enng and Adenocarcinoma

Sulpiride and ethylene glycol monomethyl ether (EGME) are known ovarian toxicants that stimulate prolactin (PRL) secretion, resulting in hypertrophy of the corpora lutea and increased progesterone (P4) production. The purpose of the present study was to investigate how the PRL stimulatory agents affected uterine carcinogenesis and to clarify the effects of PRL on endometrial adenocarcinoma progression in rats. Ten-week-old female Donryu rats were treated once with N-ethyl-N'-nitro-N-nitrosoguanidine (20 mg kg(-1) ), followed by treatment with sulpiride (200 ppm) or EGME (1250 ppm) from 11 weeks of age to 12 months of age. Sulpiride treatment inhibited the incidence of uterine adenocarcinoma and precancerous lesions of atypical endometrial hyperplasia, whereas EGME had no effect on uterine carcinogenesis. Sulpiride markedly prevented the onset of persistent estrus throughout the study period, and EGME delayed and inhibited the onset of persistent estrus. Moreover, sulpiride-treated animals showed high PRL and P4 serum levels without changes in the levels of estradiol-17β, low uterine weights and histological luteal cell hypertrophy. EGME did not affect serum PRL and P4 levels. These results suggest that the prolonged low estradiol-17β to P4 ratio accompanied by persistent estrous cycle abnormalities secondary to the luteal stimulatory effects of PRL may explain the inhibitory effects of sulpiride on uterine carcinogenesis in rats. Copyright © 2015 John Wiley & Sons, Ltd.

Topics: Adenocarcinoma; Animals; Anticarcinogenic Agents; Carcinogenesis; Carcinogens; Endometrial Hyperplasia; Endometrial Neoplasms; Endometrium; Estrus; Ethylene Glycols; Female; Infertility, Female; Methylnitronitrosoguanidine; Organ Size; Ovary; Precancerous Conditions; Progesterone; Prolactin; Rats, Inbred Strains; Sulpiride; Uterus; Weight Gain

We investigated the delayed effects of neonatal exposure to 17α-ethynylestradiol (EE) on the female reproductive tract using Wistar Hannover GALAS rats. Female pups received single injections of EE (0, 0.02, 0.2, 2, 20, or 200 μg/kg) within 24h after birth and estrous cyclicity was observed until 10 months of age. All animals were treated at 9 weeks of age with the uterine carcinogen, N-ethyl-N'-nitro-N-nitrosoguanidine. Although the vaginal opening was not affected, abnormal cycles were significantly increased from 0.2 μg/kg. Persistent estrus was prominent and the incidence increased age- and dose-dependently. Severity of atypical hyperplasia of the uterus tended to increase from 2 μg/kg. In these groups, serum progesterone level was lowered relative to estradiol level. In conclusion, estrous cyclicity was a sensitive indicator reflecting delayed effects on the female reproductive tract. Early onset of anovulation leading to prolonged estrogen exposure might be a risk factor for uterine carcinogenesis.

Topics: Adenocarcinoma; Animals; Anovulation; Carcinogens; Estradiol; Estrogens; Estrous Cycle; Ethinyl Estradiol; Female; Hyperplasia; Mammary Glands, Animal; Methylnitronitrosoguanidine; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Progesterone; Rats; Rats, Wistar; Uterine Neoplasms; Uterus; Vagina

The effects of long-term blockade of prolactin (PRL) action by bromocriptine (BRC) treatment on uterine carcinogenesis and on related ovarian physiology were investigated using a rat uterine cancer model. Ten-week-old cycling female Donryu rats, a high yield strain for uterine corpus tumors (endometrial adenocarcinomas), were treated with N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG), as a tumor initiator, and injected with 1 mg/kg body weight BRC subcutaneously 4 times per week until 14.5 months of age to block the proestrus PRL surge. The study was terminated at 15 months of age, and the results showed that long-term BRC treatment significantly inhibited endometrial adenocarcinoma development in terms of both incidence (34.6% to 13.0% with significant difference at 5%) and multiplicity (0.35 to 0.18 with significant difference at 5%), which indicates the number of adenocarcinomas per animals. While BRC did not affect estrous cyclicity in the treated animals, a significant decline was evident in the serum 17 beta-estradiol (E2) to progesterone (P) ratio (E: P ratio), and the serum E2 level showed a decreased tendency at 15 months of age. While the precise pathway to the inhibitory effect could not be determined; the pathway by which ovarian hormonal imbalance decreases the serum E: P ratio most likely plays a crucial role.

Topics: Adenocarcinoma; Animals; Bromocriptine; Carcinogens; Endometrial Neoplasms; Estradiol; Female; Follicle Stimulating Hormone; Histocytochemistry; Hormone Antagonists; Inhibins; Luteinizing Hormone; Methylnitronitrosoguanidine; Progesterone; Prolactin; Rats

Hydroxymatairesinol (HMR), obtained from the heartwood of spruce (Picea abies), has been demonstrated to exert chemo-preventive effects on the development of mammary tumors in rats. To examine the influence of HMR on uterine carcinogenesis, adult Donryu rats were initiated with a single intrauterine treatment of N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) at 11 weeks of age and fed thereafter 0, 200, or 600 ppm HMR mixed in the soy-containing diet until 15 months of age. Incidences of uterine adenocarcinoma in both 200 and 600 ppm HMR-dosed groups were significantly reduced to 11% and 15%, respectively, less than 50% of 0 ppm, at the end of the experiment (P < 0.05). A delay in the start of persistent estrus by HMR was observed at 8 months of age compared with controls given carcinogen alone. From urinalysis, HMR was metabolized mainly to enterolactone and hydroxyenterolactone. These findings suggest that HMR or its metabolites exert chemo-preventive effects in the rat ENNG-uterine carcinogenesis model.

Topics: Adenocarcinoma; Animals; Anticarcinogenic Agents; Carcinogens; Dose-Response Relationship, Drug; Estrus; Feeding Behavior; Female; Lignans; Methylnitronitrosoguanidine; Rats; Uterine Neoplasms

The present study assessed effects of estrogens and their steroid metabolites on the endometrial carcinogenesis in young adult mice initiated with N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG). A total of 272 female CD-1 (ICR) mice were used and equally divided into 17 groups. Mice were implanted cholesterol pellets to the back subcutis at 9 weeks of age. Pellets contained nothing (control) or one of the experimental agents, three different estrogens and their 13 different steroid metabolites, at a concentration of 0.5% (w/w). At 10 weeks of age, mice were given a single intra-uterine administration of ENNG at a dose of 25 mg/kg body weight. When reaching the 30 weeks of age (20 weeks after the ENNG treatment), mice were sacrificed to assess the development of endometrial proliferative lesions. While endometrial proliferative lesions, including hyperplasias and adenocarcinomas, were observed in all groups, the incidences of hyperplasias in the groups treated with 2-hydroxyestriol, 2-methoxyestradiol, 2-methoxyestriol and 16-epiestriol were significantly higher than that in the control group. On the other hand, adenocarcinomas were significantly developed in the groups treated with estrone, estradiol, estriol, 16beta-hydroxyestrone, 16alpha-hydroxyestrone and 17-epiestriol. These results indicate that, on the endometrial carcinogenesis in mice initiated with ENNG, estrogens and their metabolites belonging to the 16alpha-hydroxylation pathway and the upstream of the 16beta-hydroxylation pathway exert both promoting and progressing effects, whereas, the estrogen metabolites belonging to the 2- and 4-hydroxylation pathways (catechol estrogens) and the downstream of the 16beta-hydroxylation pathway exert only promoting or no effects. It is thus suggested that a metabolic profile of estrogens may be crucial for the endometrial carcinogenesis and that the rate of the 16alpha-hydroxylation may be associated with the increased carcinogenic risks of estrogens on the endometrium.

Topics: Adenocarcinoma; Animals; Carcinogenicity Tests; Carcinogens; Endometrial Hyperplasia; Endometrial Neoplasms; Estrogens; Female; Methylnitronitrosoguanidine; Mice; Mice, Inbred ICR

Since many risk factors are associated with the development of uterine adenocarcinomas in humans, the etiology is unclear in most cases, although it has been pointed out that estrogen may play essential roles. To clarify the effects of exposure to p-tert-octylphenol (OP), an environmental xenoestrogen, on uterine carcinogenesis, adult Donryu rats were initiated with a single intrauterine treatment of N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) at 11 weeks of age and exposed thereafter to 100 mg / kg OP by s.c. injection until 15 months of age. Adult ovariectomized (OVX) rats were also treated in a similar way. OP had no effect on occurrence of persistent estrus in middle age, although uterotrophic effects were obvious in OVX rats. At the termination, development of uterine adenocarcinomas was significantly increased in animals exposed to OP during adulthood. No tumors, but a few focal hyperplasias, developed in OVX rats. These findings suggest that OP has tumor-promoting effects on ENNG-treated endometrium of rats, possibly due to direct action on the uterus, as indicated by the uterotrophic effect when a high dose of OP was given. The results provide clues to the mechanisms of influence of hormonal disrupters on uterine carcinogenesis.

Topics: Adenocarcinoma; Animals; Carcinogens; Cell Division; Female; Methylnitronitrosoguanidine; Ovariectomy; Phenols; Rats; Uterine Neoplasms; Uterus

Sequential endoscopic observation of dog colons was performed during colon carcinogenesis. Two beagle dogs were given suppositories containing N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) every day for five months. In month 3, aberrant crypt foci (ACF), a putative preneoplastic lesion, were found in the colons of both dogs, but not in an untreated dog. The frequency of ACF increased until month 10, and then decreased. In month 9, very small lesions, less than 1 mm in diameter, which were similar to human early flat tumors, were first noticed. One of these lesions grew to about 7 mm in size without a change in its shape for 10 months. There were more than ten flat-type tumors in the two dogs, but such lesions were not found in the untreated dog. By biopsy, two of the lesions were proved to be well-differentiated adenocarcinomas histologically. Four polypoid lesions were found in one of the carcinogen-treated dogs. Thus, flat-type adenocarcinomas were induced in the dog colon by ENNG, and their development was followed by magnifying endoscopy.

Topics: Adenocarcinoma; Animals; Carcinogens; Colon; Colonic Neoplasms; Colonic Polyps; Disease Models, Animal; Dog Diseases; Dogs; Endoscopy; Methylnitronitrosoguanidine; Precancerous Conditions

Induction of endometrial adenocarcinomas by a single intra-uterine administration of N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) to aged rats was examined. Donryu rats showing spontaneously persistent estrus were given a single intra-uterine administration of ENNG (20 mg/kg) at 10 months (44 weeks) of age. At the termination of the experiment (week 34 after the ENNG-treatment), 22% and 13% incidences of endometrial adenocarcinomas were observed in the experimental and control groups, respectively, the difference being without significance. No variation was found in the endocrine environment between experimental and non carcinogen-treated control animals throughout the experimental period. These results show that ENNG-treatment alone is not sufficient in aged rats for high induction of endometrial carcinomas. Comparison of the data with those from our previous studies, in which ENNG was given at a young age (10 weeks of age), indicates that young rats may be more sensitive than their old counterparts.

Topics: Adenocarcinoma; Aging; Animals; Carcinogens; Cell Division; Endometrial Neoplasms; Estradiol; Estrus; Female; Gonadotropins, Pituitary; Injections; Methylnitronitrosoguanidine; Progesterone; Rats; Uterus; Vagina

A total of 130 female Donryu rats (10-week-old) were divided into two groups; 80 animals in the experimental group were given a single intra-uterine administration of 20 mg/kg N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) dissolved in polyethylene glycol (PEG) via the vagina without laparotomy, and 50 animals in the control group received PEG alone in the same manner. Small numbers of animals in both groups were killed at 3, 6, 9 and 12 months after ENNG treatment for sequential histological and endocrinological examination, and at 12.5 experimental months (15 months of age) all survivors were killed. At the termination, endometrial adenocarcinomas were present in 49% of the experimental group, compared to 0% in the control group. Severe endometrial hyperplasias were also found only in the experimental group and sequential histological examination showed first appearance of hyperplasia at 6 months and adenocarcinoma at 9 months. No tumors other than uterine carcinomas were induced by ENNG and the carcinogen treatment did not affect the endocrine environment of rats, persistent estrus appearing at 6 months after the start and increasing with age in both groups. The estradiol-17 beta:progesterone (E:P) ratio was also increased after 6 months, with further elevation at 12 months to about 8 times higher than the level at 6 months. These results indicate that an increased E:P ratio might act as a promoter of development of endometrial proliferative lesions initiated by ENNG in this rat strain. The study indicates that the present simple method using Donryu rats provides a good animal model for endometrial adenocarcinoma development in women.

Topics: Adenocarcinoma; Administration, Intravaginal; Animals; Carcinogens; Endometrial Neoplasms; Endometrium; Estradiol; Estrus; Female; Hyperplasia; Methylnitronitrosoguanidine; Progesterone; Rats; Rats, Inbred Strains; Time Factors

Curcumin (diferuloylmethane), a yellow pigment that is obtained from the rhizomes of Curcuma longa Linn., is a major component of turmeric and is commonly used as a spice and food-coloring agent. The inhibitory effects of feeding commercial grade curcumin (77% curcumin, 17% demethoxycurcumin, and 3% bisdemethoxycurcumin) in AIN 76A diet on carcinogen-induced tumorigenesis in the forestomach, duodenum, and colon of mice were evaluated. Administration p.o. of commercial grade curcumin in the diet inhibited benzo(a)pyrene-induced forestomach tumorigenesis in A/J mice, N-ethyl-N'-nitro-N-nitrosoguanidine-induced duodenal tumorigenesis in C57BL/6 mice, and azoxymethane (AOM)-induced colon tumorigenesis in CF-1 mice. Dietary commercial grade curcumin was given to mice at: (a) 2 weeks before, during, and for 1 week after carcinogen administration (during the initiation period); (b) 1 week after carcinogen treatment until the end of the experiment (during the postinitiation period); or (c) during both the initiation and postinitiation periods. Feeding 0.5-2.0% commercial grade curcumin in the diet decreased the number of benzo(a)pyrene-induced forestomach tumors per mouse by 51-53% when administered during the initiation period and 47-67% when administered during the postinitiation period. Feeding 0.5-2.0% commercial grade curcumin in the diet decreased the number of N-ethyl-N'-nitro-N-nitrosoguanidine-induced duodenal tumors per mouse by 47-77% when administered during the postinitiation period. Administration of 0.5-4.0% commercial grade curcumin in the diet both during the initiation and postinitation periods decreased the number of AOM-induced colon tumors per mouse by 51-62%. Administration of 2% commercial grade curcumin in the diet inhibited the number of AOM-induced colon tumors per mouse by 66% when fed during the initiation period and 25% when fed during the postinitiation period. The ability of commercial grade curcumin to inhibit AOM-induced colon tumorigenesis is comparable to that of pure curcumin (purity greater than 98%). Administration of pure or commercial grade curcumin in the diet to AOM-treated mice resulted in development of colon tumors which were generally smaller in number and size as compared to the control group of AOM-treated mice. These results indicate that not only did curcumin inhibit the number of tumors per mouse and the percentage of mice with tumors but it also reduced tumor size. Histopathological examination of the tumors sho

Topics: Adenocarcinoma; Adenoma; Adenoma, Villous; Animals; Azoxymethane; Benzo(a)pyrene; Carcinogens; Colonic Neoplasms; Curcumin; Duodenal Neoplasms; Female; Male; Methylnitronitrosoguanidine; Mice; Stomach Neoplasms

The inhibitory effect of murine interferon alpha/beta (Mu-IFN) on the induction of adenocarcinoma of the duodenum in C57BL/6 mice given N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) was examined. ENNG was given continuously in drinking water for 4 weeks and Mu-IFN was given intraperitoneally for 12 weeks. Then, the duodenal tumors of mice were examined stereomicroscopically and histologically. The level of IFN activity and natural killer (NK) activity were evaluated after an intraperitoneal single injection of Mu-IFN, and the level of NK activity was evaluated 2, 5 and 8 weeks after giving ENNG and Mu-IFN. In the mice given Mu-IFN, the incidence of duodenal tumors was significantly decreased (P less than 0.01), compared with that in mice given ENNG alone. Further, anti-asialo GM1 was given intraperitoneally every 5 days for 8 weeks to depress NK function and the incidence and size of duodenal tumors were examined. The results indicated that NK cells also have an important effect on the process of carcinogenesis. These data suggest that chemoprevention with IFN may be feasible.

Topics: Adenocarcinoma; Animals; Antigens, Surface; Asialoglycoproteins; Duodenal Neoplasms; Interferon Type I; Killer Cells, Natural; Lymphocyte Activation; Male; Methylnitronitrosoguanidine; Mice; Mice, Inbred C57BL

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

Topics: Adenocarcinoma; Animals; Carcinoma, Squamous Cell; Dogs; Dose-Response Relationship, Drug; Esophageal Neoplasms; Male; Methylnitronitrosoguanidine; Stomach Neoplasms

N-Ethyl-N'-nitro-N-nitrosoguanidine [(ENNG) CAS: 63885-23-4] was administered to 5 Macaca monkeys (Macaca mulatta and M. irus) at a concentration of 200 or 300 micrograms/ml for 11-26 months in their drinking water. Gastric carcinomas in the pyloric region were observed in all 5 monkeys between experimental months 11 and 38. Histologically, these carcinomas were mainly poorly differentiated adenocarcinomas and signet-ring cell carcinomas, and a few moderately and well-differentiated adenocarcinomas were also found. The macroscopic and histologic appearances of these carcinomas were similar to those in humans.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Animals; Female; Femoral Neoplasms; Macaca fascicularis; Macaca mulatta; Male; Methylnitronitrosoguanidine; Osteosarcoma; Stomach Neoplasms; Tracheal Neoplasms

An experimental trial in the induction of canine gastric cancers was conducted to study the relationship between the histological differentiation of adenocarcinoma and the duration of administration of the carcinogen, N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG). Twenty-three adult Beagle dogs were divided into three groups according to the duration of administration. Over 3 months administration, the total dose of ENNG per animal was 5.85 g, and only signet ring cell carcinomas and poorly differentiated adenocarcinomas were induced in the antral mucosa of the stomach in 5 of 10 recipients. During 6 and 9 months administration, the total doses per animal were 11.70 g and 17.55 g, well differentiated adenocarcinomas were observed in 12 of 13 animals and they coexisted with poorly differentiated adenocarcinomas and/or signet ring cell carcinomas. Atrophic hyperplastic gastritis and hyperplastic polyps were seen in the same stomach. The results of this study suggest that a greater amount of carcinogen, i.e., a higher total dose, is required for the development of well differentiated adenocarcinoma than for inducing poorly differentiated adenocarcinoma and signet ring cell carcinoma.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Animals; Dogs; Drug Administration Schedule; Female; Male; Methylnitronitrosoguanidine; Stomach Neoplasms

This long-term study deals with the effect of ascorbic acid on chemically induced carcinogenesis of the small intestine in rats. Carcinoma was induced in 27 animals by application of N-Ethyl-N'-nitro-N-nitrosoguanidine (ENNG) alone in the drinking water (120 mg/1). The average survival time was 238 ( 40) days. The addition of large amounts of ascorbic acid to the food (3 g/100 g food) did not suppress the development of tumors. On the contrary, a significant reduction in the survival time was seen. All animals receiving ENNG and ascorbic acid only lived 207 ( 45) days on average. Neither histological type of tumor spread was influenced by the use of ascorbic acid. Giving ascorbic acid alone had no effect on the survival time and did not lead to changes in the tissue of the small intestine.

Topics: Adenocarcinoma; Animals; Ascorbic Acid; Carcinogens; Digestive System; Gastrointestinal Neoplasms; Intestinal Polyps; Long-Term Care; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains

150 micrograms/day of N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) was administered to a total of 8 dogs, (4 mongrels at age of 4 months and 4 beagles at age of 6 months) over a period of 8 months by Kurihara 's method. As a result of the administration, we found development of minute cancer as follows: In 3 animals, male beagle killed at 575th day, male mongrel at 1, 105th days and male mongrel at 1, 245th days, a total of 20 neoplasms of the stomach was found (18 early cancers and 2 advanced cancers). 13 of which being the minute cancer measuring less than 0.5 cm. There were 11 mucosal cancers and 2 submucosal cancers. When classified by the macroscopic pathological type, none was classified as the elevated type (I, IIa types), 5 lesions as the flat type (IIb type), and 8 lesions as the depression type (IIc type). Two lesions of submucosal cancer belonged to IIc type. When classified by the histological type, 2 were classified as papillary adenocarcinoma, 2 as well differentiated tubular adenocarcinoma, 1 as moderately differentiated tubular adenocarcinoma, 5 as poorly differentiated adenocarcinoma and 3 as signet-ring cell carcinoma.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adenocarcinoma, Papillary; Animals; Dogs; Male; Methylnitronitrosoguanidine; Neoplasm Staging; Stomach Neoplasms

It is known that the nuclear DNA contents correlate with the grade of malignancy. In this study, nuclear DNA contents of biopsy specimens taken from N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG)-induced canine gastric cancer were measured by Feulgen-DNA-cytofluorometry. The DNA content and histological findings were sequentially observed after weekly administration of 7-N-(p-hydroxyphenyl)-mitomycin C (0.8 mg/kg), a kind of mitomycin C derivative. The appearance rate of cells over 4C decreased remarkably from 18.8% to 9.86% on average (p less than 0.02) and the maximum value of distribution also went down from 9.18C to 7.33C (p less than 0.01) at the early stage of administration of the oncostatic agent when no histological change was yet observable. It might be expected that this procedure will enable the future evaluation of oncostatic effects at the cellular level more objectively.

Topics: Adenocarcinoma; Animals; Carcinogens; Cell Nucleus; DNA, Neoplasm; Dogs; Flow Cytometry; Methylnitronitrosoguanidine; Mitomycin; Mitomycins; Stomach Neoplasms

Topics: Adenocarcinoma; Animals; Dogs; Female; Gastric Mucosa; Male; Methylnitronitrosoguanidine; Stomach Neoplasms

Topics: Adenocarcinoma; Animals; Dogs; Male; Methylnitronitrosoguanidine; Stomach Neoplasms

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adenocarcinoma, Papillary; Adenoma; Animals; Dogs; Male; Methylnitronitrosoguanidine; Stomach Neoplasms

We prepared a suppository containing 50 mg of N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG), and successfully produced experimental colon cancer with good reproducibility by continuous intrarectal insertion of one or two suppositories per day in dogs. The tumors were very similar to human colon cancers, macroscopically and histologically. In one of three dogs subjected to histopathological study, metastases to the lymph nodes, lung, liver and kidney were observed. This animal model produced by a simple procedure will be helpful in investigating treatment of rectal cancer.

Topics: Adenocarcinoma; Animals; Carcinoma; Colonic Neoplasms; Disease Models, Animal; Dogs; Lymphatic Metastasis; Methylnitronitrosoguanidine; Neoplasms, Experimental; Time Factors

Fine structure of poorly differentiated adenocarcinoma selectively induced in the canine stomach by a low concentration of N-ethyl-N'-nitro-N-nitrosoguanidine was studied with special reference to the so-called signet ring cells. These cells were electron microscopically classified into two groups: 1) mucin-containing cells and 2) intracellular microcyst cells. The cytoplasm of mucin-containing cells was packed with fused large and low electrondense secretory granules. In another type of signet ring cells, there were intracellular microcysts with microvilli on the internal surface. A comparison of canine and human signet ring cells revealed a close resemblance in the fine structure. Canine gastric carcinoma should be a good model for human gastric carcinoma therapeutics.

Topics: Adenocarcinoma; Animals; Carcinogens; Cell Nucleus; Cytoplasmic Granules; Dogs; Female; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Stomach Neoplasms

Experimental colonic carcinoma in a dog was induced by anal insertion of an N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) suppository (each cone containing 50 mg of ENNG) for 17 months. The dog was autopsied 20 months after the initiation insertion of the suppository. Grossly, the colonic wall from the anus of the 10-cm oral side of the colon was thickened, and there was an infiltrating tumor with shallow depressions in the rough mucosa. The lymph node around this portion were enlarged, and white spots were found in the liver and redness in the lungs. Histological examination of the colon revealed a variety of pathologic features, e.g., undifferentiated carcinoma, squamous cell carcinoma and malignant melanoma in the region adjacent to the anus. Well and moderately differentiated adenocarcinomas involving the proper muscle layer were found in a region oral to these tumors and were accompanied by marked invasion of the blood vessels and lymphatic permeation. There were metastases to the liver, lungs and lymph nodes which corresponded to the gross findings, and also metastases to renal glomeruli. A well differentiated adenocarcinoma and signet ring cell carcinoma were evident in the gastric mucosa. This experimental model should be useful for studies related to colonic carcinoma in humans.

Topics: Adenocarcinoma; Animals; Carcinogens; Carcinoma; Carcinoma, Squamous Cell; Colon; Colonic Neoplasms; Dogs; Female; Melanoma; Methylnitronitrosoguanidine; Neoplasms, Experimental; Stomach; Stomach Neoplasms; Suppositories

This study applies to the agency of vitamin C on chemical carcinogenesis in the small intestine of rats. Administration of N-Ethyl-N'-nitro-N-nitrosoguanidine (ENNG) in drinking water produced tumors of the small intestine after 18 weeks in more than 90%. The induction of tumors could not be suppressed by a large amount (2-3%) of sodium ascorbate in food, but the depth of tumor infiltration was restricted. Cancer developed in 29 of 36 rats receiving ENNG only. In 25 animals of this group growth of tumor corresponded to a P4 stage. In 24 of 35 animals, additionally receiving vitamin C, P4 stage was observed in only 13 cases. Pathological changes in the small intestine could not be observed after the sole administration of vitamin C.

Topics: Adenocarcinoma; Animals; Ascorbic Acid; Dose-Response Relationship, Drug; Duodenal Neoplasms; Duodenum; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Rats; Rats, Inbred Strains

Studies were made on the chemotherapy of gastric cancer in dogs induced by N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG). Four male Beagle dogs were given a solution of ENNG at 100 approximately 150 microgram/ml with or without 0.4% Tween 60 to drink for 5 approximately 8 months. They all developed gastric adenocarcinomas, which were confirmed by histological examination of biopsy specimens taken in months 13 approximately 32 of the experiment. After confirming the presence of gastric cancer, 1-n-hexylcarbamoyl-5-fluorouracil (HCFU), a derivative of 5-fluorouracil, was given to the dogs orally as capsules at a daily dose of 5 or 10 mg/kg body weight. One dog died from adverse effects of HCFU 12 days after the beginning of chemotherapy. The other 3 dogs were treated with CHFU for 82 approximately 424 days. In these dogs, the tumor size, measured by X-ray examination, increased during chemotherapy. On autopsy, the tumors in the stomach were found to be restricted to the antrum, and metastases of the gastric adenocarcinomas to the regional lymph nodes and/or liver were found in 2 dogs. No degenerative changes of tumor cells were found in the stomach or metastasized organs, except for necrosis of cells in a perigastric regional lymph node of the dog. The value of using canine gastric cancer in studies on chemotherapy is discussed.

Topics: Adenocarcinoma; Animals; Dogs; Fluorouracil; Humans; Male; Methylnitronitrosoguanidine; Stomach Neoplasms

The present study was designed to produce the experimental carcinoma of the biliary tract in dogs. Tube cholecystostomy was constructed in 8 mongrel dogs and 5-10 ml of 0.7-1.0 mg/ml solution of N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) was administered through the tube every day for the maximum period of 180 days. As the results: The experiment had to be cut off in 7 dogs (5 dogs: The tube was inadvertently pulled out. 2 dogs: died of general weakness). Pathological changes were observed in one dog given ENNG for 180 days and sacrificed at 372 days after the beginning of the experiment. Macroscopically, scattered foci of flat elevation of the mucosa were observed in the entire mucosal surface of common bile duct and a tiny polypoid lesion at the terminal protion. A tiny polypoid projection was adenocarcinoma confined to the mucosa, and areas of flat elevation showed marked hyperplasia of mucosa with partial atypical proliferation. No remarkable findings were noted in other organs.

Topics: Adenocarcinoma; Animals; Bile Duct Neoplasms; Common Bile Duct; Dogs; Female; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Nitrosoguanidines