JTE‐522, a selective cyclooxygenase‐2 inhibitor, inhibits induction but not growth and invasion of 1,2‐dimethylhydrazine‐induced tubular adenocarcinomas of colon in rats

We have previously demonstrated that JTE‐522, a selective cyclooxygenase‐2 (COX‐2) inhibitor, inhibited development of aberrant crypt foci (ACF) in rats, a putative preneoplastic lesion in colon, and suggested its inhibitory potential in rat colon carcinogenesis. To evaluate the chemopreventive properties of JTE‐522, the present study was design to evaluate the inhibitory effects of JTE‐522 on rat colon tumorigenesis induced by 1,2‐dimethylhydrazine (DMH). Rats at 6 weeks of age were divided into 4 groups. One week after the start of the experiment, all rats received DMH by s.c. injection at a dose of 40 mg/kg body weight once a week for 4 successive weeks. As the initiation and postinitiation treatment groups, groups 1–3 were fed diets containing 0, 50, or 150 ppm JTE‐522, respectively, from the start of the study to the end. As the postinitiation treatment group, group 4 was given 150 ppm JTE‐522 from 1 week after the last DMH injection to the end of the study. Forty weeks after the start of the experiment, administration of 150 ppm JTE‐522 during both initiation and postinitiation stages significantly inhibited the incidences of tubular adenocarcinomas and total carcinomas, as well as total tumors in the colon. The inhibitory effect of JTE‐522 was most prominent for tubular adenocarcinomas, but was not observed in the nontubular carcinomas (signet‐ring cell and mucinous carcinomas). Almost equal inhibitory effects on tubular adenocarcinomas were also observed in the rats given 150 ppm JTE‐522 during the postinitiation stage, suggesting that its major anticancer action is at the postinitiation phase. However, JTE‐522 had no effect on the size or invasive extent of tubular adenocarcinomas. Furthermore, microarray analyses revealed that JTE‐522 had no effect on gene expression levels in DMH‐induced tubular adenocarcinomas. These findings suggest that JTE‐522 possesses chemopreventive activity against induction but not progression of tubular adenocarcinomas in rat colon. In view of the significant inhibitory effects of JTE‐522 on ACF, its major anticancer action may occur in the postinitiation stage but before the malignant conversion stage of DMH‐induced colon carcinogenesis.