methylnitronitrosoguanidine and Pancreatic-Neoplasms

Topics: 4-Nitroquinoline-1-oxide; Animals; Carcinogens; Cattle; Cells, Cultured; Cricetinae; Culture Media; Gelatin Sponge, Absorbable; Humans; Methylnitronitrosoguanidine; Methylnitrosourea; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental; Nitrosamines; Organ Culture Techniques; Pancreatic Ducts; Pancreatic Neoplasms

Current experimental models of pancreatic cancer either fail to reproduce the ductal phenotype or cause simultaneous cancers in other organs also. To develop an animal of pancreatic cancer that accurately mimics the human condition, we restricted carcinogenic exposure to the pancreas and specifically targeted ductal epithelial cells. Three different carcinogens were either implanted directly into the pancreas or infused into the pancreatic duct, with or without near-total pancreatectomy (as a means of inducing pancreatic ductal cell proliferation).. Groups of male Sprague-Dawley rats were exposed to varying doses of dimethylbenzanthracine (DMBA), methynitronitrosoguanidine, or ethylnitronitrosoguanidine either through direct implantation into the pancreas or infusion into the pancreatic duct. Near-total pancreatectomy was added in all groups except two DMBA implantation groups. Surviving rats were killed at 3, 6, 9, or 12 months, and the pancreata were evaluated histologically.. All three carcinogens caused pancreatic inflammation, ductal hyperplasia, atypia, and dysplasia beginning by 3 months and becoming more prominent at later time points. Only DMBA caused frequent invasive pancreatic ductal adenocarcinoma, which was first evident by 6 months. The prevalence of pancreatic cancer among DMBA-treated rats evaluated after 10 months was 39% (19 of 49). The addition of pancreatic resection did not enhance pancreatic cancer development.. Of the strategies tested, only direct implantation of DMBA into the rat pancreas frequently produces pancreatic cancer histologically similar to human ductal adenocarcinoma. The development of hyperplastic, atypical, and dysplastic changes preceding and accompanying carcinomas suggests that these lesions are preneoplastic. This model recapitulates the progression from normal to neoplastic epithelium and is likely to be useful for the study of morphologic and molecular mechanisms underlying the early stages of pancreatic carcinogenesis and for the investigation of novel diagnostic and therapeutic techniques.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogens; Carcinoma, Ductal, Breast; Disease Models, Animal; Fibrosarcoma; Hyperplasia; Male; Methylnitronitrosoguanidine; Pancreatectomy; Pancreatic Ducts; Pancreatic Neoplasms; Rats; Rats, Sprague-Dawley; Sarcoma, Experimental

To assess the temporal changes of the pancreatic duct following the administration of N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) in two dogs, serial pancreatography was performed. They received intraductal administration of a total of 595 and 500 mg ENNG in each one, over the periods of 12 and 13.5 months, respectively. In one dog, sequential changes of the main duct were observed, a small round filling defect developed a circumferential defect and became a severe stenosis associated with proximal dilatation of the duct. While no gross tumors were macroscopically detected at autopsy, continuous lesions with features of hyperplasia, atypical hyperplasia, and cancerous change of duct epithelial cells were microscopically seen. In the other one, a small round filling defect was detected by pancreatography, which was histopathologically hyperplasia of pancreatic duct, rather than cancerous cells. The present dog model for induction of pancreatic duct carcinomas appears useful for elucidating clinico-pathological changes occurring during cancer development.

Topics: Adenocarcinoma; Animals; Carcinogens; Dogs; Epithelium; Hyperplasia; Male; Methylnitronitrosoguanidine; Pancreatic Ducts; Pancreatic Neoplasms; Radiography

It may be useful to study the incipient phase and growth behavior of pancreatic cancer if experimental pancreatic carcinoma can be produced in dogs. Twelve mongrel dogs were used. Pancreatography was done every month. N-nitrosobis (2-oxopropyl) amine (BOP) was administered through the drainage tube inserted into the dorsal pancreatic duct in 4 dogs. Macroscopically, atrophy of the pancreas was recognized, but microscopically, no tumors were observed. BOP was injected intraperitoneally in 2 dogs. No tumors were found, and the hepatic necrosis was detected in one dog. N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) was administered into the dorsal pancreatic duct in 2 dogs. Macroscopically, atrophy of the pancreas was recognized, but microscopically, no tumors were observed. ENNG was administered through the drainage tube inserted into the tail portion in 4 dogs. In one dog received a total dose of 595mg of ENNG, duct obstruction was detected by pancreatography and duct adenocarcinoma microscopically was found. Papillary hyperplasia of the epithelium of pancreatic duct was observed in all others. Pancreatic duct adenocarcinoma and papillary hyperplasia were successfully produced in dogs by intraductal administration of ENNG through the pancreatic tail portion. This method seems to be useful for producing experimental pancreatic cancer.

Topics: Adenocarcinoma; Animals; Disease Models, Animal; Dogs; Female; Male; Methylnitronitrosoguanidine; Nitrosamines; Pancreatic Ducts; Pancreatic Neoplasms

Pancreatic duct adenocarcinoma was induced by intraductal administration of N-ethyl-N'-nitro N-nitrosoguanidine (ENNG) in two mongrel dogs. A dog received a total dose of 595 mg of ENNG during 12 months and was sacrificed. Duct obstruction was detected by pancreatography and duct adenocarcinoma was found. Another dog was given a total dose of 350 mg of ENNG during 8 months and was sacrificed 26 months after the first administration of the carcinogen. Duct adenocarcinoma was found. No pancreatic tumors were found in 2 dogs given intraperitoneal N-nitrosobis(2-oxopropyl)amine at a total dose of 4000 mg or in 2 dogs given Tween 60 only. These results suggest that the direct presence of a carcinogen in the pancreatic duct was able to induce duct adenocarcinoma in dogs.

Topics: Adenocarcinoma; Animals; Carcinogens; Dogs; Male; Methylnitronitrosoguanidine; Pancreatic Ducts; Pancreatic Neoplasms

Syrian golden hamster pancreatic organ explants were treated with either methylnitrosourea (MNU) or N-methyl-N-nitroso-N'-nitroguanidine (MNNG). In control explants treated with only dimethylsulfoxide, there was evidence of autophagy and crinophagy in acinar cells. Carcinogen-exposed explants showed increased numbers of autophagic and crinophagic vacuoles. In long-term cultured explants there was an increase in the number of ducts over zero time control tissues. Eosinophilic cells similar to hepatocyte-like cells were seen in 90% of the carcinogen-treated explant experiments and in 45% of the controls. Nitrosamine exposure did not induce an increase in the overall amount of necrosis measured morphometrically. Nitrosamine exposure in vitro appears to lead to a sequence of events that follow carcinogen metabolism by the acinar cells. The changes that follow include altered cell morphology and toxic cell injury evidenced by autophagic and crinophagic processes, regeneration of ductal appearing cells, the appearance of hepatocyte-like cells and an overall increase in the amount of ductal metaplasia. Within some of these ductal foci, several ductules show atypical features.

Topics: Animals; Cell Transformation, Neoplastic; Cricetinae; Mesocricetus; Metaplasia; Methylnitronitrosoguanidine; Methylnitrosourea; Nitrosourea Compounds; Organ Culture Techniques; Pancreas; Pancreatic Neoplasms; Phenotype

In order to develop a model to study cytological alterations in human pancreatic cancer, we have exposed bovine pancreatic ductal organ explants to a single dose of 2.5 micrograms per ml of N-methyl-N-nitroso-N'- nitroguanidine (MNNG). At serial time intervals, contact cytology smears of the explants were prepared and stained with the Papanicolaou stain. Control samples contained classic tall columnar and cuboidal ductal cells. Cells were uniform in size, shape, staining characteristics, and nuclear morphology. Ductal explants exposed to MNNG progressed through a series of dysplastic and atypical stages during the first 5 to 12 days in culture. Chromatin became increasingly more granular and nucleoli increased in both number and size. Exposed cells were larger than controls and had many dysplastic features. From day 15 to 30, the cells underwent changes morphologically consistent with those of human pancreatic adenocarcinomas .

Topics: Adenocarcinoma; Animals; Cattle; Cell Transformation, Neoplastic; Methylnitronitrosoguanidine; Pancreatic Ducts; Pancreatic Neoplasms; Time Factors

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

Carcinoma of the pancreas can be produced in guinea pigs by the oral administration of 1-methyl-1-nitrosourea (MNU). Our present studies have examined the distribution of this compound in these animals following parenteral and oral administration and also its specific sites of binding within the pancreatic cell. Emphasis has been placed upon the comparison of the uptake and binding of MNU with the related compound 1-methyl-3-nitro-1-nitrosoguanidine (MNNG), which does not seem to be carcinogenic to the pancreas after oral administration. The distribution data indicate uptake into pancreas that is comparable to that of other organs. Binding data show both MNU and MNNG to extensively modify subcellular organelles and the DNA and proteins of chromatin, but that MNU does this to a somewhat greater extent than MNNG.

Topics: Animals; Binding Sites; Chromatin; DNA; Guinea Pigs; Islets of Langerhans; Methylnitronitrosoguanidine; Methylnitrosourea; Neoplasms, Experimental; Nitrosourea Compounds; Organoids; Pancreatic Neoplasms; Tissue Distribution

Topics: Animals; Azoxymethane; Benz(a)Anthracenes; Colonic Neoplasms; Cricetinae; Dogs; Duodenal Neoplasms; Esophageal Neoplasms; Gastrointestinal Neoplasms; Guinea Pigs; Methylnitronitrosoguanidine; Mice; Neoplasms, Experimental; Nitrites; Nitrosamines; Nitrosoguanidines; Pancreatic Neoplasms; Rabbits; Rats; Stomach Neoplasms