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J Korean Soc Coloproctol. 2005 Jun;21(3):121-128. Korean. Original Article.
Lee TB , Kim KJ , Min YD , Kang SI , Jung KR , Lee JU , Choi CH .
Department of Surgery, College of Medicine, Chosun University, Gwangju, Korea. kjkim@chosun.ac.kr
Research Center for Resistant Cells, College of Medicine, Chosun University, Gwangju, Korea.
Department of Pharmacology, College of Medicine, Chosun University, Gwangju, Korea.
Abstract

PURPOSE: Cyclooxygenase (COX)-2, an inducible enzyme that catalyzes the conversion of arachidonic acid to prostaglandins, is believed to be an important enzyme related to colorectal cancer. A large number of studies have supported the concept that non-steroidal anti-inflammatory drugs (NSAIDs) targeting COX alter the biologic processes of colon carcinogenesis. Although COX-2 inhibitors generally reduce the growth rate of established tumors, tumor regression is rarely observed. Hence, it is reasonable that COX-2 inhibitors be given in conjunction with standard anti-cancer therapy in treating cancer. We investigated whether aspirin and meloxicam not only are cytotoxic but also potentiate the antitumor effect of 5-Fluorouracil (5-FU) against colon cancer cells. METHODS: Expressions of COX-1 and COX-2 were determined by using the reverse transcriptase-polymerase chain reaction (RT-PCR) & Western blotting assay in 9 colon cancer cell lines. The cytotoxicities of NSAIDs and/or 5-FU were determined by using a microculture tetrazolium dye (MTT) assay. RESULTS: COX-1 mRNA and protein, as well as COX-2 mRNA, were variably expressed in all the cell lines tested whereas COX-2 protein was expressed in HT-29 and to a lesser extent in HCT-8, but not in the other cell lines. We selected two representative cell lines, HT-29 expressing COX-2 protein and SNU-C1 not expressing it. The dose-dependent cytotoxicity was observed in both cell lines treated with aspirin and with meloxicam. A combination treatment of aspirin or meloxicam with 5-FU revealed some additive effect, rather than a synergistic effect, for both cells lines. This additive effect was remarkable even for low concentrations of the drugs. Furthermore, the additive effect was highest when the combination was adminstered sequentially, 5-FU followed by aspirin or meloxicam, in both cell lines. CONCLUSIONS: These results suggest that a combination therapy using NSAIDs and 5-FU might be useful in the treatment of colon cancer cells not expressing COX-2, as well as in colon cancer cells expressing COX-2.

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