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대장암 세포에서 5-FU의 세포독성에 대한 NSAIDs의 보조적인 효과

Adjuvant Effect of NSAIDs on the Cytotoxicity of Colon Cancer Cells to 5-FU

대한대장항문학회지 2005년 21권 3호 p.121 ~ 128
이태범 ( Lee Tae-Bum ) - 조선대학교 의과대학 내성세포연구센터

김경종 ( Kim Kyung-Jong ) - 조선대학교 의과대학 외과학교실
민영돈 ( Min Young-Don ) - 조선대학교 의과대학 외과학교실
강성인 ( Kang Sung-In ) - 조선대학교 의과대학 약리학교실
정권율 ( Jung Kwon-Ryul ) - 조선대학교 의과대학 약리학교실
이재업 ( Lee Jae-Up ) - 조선대학교 의과대학 약리학교실
최철희 ( Choi Cheol-Hee ) - 조선대학교 의과대학 내성세포연구센터

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. J Korean Soc Coloproctol 2005;21: 121-128

키워드

비스테로이성 항염제; 5-FU; 부가적 효과; 대장암세포
COX-2;NSAIDs;5-FU;Additive effect;Colon cancer cells COX-2
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