; the apoptosis-inducing signal of 5-FU seems to be different from that of IFN-gamma. Thereby, 5-FU and IFN-gamma have additional effects on the induction of apoptosis. This finding provides an experimental basis for clinical therapy using 5-FU and/or IFN-gamma for colorectal cancer.
Koshiji
M
M
First Department of Pathology, Kansai Medical University, Osaka, Japan.
Adachi
Y
Y
Taketani
S
S
Takeuchi
K
K
Hioki
K
K
Ikehara
S
S
D000230:Adenocarcinoma; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020170:Caspase 1; D003110:Colonic Neoplasms; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004347:Drug Interactions; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007700:Kinetics; D011480:Protease Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D004273:DNA, Neoplasm; D011480:Protease Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012334:RNA, Neoplasm; D051028:bcl-2-Associated X Protein; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases; D020170:Caspase 1; D005472:Fluorouracil