methylnitronitrosoguanidine and Sarcoma

To investigate the chemopreventive effect and mechanisms of epigallocatechin-3-gallate (EGCG) and folic acid on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastrointestinal cancer in rats, and to investigate and compare the combinatorial effects of EGCG and folic acid on the chemoprevention of gastrointestinal carcinogenesis.. A total of 159 healthy male Wistar rats were randomly divided into seven groups to have the MNNG in drink (group M), MNNG in drink and EGCG in the feed (group ME), MNNG in drink and folic acid in the feed (group MF), MNNG in drink and EGCG+folic acid in the feed (group MEF), EGCG in the feed (group E), folic acid in the feed (group F) or normal feed (group C), respectively. At 44 weeks, all the rats were killed and assessed for the presence of gastrointestinal tumor. The occurrence of cancer was evaluated by histology. Ki-67 in cancerous tissues and in situ apoptosis were determined by immunohistochemical staining or terminal deoxyribonucleotide transferase-mediated nick-end labeling (TUNEL) assay, respectively.. The experiment was completed in 157 rats (98.74%). As compared with group M, the tumor incidence of group MEF decreased significantly (P=0.011). Ki-67 expression in cancerous tissues of group ME and MEF also decreased significantly (P=0.038, P=0.009), while apoptosis of group ME, MF and MEF increased significantly (P=0.000, P=0.003, P=0.000).. EGCG combined with folic acid has an obvious chemopreventive effect on gastrointestinal carcinogenesis induced by MNNG in rats.

Topics: Adenocarcinoma; Administration, Oral; Animals; Anticarcinogenic Agents; Apoptosis; Catechin; Cell Proliferation; Disease Models, Animal; Drug Therapy, Combination; Folic Acid; Gastrointestinal Neoplasms; Hematinics; Male; Methylnitronitrosoguanidine; Rats; Rats, Wistar; Sarcoma; Treatment Outcome

The frequency and distribution of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced structural aberrations, i.e., chromatid and chromosome gaps, breaks, and exchanges, were studied in fibroblasts from 16 patients with sarcoma, 15 with non-Hodgkin's lymphoma (NHL), and 14 controls. The mean frequencies of aberrant cells, and gap, break, and gap + break events per 100 cells were 22.9, 5.1, 28.6, and 33.7 in the sarcoma group; 19.1, 5.0, 22.5, and 27.5 in the NHL group; and 23.5, 6.1, 33.5, and 39.6 in the control group. None of the differences between the groups were statistically significant. The distribution of MNNG-induced aberrations was non-random (P less than 0.001) in all 3 groups. Eight, 11, and 17 chromosome bands in the sarcoma, NHL, and control groups, respectively, were particularly break-prone. Only 2 hot spots in the sarcoma group (1p32, 11q23), and 3 in the NHL group (1p36, 3q25, 6p21), coincided with the 25 and 60 bands known to be involved in primary rearrangements in sarcomas and NHL. We conclude that neither the frequency nor the distribution of MNNG-induced chromosomal aberrations indicates any latent chromosomal instability in sarcoma and NHL patients.

Topics: Chromosome Aberrations; Chromosome Banding; Chromosome Mapping; Chromosomes; DNA Damage; Female; Humans; Lymphoma, Non-Hodgkin; Male; Methylnitronitrosoguanidine; Sarcoma

The genesis of uterine sarcomas in vivo has been difficult to elucidate. The reasons are multifactorial and are compounded by the rarity of these tumors. In an effort to understand the biologic activity of this disease, normal endometrial tissue was subjected to tissue culture, histochemical study, and hormonal manipulation. Protein markers were used to differentiate endometrial epithelium from endometrial stromal cells in culture. The endometrial stromal cells grew rapidly following subculturing and were responsive to hormonal manipulation. When the stromal cells in culture were treated with the carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), the resultant morphologic changes mimicked uterine sarcomas grown in culture. These changes appeared to occur in a sequential manner, somewhat analogous to changes occurring in the endometrial epithelium as it undergoes transformation to endometrial adenocarcinoma. These studies, therefore, may serve as a model system in understanding the genesis and biologic activity of uterine sarcomas.

Topics: Alkaline Phosphatase; Cell Division; Cells, Cultured; Diethylstilbestrol; Endometrium; Female; Humans; Isoenzymes; L-Lactate Dehydrogenase; Methylnitronitrosoguanidine; Progesterone; Sarcoma; Uterine Neoplasms

The isoenzyme patterns of lactate dehydrogenase (LDH), hexokinase, phosphofructokinase, and aldolase were investigated in cultured normal and carcinogen-treated human endometrial stromal cells. Both normal and carcinogen-treated cells had similar phosphofructokinase and aldolase isoenzymes. Distinctive changes in hexokinase and LDH isoenzyme patterns were found in the carcinogen-treated stromal cells. The LDH isoenzyme patterns of the carcinogen-treated stromal cells were shifted toward the muscle LDH forms. This is comparable to the alteration of LDH isoenzyme profiles observed in cell lines established from human uterine sarcomas. The two tissue culture media used affected the LDH isoenzyme patterns of endometrial stromal cells but differences between the LDH isoenzyme patterns of control and carcinogen-treated cells were detected regardless of the growth medium used. Total LDH activity was not significantly different in control and carcinogen-treated stromal cells. The hexokinase isoenzyme patterns expressed by the carcinogen-treated stromal cells were distinctly different from the normal hexokinase patterns. The treated stromal cells contained both hexokinase I and II, whereas the normal cells contained only hexokinase I. Hexokinase and LDH isoenzyme patterns may serve as markers with which to evaluate carcinogen-induced neoplastic changes in cultured endometrial stromal cells.

Topics: Cell Line; Endometrium; Female; Fructose-Bisphosphate Aldolase; Hexokinase; Humans; Isoenzymes; L-Lactate Dehydrogenase; Methylnitronitrosoguanidine; Phosphofructokinase-1; Sarcoma; Uterine Neoplasms

A histological and ultrastructural survey on the histogenesis of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric sarcomas in hamsters was attempted. Within 3 months after the beginning of oral administration of MNNG, simple spindle cell proliferation in the submucosal zone of the pyloric region of the glandular stomach was evident. By 5-6 months, the cells had acquired a sarcomatous appearance. Ultrastructurally, the spindle cells in the early stage, were divided into 3 types, i.e., angiogenic cells, fibroblastic cells, and primitive mesenchymal cells. Similarly, those in the late-appearing sarcomatous tumors were also classified into different types of angiogenic, fibroblastic, histiocytic and miscellaneous cells. Among the cell population of the 2 major groups, angiogenic cells were the most predominant cell type. Some morphological transition appeared to occur between the corresponding cell types at the early and late stages. DNA content of cell nuclei of the representative forms of the nitrosamide-induced sarcomas was higher than that of early appearing spindle cells. Thus, the evidence suggests that the early appearing spindle cells are precursors for the gastric sarcomas.

Topics: Animals; Cell Division; Cricetinae; Female; Mesocricetus; Methylnitronitrosoguanidine; Microscopy, Electron; Sarcoma; Stomach Neoplasms; Time Factors

Following chronic oral administration of hot water and N-methyl-N'-Nitro-N-nitrosoguanidine (MNNG), 4 of 30 Wistar rats developed sarcoma of the esophagus. 6 animals had tumors of the stomach, the liver and in the jejunum. One malignant tumor of the mediastinum was observed. The relatively short tumor induction time may be caused by the combined action of thermal injury and subsequently administered carcinogen. Organotropy of MNNG is changed and malignancies not only developed in the glandular stomach but also at the site of thermal injury to the esophagus.

Topics: Adenocarcinoma; Administration, Oral; Animals; Burns; Colonic Neoplasms; Esophageal Neoplasms; Female; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Sarcoma; Stomach Neoplasms

Topics: Adenocarcinoma; Animals; Antioxidants; Ascorbic Acid; Carcinoma, Squamous Cell; Male; Methylnitronitrosoguanidine; Neoplasms; Rats; Rats, Inbred F344; Sarcoma; Stomach Neoplasms

The effect of tetragastrin on the incidence and histology of colonic tumors induced by intrarectal instillation of N-methyl-N'-nitro-N-nitrosoguanidine was investigated in Wistar rats. Prolonged administration of tetragastrin in depot form during and after treatment with N-methyl-N'-nitro-N-nitrosoguanidine resulted in a significant reduction in the incidence of colonic tumors in Experimental Week 35. Histological examinations showed that, unlike the well-differentiated adenocarcinomas with a typical glandular pattern in control groups, the adenocarcinomas that developed in rats treated with tetragastrin had high mucin-producing activity.

Topics: Adenocarcinoma; Adenoma; Animals; Colonic Neoplasms; Gastrins; Injections, Subcutaneous; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Rats; Rats, Inbred Strains; Sarcoma; Tetragastrin

Possible promotion of MNNG-induced gastrointestinal carcinogenicity was evaluated in male Wistar rats exposed to unconjugated bile acid given as gavage or as obtained through truncal vagotomy plus pyloroplasty. No significant difference was found compared with the relevant control groups. Even though gastroduodenal erosions were found more frequently in the bile acid gavage and MNNG groups than in MNNG-treated controls, secondary deconjugated bile acids apparently did not reach optimal promoting concentrations. In contrast to partial gastrectomy, vagotomy and pyloroplasty does not increase the tumor yield in the rat.

Topics: Adenocarcinoma; Animals; Bile Acids and Salts; Cocarcinogenesis; Enteral Nutrition; Gastrointestinal Neoplasms; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Pylorus; Rats; Rats, Inbred Strains; Sarcoma; Vagotomy

The effect of ulcers induced by iodoacetamine on the development of gastric tumors by N-methyl-N'-nitro-N-nitrosoguanidine was studied in male Wistar rats. The ulcerative lesions induced by iodoacetamide were confined symmetrically to the fundic region along the limiting ridge in the stomach and the pyloric region was unaffected. Animals treated with iodoacetamide and N-methyl-N'-nitro-N-nitrosoguanidine produced a high incidence of tumors including adenocarcinoma in the fundic region. The incidence of tumors in the pyloric region in the control group was 80% but there were no tumors in the fundic region. The tumors in the fundic region were most frequently found in the same areas that ulcers had previously been induced. These findings suggest that ulceration and regeneration of the mucosa are important factors in gastric carcinogenesis induced in rats by N-methyl-N'-nitro-N-nitrosoguanidine.

Topics: Adenocarcinoma; Adenoma; Animals; Gastric Mucosa; Iodoacetamide; Iodoacetates; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Nitrosoguanidines; Pylorus; Rats; Sarcoma; Stomach Neoplasms; Stomach Ulcer

Topics: Animals; Antigens, Neoplasm; Colonic Neoplasms; Dimethylhydrazines; Kidney; Lymphocytes; Methylnitronitrosoguanidine; Neoplasms, Experimental; Polyomavirus; Rats; Sarcoma

The effects were studied of NaCl on the production of gastric carcinomas by N-methyl-N-nitro-N-nitrosoguanidine (MNNG) and by 4-nitroquinoline-1-oxide (NQO) in male Wistar rats. Nine groups of rats were treated as follows: Group 1 was given 50 mg MNNG/liter and 6 g NaCl solution/liter to drink and was fed a stock diet supplemented with 10% NaCl. Group 2 received 1 ml saturated NaCl once a week and 50 mg MNNG/liter to drink. Group 3 was treated with MNNG alone. Group 4 was given a solution of 1 mg NQO once a week and fed a stock diet supplemented with 10% NaCl. Group 5 received a solution of 1 mg NQO saturated with NaCl. Group 6 was given NQO alone. Groups 7 and 8 were given NaCl alone. Group 9 was untreated. Adenocarcinomas developed in the glandular stomach in group 2 at a significantly higher incidence than in group 3. Poorly differentiated adenocarcinomas of the glandular stomach were detected in only groups 1 and 2. One poorly differentiated adenocarcinoma metastasized to the lymph nodes. A high incidence of squamous cell carcinomas of the forestomach was found in groups 4 and 5. No malignant tumors were seen in groups 6-9. NaCl given alone had no apparent carcinogenicity in rats but, when administered with MNNG or NQO, it enhanced the carcinogenic effects of MNNG and NQO in the stomach.

Topics: 4-Nitroquinoline-1-oxide; Adenocarcinoma; Animals; Carcinoma, Squamous Cell; Drug Synergism; Gastric Mucosa; Intestinal Neoplasms; Intestine, Small; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Nitroquinolines; Nitrosoguanidines; Papilloma; Rats; Sarcoma; Sodium Chloride; Stomach; Stomach Neoplasms