It is proposed that non-steroidal anti-inflammatory drugs (NSAIDs) reduce colorectal tumorigenesis by inhibition of cyclooxygenase (COX). COX is a key enzyme in the conversion of arachidonic acid to prostaglandins and two isoforms of COX have been characterized, COX-1 and COX-2. Multiple studies have shown that COX-2 is expressed at high levels in colorectal tumours and play a role in colorectal tumorigenesis. Recently it has been reported that selective inhibition of COX-2 inhibits colon cancer cell growth. In this study we investigated the effect of a selective COX-2 inhibitor (JTE-522) on haematogenous metastasis of colon cancer. For this purpose, we selected a murine colon cancer cell line, colon-26, that constitutively expresses the COX-2 protein. The subclone P expressed a high level of COX-2 and the subclone 5 expressed a low level. The colon-26 subclones were injected into the tail vein of BALB/c mice. JTE-522 was given intraperitoneally every day from the day prior to cancer cell injection, and the mice were sacrificed 16 days after cell injection. Lung metastases were compared between groups with and without JTE-522. In the mice injected with subclone P, the number of lung metastatic nodules was significantly reduced in the treated group. However, in the mice injected with subclone 5, there was little difference between the control and the treated groups. These results indicate that there may be a direct link between inhibition of haematogenous metastasis of colon cancer and selective inhibition of COX-2, and that selective COX-2 inhibitors may be a novel class of therapeutic agents not only for colorectal tumorigenesis but also for haematogenous metastasis of colon cancer.
Chamber, AF & Matrysian, LM (1997). Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 89: 1260–1270.
DuBois, RN, Awad, J, Morrow, J, Roberts, LJ & Bishop, PR (1994). Regulation of eicosanoid production and mitogenesis in rat intestinal epithelial cells by transforming growth factor and phorbol ester. J Clin Inves 93: 493–498.
Eberhart, CE, Coffey, RJ, Radhika, A, Giardiello, FM, Ferrenbach, S & DuBois, RN (1994). Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 107: 1183–1188.
Elder, DJE, Halton, DE, Hague, A & Paraskeva, C (1997). Induction of apoptotic cell death in human colorectal carcinoma cell lines by a cyclooxygenase-2 (COX-2)-selective nonsteroidal anti-inflammatory drug: independence from COX-2 protein expression. Clin Cancer Res 3: 1679–1683.
Folkman, J (1990). What is the evidence that tumors are angiogenesis dependent?. J Natl Cancer Inst 82: 4–6.
Form, DM & Auerbach, R (1983). PGE2 and angiogenesis. Prog Soc Exp Biol Med 172: 214–218.
Fujimoto-Ouchi, K, Tamura, S, Mori, K, Tanaka, Y & Ishitsuka, H (1995). Establishment and characterization of cachexia-inducing and -non-inducing clones of murine colon 26 carcinoma. Int J Cancer 61: 522–528.
Giovannucci, E, Rimm, EB, Stampfer, MJ, Colditz, GA, Ascherio, A & Willett, WC (1994). Aspirin use and the risk for colorectal cancer and adenoma in male health professionals. Ann Intern Med 121: 241–246.
Giovannucci, E, Egan, KM, Hunter, DJ, Stampfer, MJ, Colditz, GA, Willett, WC & Speizer, FE (1995). Aspirin and the risk of colorectal cancer in women. N Engl J Med 333: 609–614.
Hara, A, Yoshimi, N, Niwa, M, Ino, N & Mori, H (1997). Apoptosis induced by NS-398, a selective cyclooxygenase-2 inhibitor, in human colorectal cancer cell lines. Jpn J Cancer Res 88: 600–604.
Hasegawa, M, Arai, T & Ihara, Y (1990). Immunochemical evidence that fragments of phosphorylated MAP5 (MAP1B) are bound to neurofibrillary tangles in Alzheimer’s disease. Neuron 4: 909–918.
Horak, ER, Leek, R, Klenk, N, Lejeune, S, Smith, K, Stuart, N, Greenall, M, Stepniewska, K & Harris, AL (1992). Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as an indicator of node metastases and survival in breast cancer. Lancet 340: 1120–1124.
Jones, DA, Carlton, DP, McIntyre, TM, Zimmerman, GA & Prescott, SM (1993). Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expression in response to cytokines. J Biol Chem 268: 9049–9054.
Kargman, SL, O'Neil, GP, Vickers, PJ, Evans, JF, Mancini, JA & Jothy, S (1995). Expression of prostaglandin G/H synthase-1 and -2 protein in human colon cancer. Cancer Res 55: 2556–2559.
Kato, N, Nawa, A, Tamakoshi, K, Kikkawa, F, Suganuma, N, Okamoto, T, Goto, S, Tomoda, Y, Hamaguchi, M & Nakajima, M (1995). Suppression of gelatinase production with decreased invasiveness of choriocarcinoma cells by human recombinant interferon beta. Am J Obstet Gynecol 172: 601–606.
Kawamori, K, Rao, CV, Seibert, K & Reddy, BSC (1998). Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, against colon carcinogenesis. Cancer Res 58: 409–412.
Kujubu, DA, Fletcher, BS, Varnum, BC, Lim, RW & Herschmann, HR (1991). TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem 266: 12866–12872.
Liotta, LA, Rao, CN & Wewer, UM (1986). Biochemical interactions with the basement membranes. Annu Rev Biochem 55: 1037–1057.
Mahadevan, V & Hart, IR (1990). Metastasis and angiogenesis. Acta Oncol 29: 97–103.
Majima, M, Isono, M, Ikeda, Y, Hayashi, I, Hatanaka, K, Harada, Y, Katsumata, O, Yamashita, S, Katori, M & Yamamoto, S (1997). Significant roles of inducible cyclooxygenase (COX)-2 in angiogenesis in rat sponge implants. Jpn J Pharmacol 75: 105–114.
Marnett, LJ (1992). Aspirin and the potential role of prostaglandins in colon cancer. Cancer Res 52: 5575–5589.
Marnett, LJ (1995). Aspirin and related nonsteroidal anti-inflammatory drugs as chemopreventive agents against colon cancer. Prev Med 24: 103–106.
Matsushita, M, Masaki, M, Yagi, Y, Tanaka, T & Wakitani, K (1997). Pharmacological profile of JTE-522, a novel prostaglandin H synthase-2 inhibitor, in rats. Inflamm Res 46: 461–466.
O'Banion, MK, Sadowsky, HB, Winn, V & Young, DA (1991). A serum and glucocorticoid-related 4-kilobase mRNA encodes a cyclooxygenase-related protein. J Biol Chem 266: 23261–23267.
Oshima, M, Dinchuk, JE, Kargman, SL, Oshima, H, Hancock, B, Kwong, E, Trzaskos, JM, Evans, JF & Taketo, MM (1996). Suppression of intestinal polyposis in APC▵716 knockout mice by inhibition of cyclooxygenase-2 (COX-2). Cell 87: 803–809.
Piazza, GA, Rahm, AK, Finn, TS, Fryer, BH, Li, H, Stoumen, AL, Pamukcu, R & Ahnen, DJ (1997). Apoptosis primarily accounts for the growth-inhibitory properties of sulinduc metabolites and involves a mechanism that is independent of cyclooxygenase inhibition, cell cycle arrest, and p53 induction. Cancer Res 57: 2452–2459.
Reddy, BS, Rao, CV & Seibert, K (1996). Evaluation of cyclooxygenase-2 inhibitor for potential chemopreventive properties in colon carcinogenesis. Cancer Res 56: 4566–4569.
Sano, H, Kawahito, Y, Wilder, RL, Hashiramoto, A, Mukai, S, Asai, K, Kimura, S, Kato, H, Kondo, M & Hla, T (1995). Expression of cyclooxygenase-1 and -2 in human colorectal cancer. Cancer Res 55: 3785–3789.
Seed, MP, Brown, JR, Freemantle, CN, Papworth, JL, Colville-Nash, PR, Willis, D, Somerville, KW, Asculai, S & Willoughby, DA (1997). The inhibition of colon-26 adenocarcinoma development and angiogenesis by topical diclofenac in 2.5% hyaluronan. Cancer Res 57: 1625–1629.
Sheng, H, Shao, J, Kirkland, SC, Isakson, P, Coffey, RJ, Morrow, J, Beauchamp, RJ & DuBois, RN (1997). Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2. J Clin Invest 99: 2254–2259.
Thun, MJ, Namboodiri, MM & Heath, CWJ (1991). Aspirin use and reduced risk of fatal colon cancer. N Engl J Med 325: 1593–1596.
Thun, MJ, Namboodiri, MM, Calle, EE, Flanders, WD & Heath, CWJ (1993). Aspirin use and risk of fatal cancer. Cancer Res 53: 1322–1327.
Tsuji, M, Kawano, S & DuBois, RN (1997). Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA 94: 3336–3340.
Tsujii, M, Kawano, S, Tsuji, S, Sawaoka, H, Hori, M & DuBois, RN (1998). Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93: 705–716.
Williams, CW & DuBois, RN (1996). Prostaglandin endoperoxide synthase: why two isoforms?. Am J Physiol 270: G393–G400.
Xie, W & Herschman, HR (1995). v-src induces prostaglandin synthase 2 gene expression by activation of the c-Jun N-terminal kinase and the c-Jun transcription factor. J Biol Chem 270: 27622–27628.
Ziche, M, Jones, J & Gullino, PM (1982). Role of prostaglandin E1 and copper in angiogenesis. J Natl Cancer Inst 69: 475–482.
About this article
Cite this article
Tomozawa, S., Nagawa, H., Tsuno, N. et al. Inhibition of haematogenous metastasis of colon cancer in mice by a selective COX-2 inhibitor, JTE-522. Br J Cancer 81, 1274–1279 (1999). https://doi.org/10.1038/sj.bjc.6694262
- colon cancer
- selective COX-2 inhibitor
Progress in Drug and Formulation Development for the Chemoprevention of Oral Squamous Cell Carcinoma: A Review
Recent Patents on Drug Delivery & Formulation (2019)
Inhibition of cancer migration and invasion by knocking down delta-5-desaturase in COX-2 overexpressed cancer cells
Redox Biology (2017)
Prognostic impact of COX-2 in non-small cell lung cancer: A comprehensive compartment-specific evaluation of tumor and stromal cell expression
Cancer Letters (2015)
Design, synthesis and structure–activity relationship studies of novel and diverse cyclooxygenase-2 inhibitors as anti-inflammatory drugs
Journal of Enzyme Inhibition and Medicinal Chemistry (2014)
Phytotherapy Research (2014)