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

Abstract

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.Key words: JTE-522; selective cyclooxynenase-2 inhibitor; colon carcinogenesis; tubular adenocarcinoma; chemoprevention Colorectal cancer leads to approximately 550,000 annual deaths worldwide 1 and is therefore a major public health problem and underlines the need for effective chemopreventive strategies. The protective effect of traditional nonsteroidal antiinflammatory drugs (NSAIDs), such as aspirin and sulindac, for colon cancer has been well documented in epidemiologic and animal studies. 2 However, their use for chemoprevention of colon cancer has been hindered by their potential gastrointestinal and renal toxicity. It is now known that nonselective NSAIDs inhibit activities of cyclooxygenases (COX), and inhibition of COX-2 may well explain their chemopreventive effect, whereas inhibition of COX-1 is believed to be responsible for man...

Chemoprevention by cyclooxygenase-2 inhibition reduces immature myeloid suppressor cell expansion

“…The inability of celecoxib chemoprevention to prolong survival suggests that although the number of large intestinal tumors was reduced, significant tumor burden remained. This is consistent with previously reported studies using COX-2 inhibitors and the 1,2-DMH-induced tumor model in rats in which no effect on tumor growth and invasion was observed [15]. We suggest that the lack of effect on survival is due to the remaining tumor, whose growth was not prevented by celecoxib administration.…”

“…This revealed a four-fold increase in splenic IMSC numbers, a cellular phenotype with immune suppressive activity [14][15][16][17][18][19][20][21]32,[38][39][40]. IMSCs have been reported to increase within the spleen, blood, and tumors of mice bearing transplantable or autochthonous tumors [38,40].…”

“…COX-2 is over-expressed in human colorectal tumors [1,13] and in chemically-induced [14][15][16] and transgenic rodent colon tumors [17][18][19][20][21]. The inhibition of COX-2 activity has been shown to suppress intestinal carcinogenesis in experimental models [14][15][16][17][19][20][21] and patients with familial adenomatous polyposis (FAP) [2]. Preclinically, COX-2 inhibition has been shown to reduce the number of tumors in the 1,2-DMH colon carcinogenic rat model [15] and the multiplicity and size of intestinal tumors, as well as prolong survival in the transgenic multiple intestinal neoplasia (Min) mouse model [17,19,21].…”

“…Further, COX-2 inhibitors alter the balance of immunosuppressive and immunostimulatory cytokines [9] and reduce PGE-2 suppression of dendritic cell (DC) and monocyte differentiation and maturation [10,11], allowing more effective augmentation of antitumor immune responses International Immunopharmacology 7 (2007) 140 -151 www.elsevier.com/locate/intimp [12]. COX-2 is over-expressed in human colorectal tumors [1,13] and in chemically-induced [14][15][16] and transgenic rodent colon tumors [17][18][19][20][21]. The inhibition of COX-2 activity has been shown to suppress intestinal carcinogenesis in experimental models [14][15][16][17][19][20][21] and patients with familial adenomatous polyposis (FAP) [2].…”

Inhibition of Cyclooxygenase-2 Disrupts Tumor Vascular Mural Cell Recruitment and Survival Signaling

“…This effect on angiogenesis has been postulated to result from a direct effect on endothelial cells (13), although indirect effects on the same cells have also been suggested (e.g., by decreasing the expression of vascular endothelial growth factor or VEGF; ref. 15). …”