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M C Archer

Publications and source records attributed to M C Archer.

At least 19 recordsLinked to original sources
PubMed1992

Mammary tumor induction by N-methyl-N-nitrosourea in genetically resistant Copenhagen rats.

The Copenhagen rat is completely resistant to mammary cancer induction by N-methyl-N-nitrosourea (MNU) when the carcinogen is administered during sexual development, a period when other strains of rats are normally susceptible to mammary gland carcinogenesis. Here we administered 30 mg/kg MNU i.p. to two groups of neonatal (2-3-day-old) Copenhagen rats. One group (group B, 18 animals) received no further treatment, while the other group (group C, 17 animals) received a second dose of 30 mg/kg MNU via the tail vein at 50 days of age. About 30% of the rats in group B and about 70% of those in group C developed mammary carcinomas before they were 1 year of age. About one-half of the tumors in both groups were cribriform adenocarcinomas and one-half were adenosquamous carcinomas. The latter tumor type has not been observed previously in susceptible rat strains. The ability to induce these mammary tumors in the Copenhagen rat suggests that the putative mammary carcinoma suppressor gene is functionally inactive in neonatal animals or is inactivated when these animals are treated with MNU.

Adenocarcinoma↗
PubMed1992

Promotion of aberrant crypt foci and cancer in rat colon by thermolyzed protein.

BACKGROUND: We have previously shown that thermolyzed protein (casein) cooked with fat in the diet of the rat promotes the growth of aberrant crypt foci (putative precursors of colon cancer) assessed at 100 days. PURPOSE: To determine how thermolysis affects this promotion, we examined thermolysis conditions, quantity of thermolyzed protein in the diet, and duration of thermolysis. To determine whether the previous finding of promotion of aberrant crypt foci corresponds to promotion of cancers assessed much later, we carried out promotion studies until colon cancers appeared. METHODS: F344 rats were given an initiating dose of azoxymethane and were then randomly allocated to groups receiving diets differing in their quantity and quality of casein. The groups were examined for aberrant crypt foci and tumors in the colon. RESULTS: Aberrant crypt foci were promoted by diets containing thermolyzed casein (180 degrees C, 2 hours). Promotion increased with increasing level of thermolyzed casein in the diet (to 20%) and with increasing thermolysis time (to 4 hours). The number of animals with polyps and cancers was higher in the animals receiving thermolyzed protein (2 hours), 16/23 versus 9/26 (P less than .05) and 10/26 versus 3/27 (P less than .05), respectively. The number of aberrant crypts per focus and the number of large aberrant crypt foci were higher in the tumor-bearing animals. CONCLUSIONS: Thermolyzed casein promotes early colonic precursor lesions in a dose-dependent and thermolysis time-dependent manner; thermolyzed casein also promotes colon cancer. IMPLICATIONS: The promoter formed on thermolysis could be involved in colon cancers associated with diets cooked at elevated temperatures, such as can occur with high-fat diets.

Animals↗
PubMed1992

Ha-ras oncogene activation in mammary glands of N-methyl-N-nitrosourea-treated rats genetically resistant to mammary adenocarcinogenesis.

A single dose of N-methyl-N-nitrosourea given to sexually immature female Buf/N rats produces a high incidence of mammary adenocarcinomas. A large percentage of these tumors contain the Ha-ras oncogene, activated by a G----A transition at the second nucleotide of codon 12. Copenhagen rats, on the other hand, are completely resistant to mammary tumor induction by a number of carcinogens, including N-methyl-N-nitrosourea. Here we show, using a sensitive method involving PCR, that codon 12 Ha-ras mutations occur in the mammary glands of both Buf/N and Copenhagen rats 30 days after N-methyl-N-nitrosourea treatment. These mutations were evenly distributed among individual mammary glands and were present in purified mammary epithelial cells. In Buf/N rats, the fraction of cells containing a mutated Ha-ras allele increased by a factor of 10-100 between 30 and 60 days, whereas in Copenhagen rats, there was no such increase during this time period. We conclude that the resistance of the Copenhagen rat to mammary carcinogenesis is not due to a defect in initiation but rather appears to be due to the inability of cells containing a mutated ras allele to undergo sustained clonal expansion.

Animals↗
PubMed1992

ras oncogene activation in mammary carcinomas induced by N-methyl-N-nitrosourea in Copenhagen rats.

The occurrence of Ha-ras and Ki-ras oncogenes was investigated in mammary tumors produced by treating genetically resistant Copenhagen (Cop) rats with N-methyl-N-nitrosourea. G35-->A codon 12 mutations in both Ha-ras and Ki-ras genes were analyzed by a polymerase chain reaction/liquid hybridization and gel retardation assay. More than half of the adenocarcinomas analyzed contained an activated Ha-ras gene. This was also the predominant mutation in similar tumors from susceptible Buf/N rats, suggesting a common mechanism of initiation. In contrast, only two of 15 mammary adenosquamous carcinomas from the Cop rats contained an activated Ha-ras gene, suggesting a different initiation mechanism for most of these tumors. Ki-ras activation was found in none of five and one of five adenocarcinomas from Buf/N and Cop rats, respectively, and in none of 13 adenosquamous carcinomas from Cop rats. These results suggest that Ki-ras activation does not play a major role in the initiation of the mammary tumors.

Adenocarcinoma↗
PubMed1992

Formation and repair of O6-methylguanine and methylation of the Ha-ras proto-oncogene by N-methyl-N-nitrosourea are not associated with mammary tumor resistance in the Copenhagen rat.

A high incidence of mammary adenocarcinomas is induced in sexually immature, female Buf/N rats by a single dose of N-methyl-N-nitrosourea (MNU). The Ha-ras gene is activated in a majority of these tumors. The Copenhagen (Cop) rat is completely resistant to mammary gland carcinogenesis by a number of carcinogens, including MNU. Here we show that MNU-treated Buf/N and Cop rats do not differ in the extent of formation and rate of repair of O6-methylguanine in DNA isolated from their mammary epithelial cells. Furthermore, we show that the transcriptional activities of the Ha-ras genes are similar in the mammary glands of Buf/N and Cop rats and that the extents of methylation by MNU of restriction fragments containing the Ha-ras gene from mammary gland DNA are not different for the two strains. Resistance of the Cop rat to mammary carcinogenesis, therefore, appears not to be due to a defect in the interaction of the carcinogen with the target DNA.

Animals↗
PubMed1992

Aberrant crypt foci and microadenoma as markers for colon cancer.

Foci of aberrant crypts similar to those seen in experimental animals exposed to colon carcinogens have been identified and quantified on the mucosal surface of fixed resections of human colon after methylene blue staining. Many of the foci in humans showed dysplasia on histologic examination and were considered to be microadenoma (MA). These lesions may be precursors for adenomatous polyps and colorectal cancer. Rats and mice initiated with azoxymethane, then fed diets containing sucrose or casein heated at 180 degrees C to stimulate normal cooking conditions, had three to five times more large MA after 100 days than controls. Thus, cooked sugar and protein contain promoters of the growth of colonic MA. 5-Hydroxymethylfuraldehyde was identified as a promoter in cooked sugar.

Adenoma↗
PubMed1991

Preferential methylation of the Ha-ras proto-oncogene by methylnitrosourea in rat mammary glands.

Activation of the Ha-ras proto-oncogene, but not the Ki-ras or N-ras genes, has been found in mammary gland carcinomas induced in female rats by a single dose of methylnitrosourea (MNU). Here we show that a 10-kb restriction fragment containing the Ha-ras gene was extensively methylated by MNU in DNA isolated from mammary glands of female rats 4 h after carcinogen treatment. Fragments of similar size containing either the Ki-ras or N-ras genes were methylated less extensively. The extent of methylation of the three ras genes by MNU correlated with their transcriptional activity. These results suggest that the extent of interaction of a carcinogen with an oncogene, which depends on its transcriptional activity, may be a factor in determining whether the gene is mutated during the initiation of carcinogenesis.

Animals↗
PubMed1991

Selective cytotoxicity of N-nitrosamines to cultured rat esophageal epithelial cells.

The rat esophageal carcinogen N-nitrosomethylbenzylamine was shown to be highly toxic to rat esophageal epithelial (REE) cells in short-term primary culture. A significant level of cell killing could be observed at 10(-6) M. Several other esophageal carcinogens were also cytotoxic in a dose-dependent manner. Nitrosamines that do not produce esophageal tumors in the rat were generally unable to kill the esophageal cells. The results demonstrate that REE cells retain their metabolic capacity to activate specific nitrosamines to toxic metabolites. The culture system will be useful for mechanistic studies on the tissue specificity of these carcinogens, as well as to search for environmental agents that kill esophageal cells that may be involved in the causation of esophageal cancer.

Animals↗
PubMed1991

DNA methylation in specific cells of rat liver by N-nitrosodimethylamine and N-nitrosomethylbenzylamine.

Dose-response curves for the O6-methylation of guanine in the hepatic DNA of Wistar and Sprague-Dawley rats were determined after administration of N-nitrosomethylbenzylamine (NMBzA) or N-nitrosodimethylamine (NDMA). Similar results were obtained for both rat strains but methylation of hepatic DNA by NDMA was approximately 9-fold more efficient than with NMBzA when doses were compared on a molar basis. Comparison by immunohistochemical analysis of the distribution of nuclei containing O6-methylguanine within the liver lobules showed that both agents tended to alkylate cells close to the central veins at the lower doses. With increasing doses, the band width of alkylated cells around the central vein increased, spreading in the case of NDMA virtually into the portal zones, whereas with NMBzA the zone of alkylated nuclei reached little more than halfway from the central vein to the portal zone. These differences in the distribution of alkylated cells may explain the differing hepatic responses to these two nitrosamines.

Animals↗
PubMed1991

Specificity in the methylation of DNA by N-nitroso compounds.

A sequencing assay was used to determine the reactivity of N-nitroso compounds that are simple methylating agents with individual nucleotides in a defined DNA sequence. The maximal difference in reactivity between guanines is about five fold. DNA in the Z, cruciform and H conformations was shown to be methylated by N-methyl-N-nitrosourea in a manner which was indistinguishable from the reactivity of B-DNA. Electronic factors rather than steric factors appear to dominate the methylation reaction. Transcriptionally active genes were shown to be methylated by N-nitroso compounds in vivo more extensively than untranscribed genes. The results suggest that local sequence, secondary conformation and transcriptional activity may all influence the carcinogenic potential of N-nitroso compounds.

Base Sequence↗
PubMed1990

Promotion of colonic microadenoma growth in mice and rats fed cooked sugar or cooked casein and fat.

We studied the effect of cooked food components on the promotion of microadenoma growth in the colons of mice and rats. CF1 mice and Fisher 344 rats were initiated with azoxymethane, with 152 mice receiving four weekly i.p. injections of 5 mg/kg, 59 rats receiving a single injection of 20 mg/kg, and 24 rats receiving 30 mg/kg. A week after the last injection, the animals were randomly assigned to one of eight diets with identical ingredients, but the three components, sucrose, casein, and beef tallow, either uncooked or cooked. Control animals were given diets with uncooked ingredients. Experimental animals were fed diets in which one, two, or three of the components were cooked in an oven at 180 degrees C until golden brown before they were added to the diet. After 100 days on the diets, the colons were fixed, stained with methylene blue, and scored for microadenomas. The mice and the rats fed cooked sucrose, or casein and beef tallow cooked together, had three to five times more large microadenomas than did the controls (P ranging from 0.02 to 0.0001). No significant increase was observed with the five other cooked diets. Two rats fed the casein and beef tallow cooked together had adenocarcinomas. Thus, a diet containing 20% of cooked sucrose, or 40% of casein and beef tallow cooked together, promotes the growth of colonic microadenomas in initiated mice and rats, and would appear to contain promoters for colon cancer.

Adenoma↗
PubMed1990

Toxicity of N-nitrosodimethylamine, N-nitrosomethylbenzylamine, and 1,2-dimethylhydrazine in isolated rat hepatocytes.

N-Nitrosodimethylamine and 1,2-dimethylhydrazine were shown to injure lethally primary monolayer cultures of rat hepatocytes only after incubation periods in excess of 24 hr. The toxic action of these agents, therefore, mimics the time dependency of their hepatoxicity in vivo. The viability of hepatocytes treated with N-nitrosomethylbenzylamine was not different from controls at times up to 54 hr following treatment, a result which is also consistent with the inability of this compound to produce hepatotoxicity in vivo.

1,2-Dimethylhydrazine↗
PubMed1990

The reaction of N-methyl-N-nitrosourea with DNA in B and non-B conformations.

Reaction of N-methyl-N-nitrosourea (MNU) with DNA in B and non-B conformations was investigated using plasmids containing inserts in which the non-B topological isomers could readily be prepared by topoisomerase I catalyzed relaxation in the presence of ethidium. DNA sequences in the Z, cruciform and H conformations were shown to be methylated by MNU at the N7 position of guanines or the N3 position of adenines in a manner that was indistinguishable from the reaction of MNU with the same sequences in the B conformation. Electronic factors rather than steric factors, therefore, appear to dominate methylation of DNA by MNU.

Base Sequence↗
PubMed1990

Links between passive smoking and disease: a best-evidence synthesis. A report of the Working Group on Passive Smoking.

We reviewed the toxicologic, clinical, and epidemiologic evidence on the health effects of environmental tobacco smoke (ETS). For each type of exposure to environmental tobacco smoke we have sought articles in the English language reporting studies of effects on human health. Formal criteria that stressed study design, quality of execution and generalizability of results were used to select 116 scientifically admissible reports from over 2,900 articles. We concluded that: (a) there is strong evidence of an association between residential exposure to environmental tobacco smoke and both respiratory illness and reduction of lung function, and also between maternal smoking and reduced birth weight; (b) the weight of evidence is compatible with an association between active maternal smoking during pregnancy and increased infant mortality, and also between residential exposure to environmental tobacco smoke (primarily spousal smoking) and the risk of lung cancer; (c) there is evidence consistent with a relationship between exposure to environmental tobacco smoke in the workplace and respiratory symptoms, (d) the evidence is insufficient to implicate residential exposure to environmental tobacco smoke in relation to other forms of malignant disease or congenital malformations; (e) there is no evidence in the literature of an association between nonresidential exposure to environmental tobacco smoke and any form of cancer. Further studies are required to address the effects of exposure to environmental tobacco smoke, especially nonresidential exposure, in carcinogenesis and as a risk factor for atherosclerosis. Further work is also needed to improve measurement of exposure in such studies and to assess the importance of confounding factors.

Adolescent↗
PubMed1989

Activation of the c-Ha-ras-1 proto-oncogene by methylation in vitro with alpha-acetoxy-N-nitrosodimethylamine.

alpha-Acetoxy-N-nitrosodimethylamine, an activated derivative of the carcinogen N-nitrosodimethylamine, methylated in vitro a plasmid containing the human c-Ha-ras-1 proto-oncogene, resulting in the generation of a transforming oncogene, assayed by transfection into NIH 3T3 cells. The resulting transformed cells were tumorigenic and metastatic in immune-deprived mice. Further transfection using tumor DNA led to the formation of three secondary NIH 3T3 transformants. DNA from these secondary transformants contained human ras gene sequences. Two of the three secondary transformants contained G----A mutations at guanine 35 in codon 12, and the third secondary transformant retained the wild-type sequence at codons 12, and 61. For the latter, the activating mutation was not determined. These results demonstrate that a simple methylating agent can activate a normal human ras proto-oncogene to a transforming oncogene.

Animals↗
PubMed1989

Methylation of DNA by three N-nitroso compounds: evidence for sequence specific methylation by a common intermediate.

Methylation in vitro of calf thymus DNA, a supercoiled plasmid, poly(dG).poly(dC), and poly(dGdC).poly(dGdC) by N-nitroso(acetoxy-methyl)methylamine and N-nitroso(acetoxybenzyl)methylamine in the presence of esterase, and by N-nitrosomethylurea was investigated. Although there were differences in the amounts of 7-methylguanine and O6-methylguanine formed in the various DNA substrates, the methylation pattern was the same for each of these methylating agents. The three compounds reacted identically when methylation of a portion of a 345 bp restriction fragment of the plasmid pBR322 was examined at nucleotide resolution by a sequencing assay. They also showed a tendency to react preferentially with particular guanines. These data suggest that the three N-nitroso compounds methylate DNA via a common intermediate such as the methyl diazonium ion, which exhibits some sequence specificity.

Base Sequence↗
PubMed1989

Mechanisms of action of N-nitroso compounds.

There is ample evidence from studies in experimental animals that N-nitroso compounds are carcinogenic because in the body they form potent electrophilic alkylating agents. These reactive intermediates are formed by spontaneous decomposition in the case of nitrosoureas and related compounds, or by metabolic activation in the case of N-nitrosamines. The electrophiles subsequently react with DNA of target tissues to form altered bases which leads to the initiation of carcinogenesis. There is now convincing evidence that the biological activity of N-nitroso compounds in humans does not differ substantially from that in experimental animals. We can therefore predict with a high degree of confidence that N-nitroso compounds including nitrosamines are carcinogenic in man.

Animals↗