Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to elucidate the mechanism of tumor prevention of beta-carotene, its effect on sister chromatid exchanges (SCE) induced by MNNG in cultured V79 cells, under condition free of the enzyme system to convert beta-carotene into vitamin A, was studied. It was found that SCE level was significantly increased by high doses beta-carotene (10(-5)-10(-4) M) and the enhancement of SCE was restored to its original level by addition of alpha-tocopherol (final concentration 2 micrograms/ml). This may be due to the latter inhibiting the oxidation of beta-carotene and reducing the amount of oxidated carotene, which is toxic for cultured cells. Combination of beta-carotene and alpha-tocopherol at low doses inhibited SCE induced by MNNG (P less than 0.05) but no protective activity was observed when used separately. It was also found that beta-carotene (2 x 10(-7) M) and retinol (16 micrograms/ml) inhibited SCE induced by aflatoxin B1, which is activated by S-9 mixture. The present data clearly show that the antitumor activity of beta-carotene may be attributed to both itself and its degraded compound vitamin A, and may take part in the initiation of carcinogenesis. Combination of beta-carotene and other cancer preventive drugs is more effective and safer than it used individually.
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PMID:[Effect of beta-carotene on sister chromatid exchanges induced by MNNG and aflatoxin B1 in V79 cells]. 314 77

N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG) induces a high incidence of carcinomas in the glandular stomach of rats following chronic administration in the drinking water. We determined the level of 7-methylguanine and O6-methylguanine in gastric and duodenal DNA during chronic exposure to MNNG (80 p.p.m.). After considerable fluctuations during the initial 3 weeks, levels of methylpurines reached a steady state which was approximately three times higher in the pylorus (i.e. the preferential site of tumor induction) than in the fundus and duodenum, with 7-methylguanine and O6-methylguanine values in the range of 520 and 110 mumol/mol guanine, respectively. When rats were given MNNG in the drinking water at concentrations ranging from 10 to 80 p.p.m. for 3 weeks, levels of methylpurines reached maximum values already at 10-20 p.p.m. At higher MNNG concentrations, there was no further increase in DNA alkylation. The reason for this lack of dose response remained unclear. Immunohistochemical analyses showed that DNA methylation by MNNG is restricted to epithelial cells bordering the luminal surface. The possibility exists that in this target cell population the content of free thiols is a limiting factor for the decomposition of MNNG and its reaction with macromolecules in the gastric mucosa. Addition to the diet of sodium taurocholate, a bile acid previously shown to enhance MNNG-induced stomach carcinogenesis, did not influence the extent of DNA methylation, indicating that it acts as a promoter.
Carcinogenesis 1988 Dec
PMID:DNA methylation in rat stomach and duodenum following chronic exposure to N-methyl-N'-nitro-N-nitrosoguanidine and the effect of dietary taurocholate. 319 72

Sequential changes of numbers of pepsinogen 1 (Pg 1)-decreased pyloric glands (PDPG) detected by immunohistochemistry and of the incidence of gastric carcinomas were examined in five different strains of rats treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG;CAS:70-25-7). Male SD (Crj:CD), WKY (WKY/NCrj), Lewis (LEW/Crj), Wistar (Crj:Wistar) and F344 (F344/DuCrj) rats (40 per strain), were given drinking water containing 100 micrograms/ml MNNG for 30 weeks and then normal tap water, and were killed at week 10, 30 and 50 of the experiment. Adenocarcinomas of the glandular stomach were found in nine of 15 SD rats (60%), in eight of 12 WKY rats (67%), in eight of 15 Lewis rats (53%), in three of 13 Wistar rats (23%) and in one of 18 F344 rats (6%) at week 50. These incidences of carcinomas in SD, WKY and Lewis were significantly higher (P less than 0.01) than that in F344 rats. From week 10, the numbers of PDPG in SD, WKY and Lewis rats were significantly greater (P less than 0.01) than that in F344 rats. From week 30, the numbers of PDPG in Wistar rats were also significantly greater (P less than 0.05-0.01) than that of F344. The susceptibility of rats to induction of gastric carcinoma by MNNG correlated with the susceptibility to induction of PDPG by MNNG in each strain, suggesting that induction of PDPG is a preneoplastic change in chemical gastric carcinogenesis.
Carcinogenesis 1988 Mar
PMID:Coefficient induction of pepsinogen 1-decreased pyloric glands and gastric cancers in five different strains of rats treated with N-methyl-N'-nitro-N-nitrosoguanidine. 334 88

N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG) dissolved in distilled water (5 g/l) was administered orally once by gastric tube at a dose of 0.25 ml/10 g body weight to 5-day-old or 28-day-old Wistar Furth (W/Fu) or ACI rats. Gastric tumors in the glandular stomach were found in 58% of 5-day-old ACI rats, but none were found in the rest of the groups. Forestomach tumors were found in both strains of rats at both age groups with incidences of 68-100%. Lung tumors were induced in 64% of 5-day-old and 6% of 28-day-old W/Fu rats, but not in ACI rats. Besides the tumors, a high frequency of hepatic cysts was also noted in ACI rats. Intestinal metaplastic foci with alkaline phosphatase activity were found in the group of 5-day-old ACI rats and none in the rest of the groups. The results showed that the incidences and the locations of tumors in rats induced by MNNG are greatly influenced by both strain and age.
Carcinogenesis 1988 Jul
PMID:Effect of age and strain on N-methyl-N'-nitro-N-nitrosoguanidine tumorigenesis in ACI and Wistar Furth rats. 338 48

Sequential histologic changes of the stomach during carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG; CAS: 70-25-7) were studied in susceptible ACI and resistant BUF strain rats. Rats were given MNNG at a concentration of 83 micrograms/ml in their drinking water for 32 weeks and then tap water and were sacrificed sequentially between weeks 1 and 57. In ACI rats, erosions, regenerative changes, focal and slightly atypical changes, and diffuse and severe atypical changes were observed sequentially in the pyloric region during the period of MNNG administration, where adenocarcinomas were observed after the cessation of MNNG treatment. In BUF rats, the main histologic changes induced by MNNG were erosions and hyperplasia of the glandular portion of pyloric glands at the margin of erosions. After the cessation of MNNG treatment, the hyperplasia of the pyloric glands subsided and was followed by atrophy of these glands. The results suggested that the responses of the gastric mucosa to MNNG in ACI and BUF rats were qualitatively different.
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PMID:Sequential histologic changes during gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in susceptible ACI and resistant BUF rats. 346 13

There are still only a few in vivo short-term assay methods for predicting potential organ-specific carcinogens and mutagens in mammals, although such methods are required for evaluating the in vivo effects of in vitro mutagens. In the in vivo/in vitro UDS assay methods described here, chemicals are given to experimental animals and induction of UDS in target organs is determined by in vitro organ culture or primary cell culture in the presence of [3H]dThd. Incorporation of [3H]dThd into DNA is measured with a liquid scintillation counter or by autoradiography. These methods have now been applied to the glandular stomach, forestomach, colon, liver, kidney, pancreas, tracheal epithelium, nasal epithelium, and spermatocytes. With minor modifications, they may also be applied to other organs. The present review shows that induction of UDS in various organs correlated well with the induction of cancer in these organs. The present authors have used the present methods to identify some potential organ-specific mutagens and carcinogens in mammals. The present authors found that three dicarbonyl compounds, glyoxal, methylglyoxal, and diacetyl, induced apparent UDS and TDS in the glandular stomach, and other groups found that 2-NT, MA6BT, and CNEt6BT induced UDS in the liver. These in vivo/in vitro UDS assays are better than in vitro UDS assay for identification of potential organ-specific mutagens and carcinogens in mammals and are especially useful for identifying potential mutagens and carcinogens that are specific for certain organs, such as the stomach, liver, and kidney. They are also useful for examining the potential mutagenicities and carcinogenicities of carcinogen analogs. However, these methods are not suitable for general in vivo screening because they are not yet available for all organs. A further advantage of the methods is that they can be used to examine larger numbers of animals at one time than other methods for detecting DNA damage, such as alkaline elution or alkaline sucrose density gradient centrifugation. Glyoxal enhanced cancer induction in the glandular stomach by the administration of a limited amount of MNNG and then glyoxal afterward in the two-stage stomach carcinogenesis.
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PMID:Use of in vivo/in vitro unscheduled DNA synthesis for identification of organ-specific carcinogens. 355 21

Certain chemicals that are either weak or non-carcinogens had been previously shown to induce DNA single-strand breaks in rat hepatocytes, but only at cytotoxic doses. In contrast, stronger carcinogens induced DNA single-strand breaks at non-toxic doses. This report shows that the strong carcinogens and mutagens cadmium sulfate, sodium dichromate, dimethyl sulfate, and N-methyl-N'-nitro-N-nitrosoguanidine all induce DNA single-strand breaks at non-toxic concentrations, but that they also induce DNA double-strand breaks at concentrations that are closely correlated with cytotoxicity. Some weak carcinogens produced DNA single- and double-strand breaks, but only at acutely cytotoxic concentrations. We suggest that the DNA double-strand breaks result from a cell-mediated process such as release of DNAase from lysosomes or other cellular compartments, that might occur during cellular response to acutely toxic damage. Experiments with N-dodecyl imidazole (NDI), a lysosomal detergent, show that lysosomal breakdown alone is only a weak inducer of DSBs, but that lysosomal breakdown in combination with prior chemical damage produced by MNNG synergistically induces DNA DSBs in BHK cells. N-Dodecyl imidazole also induces chromosomal aberrations in CHO cells at concentrations which cause cytotoxicity, cell cycle delay, and lysosomal breakdown. These results all suggest that chemical toxicity leads to limited lysosomal breakdown that induces DNA DSBs and chromosomal aberrations. Cells that have been sublethally damaged and that can repair these damages and survive could become transformed by the DNA-damaging mechanisms associated with carcinogenesis.
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PMID:Relationships among cytotoxicity, lysosomal breakdown, chromosome aberrations, and DNA double-strand breaks. 362 50

In an attempt to elucidate histogenesis of stomach cancer, quantitative analysis and measurement of DNA contents of various atypical lesions were sequentially made in the process of gastric carcinogenesis of Wistar strain of rats. Along with this, the effect of vagotomy on the development of atypical or neoplastic lesions were studied. A variety of focal lesions in the glandular stomach were seen in the middle or 4 and 12 weeks after the oral administration of N-methyl-N'-nitrosoguanidine (MNNG, 83 mg/l in drinking water) for 25 weeks. Both upward and downward growth was found in the intramucosal atypical lesions as well as frank carcinoma; the former lesions were histologically classified into 3 (Type I--Type III). On the basis of DNA distribution pattern, Type III lesions were considered to be intramucosal carcinoma and Type II to include precancerous state in some instances. In a group of rats vagotomized 1 week prior to the start of MNNG administration, there were significantly more lesions than in a group of MNNG alone. In contrast to the latter group which developed lesions in an uniform distribution pattern along the lesser curvature in the pyloric region, lesions in the former were characterized by random distribution pattern.
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PMID:[Study of the histogenesis and effect of vagotomy during gastric carcinogenesis by N-methyl-N'-nitro-N-nitrosoguanidine in rats--with special reference to atypical lesions]. 371 98

Sodium chloride is known to have a modifying effect on MNNG--induced carcinogenesis in rats. Its stimulating effect manifested itself in an increased frequency of MNNG--induced tumors of the stomach and small intestine and shorter latency of gastric tumor. Feeding with highly-salted food was followed by a relatively higher number of multiple lesions in the gastrointestinal tract.
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PMID:[Effect of NaCl on the induction of gastrointestinal tumors in rats]. 373 98

Epidemiological studies have demonstrated an association of pathological conditions in the stomach with high intake of salted foods. Utilizing a two-step carcinogenesis model in rats treated with MNNG plus high salt diet as the initiator, we concluded the possible promoting effects of sodium chloride in gastric carcinogenesis and compared the results with the actions of other chemicals. Biological changes of the gastric mucosa were examined after chronic administration or a single oral intubation of NaCl. Morphological lesions observed included diffuse mild erosions, atrophy of the glands and hyperplasia of the foveolar epithelium when rats were given 10% NaCl diet chronically. Increased tritiated thymidine labeling index was evident in the pyloric and fundic mucosa after the oral administration of NaCl. These results suggest that NaCl exerts an enhancing effect at both initiation and promotion steps in the two stage model system applied, and that these effects of NaCl are related to its mucosal damaging activity.
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PMID:[Enhancing effect of a high salt diet on gastrointestinal carcinogenesis]. 374 41


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