Potentiation of dimethylhydrazine bowel carcinogenesis in rats

Abstract

An animal model of organ-specific chemical carcinogenesis has been used to study environmental effects on the incidence of human colorectal adenocarcinoma. Wistar/Furth weanling rats underwent connection of their urinary and fecal streams (ureterosigmoidostomy), connection of their urinary and fecal streams with proximal fecal diversion (rectal bladder), or sham operations. Age-matched, unoperated control and operated animals then received either no carcinogen, 1,2-dimethylhydrazine (DMH) 20 mg/kg body weight, s.c. once weekly for 16 weeks, N-[4-(5-nitro-2-furyl)-2-thiazolylformamide (FANFT) 0.2% of the feed for 16 weeks, or DMH + FANFT concurrently. Thirty-three weeks after carcinogen exposure, surviving animals were killed and examined for bowel and urinary bladder tumors. The incidence of adenocarcinoma of the colon adjacent to the junction between bladder and bowel was significantly higher in animals after ureterosigmoidostomy compared with animals whose fecal stream had been proximally diverted (14/22 vs. 0/34, P less than 0.001). This effect was not dependent upon chemical carcinogen exposure. Nonexposed animals still developed a significantly higher incidence of colon adenocarcinomas adjacent to their bladder-bowel junctions as compared with animals with proximal fecal diversion (5/8 vs. 0/13, P less than 0.01). In unoperated or sham operated animals, adenocarcinomas of the bowel occurred in 33% of DMH-treated animals and transitional cell carcinomas of the urinary bladder in 33% of the FANFT-treated animals. After concurrent exposure to both carcinogens, no increased incidence of bladder tumors was noted when compared with FANFT treatment alone. However, the number of animals with one or more adenocarcinomas of the bowel (22/30 vs. 17/50, P less than 0.001), the mean number of tumors per animal (2.1 +/- 0.2 vs. 1.1 +/- 0.1, P less than 0.01), and the invasiveness of the tumors were all increased after DMH + FANFT as compared with DMH exposure alone. The carcinogenic potential of direct bladder to bowel connection with intact fecal and urinary streams, and the potentiation by FANFT of DMH-induced colon carcinogenesis may have implications in the genesis of human colorectal cancer.

Evaluation of the antitumor activity of interleukin-12 in an experimental murine model of colorectal cancer induced by 1,2 dimethylhydrazine (DMH)

“…Most authors consider that only one dose of 20 mg per kilogram of weight, injected weekly for 26 weeks, may induce a very high incidence of colorectal adenocarcinomas (18,19,(21)(22)(23)(24). However, even in these models a high incidence of tumors may be found, which rarely reaches 100% (25). Several modifications of these models were proposed in order to facilitate carcinogenesis, such as the addition of 5FU (26) or complex surgical modifications (25).…”

“…However, even in these models a high incidence of tumors may be found, which rarely reaches 100% (25). Several modifications of these models were proposed in order to facilitate carcinogenesis, such as the addition of 5FU (26) or complex surgical modifications (25). In our model, we decided to use a 20-mg dose in subcutaneous injection plus the addition of a diet that was low in fiber but very high in fat and carbohydrates; based on recent studies over the anticarcinogenic action of calcium-rich diets (27), we used a diet poor in calcium.…”

The Chemopreventive Effect of Nigella Sativa on 1,2-dimethylhydrazine-induced Colon Tumor

“…Pleomorphism, hyperchromasia, increased nucleus cytoplasm ratio and large nucleolus were the microscopic specifications of the malignant cells in this group. Other studies also confirmed this result indicating the colon tumour induction through injection or oral administration of DMH in 23-33 weeks [32][33][34] . Also, in shorter period (10 weeks) after DMH administration, preneoplastic lesions such as aberrant crypt foci (ACF) were observed 35 .…”

Asynchronous bilateral anastomosis site sigmoid colon cancer after ureterosigmoidostomy: a case report

“…Another theory is the urine-stool admixture concept, which suggests that hydrolytic enzymes in the urine activate conjugated carcinogens in the stool. These carcinogens are most active at the junction of the two streams where the greatest concentration exists [ 5 , 10 , 11 ]. Other factors, such as chronic irritation of the bowel epithelium, instability of the borderline between the urothelium and colonic epithelium, metabolic changes, and the presence of a fresh colonic suture line may contribute to the induction of colon carcinoma after ureterosigmoidostomy [ 2 , 10 – 13 ].…”