Inhibition Of Colon Carcinogenesis Research Articles

INHIBITION BY CALMODULIN ANTAGONIST TRIFLUOPERAZINE OF EXPERIMENTAL CARCINOGENESIS IN RAT COLON INDUCED BY AZOXYMETHANE

The effects of the calmodulin antagonist trifluoperazine on the development of colon tumors induced by azoxymethane (AOM), and on the labeling index of the colon mucosa and the activity of ornithine decarboxylase (ODC) in the colon wall were investigated in Wistar rats. Prolonged administration of trifluoperazine significantly reduced the number of colon tumors in week 35. Administration of trifluoperazine caused a significant decrease in the labeling index of the colon mucosa and the AOM-induced ODC activity in the colon wall during administration of the carcinogen, but not after its cessation. A possible mechanism of inhibition of colon carcinogenesis by trifluoperazine could be its inhibition of AOM-induced increase in ODC activity of the colon wall with consequent suppression of cell proliferation in the colon.

Colonoscopic colostomy model in rats for colon tumorigenesis studies.

A colonoscopic colostomy model for colorectal carcinogenesis and chemoprevention was developed in F344 rats. The colon was transected at the middle of the transverse colon and sutured to two openings. The proximal opening, located on the middle line of the upper abdominal wall, was for the exit of feces. The distal one located on the left back was the colostomy for the lower part of colorectum, which was approximately 9 cm in length and isolated from the feces. The two openings of the colostomy were completely separated with at least 4 cm distance between them. The animals were treated with 1,2-dimethylhydrazine (DMH) or methylazoxymethanol acetate (MAMAc) systemically or topically. Colon tumors in the isolated colorectum were observed by colonoscopy. Twenty six tumors in the isolated colorectum were found by colonoscopy with a mean latent period of 25.6 weeks in 10/15 (66.6%) animals treated with DMH (30 mg/kg subcutaneously, weekly for 30 weeks). Twelve tumors were found by colonoscopy with a mean latent period of 32.8 weeks in 6/17 (35.3%) animals treated with MAMAc (5 mg/kg enema, weekly for 35 weeks). Tumors with 0.5 mm diameter were detected as early as 21 weeks following the first dose of DMH and 28 weeks following the first dose of MAMAc respectively. Video camera-assisted endoscopic examination detected suspected small tumors 6 weeks earlier than endoscopic evaluation alone. The number, size and location of the tumors observed by colonoscopy were significantly correlated with those observed at necropsy. The tumor growth rate was monitored weekly. The tumor growth curve was expressed as the mean tumor diameters and calculated tumor volumes. Histological study at necropsy showed that 48.1% of the tumors were adenomas and 51.9% were adenocarcinomas. With a complete fecal diversion and colonoscopy, the model is potentially useful to study colon carcinogenesis and the inhibition of colon carcinogenesis.

Inhibition of colon carcinogenesis by prostaglandin synthesis inhibitors and related compounds

The inhibitory effect of 40 and 80% maximum tolerated dose (MTD) levels of piroxicam, ibuprofen, ketoprofen and glycyrrhetinic acid on colon carcinogenesis was investigated in male F344 rats. The MTD levels of piroxicam, ibuprofen, ketoprofen and glycyrrhetinic acid as determined in male F344 rats were 500, 500, 250 and 3000 p.p.m. respectively. At 5 weeks of age, groups of male F344 rats were fed the control (AIN-76A) diet and 40 and 80% MTD levels of each test agent in AIN-76A diet. At 7 weeks of age, all animals except the vehicle (saline)-treated controls received azoxymethane (AOM) at a dose rate of 15 mg/kg body wt, once weekly for 2 weeks. All animals were necropsied 50 weeks after the second AOM injection and colon tumor incidences were compared among the groups fed the control diet and chemopreventive agents. Animals fed 400 (80% MTD) and 200 p.p.m. (40% MTD) of piroxicam, 400 p.p.m. (80% MTD) of ibuprofen and 200 p.p.m. (80% MTD) of ketoprofen showed a significant inhibition of colon tumorigenesis as compared to those fed the control diet. Results analyzed by the linear regression method suggested a dose-dependent inhibition of colon carcinogenesis with increasing levels of piroxicam or ibuprofen. In contrast, glycyrrhetinic acid had no measurable chemopreventive effect on colon carcinogenesis.