methylnitronitrosoguanidine and Leiomyosarcoma

Promotion effects of the o-dihydroxybenzene derivatives, protocatechuic acid (PCA), dopamine hydrochloride (DAH), dl-dopa and caffeic acid on forestomach and glandular stomach carcinogenesis were investigated in rats pretreated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Groups of 20 male F344 rats were given a single intragastric administration of 150 mg/kg body wt MNNG and starting 1 week later than received diet containing 1.5% PCA, 1.5% DAH, 1.5% dl-dopa or 1% caffeic acid or basal diet alone for 51 weeks and then killed. Other groups of 10-15 rats were given PCA, DAH, dl-dopa or basal diet alone without the MNNG pretreatment. On histological assessment, the incidences of forestomach papillomas and squamous cell carcinomas were significantly enhanced in the group treated with caffeic acid (95 and 100%) as compared with the control values (35 and 10%). Although the incidence was not different, the number of papillomas per rat in the group given DAH (0.79 +/- 0.79) was also significantly increased (0.35 +/- 0.49). PCA and dl-dopa treatments did not modify the development of neoplastic lesions in the forestomach epithelium to any significant extent. None of the four chemicals enhanced glandular stomach carcinogenesis. The results thus demonstrated that whereas caffeic acid and DAH respectively, exert strong and weak promotion activity for rat forestomach carcinogenesis this promotion potential is not shared by all dihydroxybenzene derivatives. An influence of substituents in the para position in addition to the o-dihydroxy moiety is indicated.

Topics: Adenocarcinoma; Animals; Body Weight; Caffeic Acids; Carcinogens; Carcinoma, Squamous Cell; Dihydroxyphenylalanine; Dopamine; Drug Synergism; Epithelium; Hydroxybenzoates; Hyperplasia; Leiomyosarcoma; Male; Methylnitronitrosoguanidine; Papilloma; Rats; Rats, Inbred F344; Stomach; Stomach Neoplasms

The effect of exogenous synthetic prostaglandins and the inhibition of endogenous prostaglandin synthesis on gastrointestinal tumorigenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine [(MNNG) CAS: 70-25-7] was studied in female Wistar rats (100 g). Animals were divided into 6 groups: Group I was treated with MNNG alone (No. = 43); group II was treated with MNNG after application of the cyclo-oxygenase inhibitor flurbiprofen (No. = 44); group III was treated with MNNG after oral administration of 16,16-dimethyl-prostaglandin E2 (16,16-dm-PGE2; No. = 43); group IV received flurbiprofen alone (No. = 15); group V was treated with 16,16-dm-PGE2 alone (No. = 11). Animals in group VI served as controls (No. = 15). All drugs were administered orally. Hyperkeratosis and hyperplasia of the forestomach developed by 10 days after the first treatment with the carcinogen. Later, benign papillomas and dysplastic lesions were noted. Progressive ingrowth of squamous epithelium from the forestomach ridge into the glandular stomach started as early as day 13 and was more frequent in animals treated with a combination of MNNG plus flurbiprofen (P less than .001). The first squamous cell carcinomas of the forestomach were detected on day 51. Their incidence was 38, 60, and 42% in groups I, II, and III, respectively. This difference was not statistically significant. The incidence of mesenchymal tumors (leiomyosarcoma) in the stomach and duodenum was higher following treatment with MNNG plus flurbiprofen as compared to the incidence following treatment with MNNG alone or in combination with 16,16-dm-PGE2 (P less than .005). No malignant tumors developed in the gastrointestinal tracts of animals treated with flurbiprofen or 16,16-dm-PGE2 alone or in controls. The higher incidence of gastric and duodenal leiomyosarcomas after treatment with flurbiprofen suggests that reduction of prostaglandin synthesis favored the development of MNNG-induced cancer in mesenchymal tissues of the upper gastrointestinal tract.

Topics: Animals; Body Weight; Carcinoma, Squamous Cell; Female; Flurbiprofen; Gastric Acid; Gastrointestinal Neoplasms; Leiomyosarcoma; Methylnitronitrosoguanidine; Papilloma; Propionates; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Stomach Neoplasms

Dominant transforming genes that were transferred to mouse NIH3T3 cells by cellular DNAs prepared from a chemically transformed human cell line (MNNG-HOS), a human teratocarcinoma cell line (PA1), and a human pancreatic carcinoma cell line (A1165) were characterized (a) analyzing the repetitive human DNA sequences that were associated with the transforming gene and (b) determining their relationship to the oncogenes of the Harvey (rasH) and Kirsten (rasK) sarcoma viruses and to the human neuroblastoma transforming gene (rasN). The results show that the transforming gene activated in the teratocarcinoma cell line is identical to the neuroblastoma transforming gene and that the transforming gene of the pancreatic carcinoma cell line is a human homologue of rasK. In contrast, the transforming gene activated in the chemically transformed human cell line showed no detectable homology to rasK, rasH, and rasN.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Cell Line; Cell Transformation, Neoplastic; Cells, Cultured; Fibrosarcoma; Humans; Kidney Neoplasms; Leiomyosarcoma; Methylnitronitrosoguanidine; Mice; Mice, Nude; Neoplasm Transplantation; Oncogenes; Pancreatic Neoplasms; Teratoma; Transfection; Transplantation, Heterologous

A series of experiments was devised to determine possible modifying effects of stress, aspirin, and sodium taurocholate on the activity of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in the Buffalo rat stomach. MNNG is a well known, direct-reacting carcinogen, and has been a reliable agent for the experimental production of gastric adenocarcinoma. The authors were able to produce adenocarcinomas in rats, but found a great number of gastric leiomyosarcomas. These occurred only in the groups given MNNG in combination with stress, aspirin, or sodium taurocholate, and did not occur in experimental groups given either MNNG, stress, aspirin, or sodium taurocholate alone, and did not occur in the control group.

Topics: Adenocarcinoma; Animals; Aspirin; Cocarcinogenesis; Diet; Disease Models, Animal; Leiomyosarcoma; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred BUF; Stomach Neoplasms; Stress, Physiological; Taurocholic Acid

After 12 oral applications of 80 mg/kg MNNG as a suspension in 30% aqueous ethanol at weekly intervals, 98 Sprague-Dawley rats died with multiple tumors of the forestomach after a medium latency period of 226 days. Histological examination showed generalized papillomatosis developing into keratinizing squamous cell carcinomas with infiltrative growth in 88/98 (89%) animals. Tumorigenic lesions in the glandular stomach ware only observed in 3/98 rats. In two of these animals, mucosal adenocarcinomas were found and in the third a leiomyosarcoma. In about 30% of the animals treated with MNNG, degenerative liver changes were found, especially single cell and focal necroses, cystic alterations, and bile-duct proliferations.

Topics: Adenocarcinoma; Animals; Carcinoma, Squamous Cell; Leiomyosarcoma; Liver; Methylnitronitrosoguanidine; Neoplasms, Experimental; Papilloma; Rats; Rats, Inbred Strains; Stomach Neoplasms

When N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was orally intubated to conventional newborn rats by the catheter technique, the rats were found with tumors almost exclusively developed in the glandular stomach, mostly until 280 days after the first intubation. Tumor incidence was about 50% in both sexs of rats that survived the intubation of a single dose of MNNG in rats of less than 24 hr after birth and almost 100% in both sexes of rats that survived the intubation of three consecutive daily doses of MNNG on 5th day after birth. Out of 52 rats treated with MNNG, 40.4% developed carcinomas (20 adenocarcinomas and 1 squamous cell carcinoma), three of them having metastatic lesions. The predilective localization of tumors in the glandular, especially fundic, portion of the stomach, might be attributed to the use of newborns and to the catheter technique devised here.

Topics: Adenocarcinoma; Administration, Oral; Animals; Animals, Newborn; Carcinoma, Squamous Cell; Female; Leiomyosarcoma; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Rats; Stomach; Stomach Neoplasms

Leiomyosarcomas of the small intestine were found in dogs during experimental induction of gastric carcinoma by oral administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Leiomyosarcomas were found most frequenly in the duodenum and jejunum, and occasionally in the stomach but never in the ileum, colon, or rectum. The leiomyosarcomas developed in all the dogs given 50 mug/ml of MNNG in deionized water to drink but not in dogs fed on porridge food made from standard pellet diet mashed with MNNG at the same concentration in tap water. Intestinal sarcomas developed in 3 months to 5 years after the end of MNNG administration, and frequently metastasized to the liver and/or the peritoneum.

Topics: Administration, Oral; Animals; Dogs; Female; Intestinal Neoplasms; Intestine, Small; Leiomyosarcoma; Male; Methylnitronitrosoguanidine; Neoplasm Metastasis; Nitrosoguanidines; Sarcoma, Experimental; Stomach Neoplasms; Time Factors