Sawaoka H, Kawano S, Tsuji S, Tsujii M, Gunawan E S, Takei Y, Nagano K, Hori M
First Department of Medicine, Osaka University School of Medicine, Osaka, Japan.
Am J Physiol. 1998 Jun;274(6):G1061-7. doi: 10.1152/ajpgi.1998.274.6.G1061.
To clarify the role of mitogen-inducible cyclooxygenase (COX-2) in the development of malignant tumors, we investigated the effects of COX-2 inhibitors on the growth of gastric cancer xenografts in nude mice in vivo. MKN45 gastric cancer cells (5 x 10(6) cells/animal) that overexpress COX-2 were inoculated subcutaneously into athymic mice. NS-398, a specific COX-2 inhibitor, or indomethacin, a nonspecific COX-2 inhibitor, was administered orally to animals every day for 20 days. These drugs reduced the tumor volume significantly. Immunohistochemistry using bromodeoxyuridine, nick end labeling, and electron microscopy showed that NS-398 induced apoptosis in cancer cells in a dose-dependent manner and inhibited cancer cell replication slightly. Indomethacin also induced apoptosis and suppressed replication of tumor cells. There was a significant negative correlation between tumor volume and apoptotic cell number within the tumor. These results are consistent with the hypothesis that COX-2 inhibitors suppress growth of gastric cancer xenografts mainly by inducing apoptosis and suppressing replication of the neoplastic cells. It follows that COX-2 plays an important role in the development of gastric cancer.
为阐明丝裂原诱导型环氧化酶（COX-2）在恶性肿瘤发生中的作用，我们在体内研究了COX-2抑制剂对裸鼠胃癌异种移植瘤生长的影响。将过表达COX-2的MKN45胃癌细胞（5×10⁶个细胞/只动物）皮下接种到无胸腺小鼠体内。每天给动物口服特异性COX-2抑制剂NS-398或非特异性COX-2抑制剂吲哚美辛，持续20天。这些药物显著减小了肿瘤体积。使用溴脱氧尿苷、缺口末端标记法进行的免疫组织化学以及电子显微镜检查显示，NS-398以剂量依赖方式诱导癌细胞凋亡，并轻微抑制癌细胞复制。吲哚美辛也诱导肿瘤细胞凋亡并抑制其复制。肿瘤体积与肿瘤内凋亡细胞数之间存在显著负相关。这些结果与以下假说一致，即COX-2抑制剂主要通过诱导凋亡和抑制肿瘤细胞复制来抑制胃癌异种移植瘤的生长。由此可见，COX-2在胃癌发生中起重要作用。
