tretinoin and Intestinal-Neoplasms

Chemopreventive activity by retinoic acid (RA) has been demonstrated previously in rat colon. The spontaneous tumourigenesis in the Min/+ mouse, which harbours a germline mutation in the tumour suppressor gene adenomatous polyposis coli (Apc), is characterized by inactivation of Apc, nuclear accumulation of beta-catenin and the enhanced expression of specific genes activated by T cell factor (TCF)/beta-catenin signalling. Recently it was reported that beta-catenin interacts with retinoic acid receptor in a retinoid-dependent manner, reducing beta-catenin/TCF regulated transcription. Our hypothesis was therefore that dietary supplementation with all-trans RA may inhibit the Apc-driven tumourigenesis in Min/+ mice. Surprisingly, in two different experiments the results showed that dietary RA significantly stimulated both the formation and growth of small intestinal tumours. In the first experiment Min/+ mice were exposed to 50 mg 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine/kg bodyweight at day 3-6 after birth and then treated with 50 mg/kg dietary RA in 1-3 weeks from the age of 2 weeks. In the second experiment the mice were not treated with carcinogen, and the diet was supplemented with 5 or 10 mg/kg RA from the age of 4 weeks until termination of the experiment at 11 weeks. Immunohistochemical studies revealed no differences in beta-catenin, cyclin D1 or proliferating cell nuclear antigen staining following RA treatment. There was no intestinal toxicity in mice fed 10 mg/kg RA, indicating that the increased tumourigenesis in Min/+ mice is a specific effect of all-trans RA.

Topics: Animals; beta Catenin; Body Weight; Cyclin D1; Cytoskeletal Proteins; Dietary Supplements; Female; Genes, APC; Germ-Line Mutation; Imidazoles; Intestinal Neoplasms; Male; Mice; Mice, Inbred C57BL; Proliferating Cell Nuclear Antigen; Trans-Activators; Tretinoin

The possible effect of oral 13 cis retinoic acid (13-cis-RA) on the carcinogenic process induced by 28 weekly s.c. injections of 1,2-dimethylhydrazine (DMH) in 34 Wistar rats was investigated. Using immunohistology, precancerous and cancerous stages were compared with the same stages induced by DMH without additional 13-cis-RA in 33 rats. M1 antigens, which characterize modifications in goblet-cell differentiation occurring early in rat colonic carcinogenesis, were used to investigate the possible effect of retinoids on differentiation during precancerous stages. From 3-20 weeks after the start of the experiment, no significant differences were observed in the timing of M1 antigens in the 2 groups of rats. It was also observed that 13-cis-RA had no effect on histological lesions associated with precancerous mucosa, nor on the occurrence of intestinal adenocarcinomas. Thus, under these conditions, oral administration of 13-cis-RA did not significantly inhibit precancerous or cancerous stages of intestinal carcinoma development.

Topics: 1,2-Dimethylhydrazine; Adenocarcinoma; Animals; Carcinogens; Colonic Neoplasms; Dimethylhydrazines; Female; Intestinal Neoplasms; Isotretinoin; Methylhydrazines; Neoplasm Metastasis; Neoplasms, Experimental; Precancerous Conditions; Rats; Rats, Inbred Strains; Tretinoin

Outbred male Sprague-Dawley CD rats were fed a complete semisynthetic diet and were given supplemental low doses (2 ppm) of selenium as H2SeO3 in their drinking water or 50 mg 13-cis-retinoic acid (13-cis-RA) and 2 g beta-sitosterol/kg diet either singly, in combinations of two, or in combinations of all three. Intestinal tumors were induced with eight weekly sc injections of 8 mg azoxymethane (AOM)/kg body weight, and inhibition of tumor formation was determined by tumor counts after 26 weeks. Noncarcinogen controls for each dietary group received eight injections of sterile water. Tumor inhibition was statistically significant in 2 groups of animals: Dietary control animals had a tumor frequency of 5.07 tumors/rat, rats receiving selenium- plus 13-cis-RA supplementation had a tumor frequency of 3.77, and those being given the combination of all three inhibitors had 2.75 tumors/rat. Analysis of fecal steroids from 3 AOM groups (dietary controls, the beta-sitosterol plus 13-cis-RA-supplemented group, and the group receiving all three additives) after 4 months of supplementation showed that the addition of beta-sitosterol to the diet had no effect on acidic or neutral steroids, regardless of the observed difference in tumor frequency. These results suggest that subpharmacologic doses of inhibitors, particularly those that inhibit the process by different mechanisms, while ineffective alone, may provide significant inhibition of tumorigenesis when used in combination.

Topics: Animals; Azo Compounds; Azoxymethane; Body Weight; Drinking; Eating; Intestinal Neoplasms; Male; Rats; Rats, Inbred Strains; Selenium; Sitosterols; Tretinoin

After ten times monthly, subcutaneous, injections of 30 mg/kg 1,2-dimethylhydrazine (DMH) to Sprague-Dawley-rats, malignant tumors were found in approximately 90% of the animals after a mean induction period of approximately 330 days. Injections were started on the 2nd day of life and maintained during 10 months. 72% of the tumors induced were formed in the colon, 17% were squamous cell carcinomas of the ear duct, adenosarcomas of the kidney and hepatocellular carcinomas were found in 13 and 11% of the animals, respectively. Additional treatment with immunodepressive (cyclophosphamide, methotrexat, hydrocortisone) and immunostimulating substances (BCG, albumin, vitamin A-acid) as well as an enzyme-stimulating agent (Luminal) did not alter incidences and induction periods of tumors. After application of a vegetarian diet, the rate of liver and kidney tumors was diminished significantly and induction periods of intestinal and ear duct tumors increased.

Topics: Animals; BCG Vaccine; Diet; Dimethylhydrazines; Ear Neoplasms; Female; Hydrazines; Immunosuppressive Agents; Intestinal Neoplasms; Kidney Neoplasms; Liver Neoplasms; Male; Neoplasms, Experimental; Phenobarbital; Rats; Serum Albumin; Tretinoin