Koshiji M, Adachi Y, Taketani S, Takeuchi K, Hioki K, Ikehara S
First Department of Pathology, Kansai Medical University, Osaka, Japan.
Biochem Biophys Res Commun. 1997 Nov 17;240(2):376-81. doi: 10.1006/bbrc.1997.7657.
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.
几位研究者报告了5-氟尿嘧啶（5-FU）或5-FU联合γ-干扰素（IFN-γ）对晚期结直肠癌患者的临床疗效。也有报道称，5-FU诱导的细胞凋亡是由于其对DNA合成和功能性RNA合成的影响。在本研究中，我们使用结肠癌细胞系COLO 201研究5-FU或5-FU联合IFN-γ的生物学机制，5-FU和IFN-γ单独或联合使用均以剂量和时间依赖性方式诱导COLO 201细胞凋亡，这与Bcl-2的下调和Bax的上调相关。一种白细胞介素-1β转换酶（ICE）样蛋白酶抑制剂（而非ICE抑制剂）可阻断仅由5-FU诱导的细胞凋亡。这些结果表明，5-FU具有在COLO 201细胞中诱导细胞凋亡的能力，这是由Bax的上调所致；5-FU的凋亡诱导信号似乎与IFN-γ不同。因此，5-FU和IFN-γ在诱导细胞凋亡方面具有附加作用。这一发现为使用5-FU和/或IFN-γ治疗结直肠癌的临床治疗提供了实验依据。
