Chemopreventive effect of JTE-522, a selective cyclooxygenase-2 inhibitor, on 1, 2-dimethylhydrazine-induced rat colon carcinogenesis Min Wei, Keiichirou Morimura, Hideki Wanibuchi, Jun Shen, Kenichiro Doi, Makoto Mitsuhashi, Masaharu Moku, Elsayed I. Salim, Shoji Fukushima * Department of Pathology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan Received 12 June 2003; received in revised form 15 July 2003; accepted 18 July 2003 Abstract Selective COX-2 inhibitors have been suggested to be an effective strategy in the prevention of colon cancer without the adverse side effects of non-selective, nonsteroid anti-inflammatory drugs. The present experiment was designed to assess the potential chemopreventive properties of JTE-522, a new selective cyclooxygenase-2 inhibitor, on the induction of 1,2- dimethylhydrazine (DMH)-induced colonic aberrant crypt foci (ACF), a marker of rat colon carcinogenesis. A total of 80 male F344 rats were treated with 3 or 10 mg/kg of body weight JTE-522 or vehicle by oral gavage five times weekly from the start of the experiment. One week later, rats received s.c. injections of saline or 20 mg/kg of body weight DMH once weekly for four successive weeks. At the end of 12 weeks after the start of experiment, all rats were sacrificed and colons were evaluated for ACF. 10 mg/kg JTE522 significantly suppressed the total ACF/colon. No inhibitory effect was observed in the 3 mg/kg JTE- 522 treatment group. This result suggests that JTE-522 possesses chemopreventive activity against colon carcinogenesis. q 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: JTE-522; Selective cyclooxygenase-2 inhibitor; Colon carcinogenesis; Chemoprevention 1. Introduction The protective effect of nonsteroid anti-inflamma- tory drugs (NSAIDs), such as aspirin and sulindac, for colon cancer has been well documented in epidemiological and animal studies [1]. However, use of traditional NSAIDs for chemoprevention of colon cancer has been hindered by their potential gastrointestinal toxicity that occurs with long-term administration. It is well known that NSAID’s inhibition of colon carcinogenesis is related to their inhibition of prostaglandin production by cycloox- ygenase (COX), the constitutively expressed COX-1 and the inducible COX-2 [2,3]. Non-selective NSAIDs can inhibit the activities of both COX-1 and COX-2 [4]. Inhibition of the production of COX- 1-derived prostaglandins needed for maintenance of gut, kidney, and platelet functions has been suggested as the cause of adverse side effects of nonselective NSAIDs [5]. In contrast, in addition to 0304-3835/$ - see front matter q 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S0304-3835(03)00477-4 Cancer Letters 202 (2003) 11–16 www.elsevier.com/locate/canlet * Corresponding author. Tel.: þ81-6-6645-3737; fax: þ 81-6- 6646-3093. E-mail address: fukuchan@med.osaka-cu.ac.jp (S. Fukushima).