PubMed Health⌕ Search

Biomedical subjects

V M Craddock

Publications and source records attributed to V M Craddock.

At least 19 recordsLinked to original sources
PubMed1992

Aetiology of oesophageal cancer: some operative factors.

Of the thousands of chemicals tested, the only compounds found to be potent carcinogens for the oesophagus are the N-nitrosamines. Many of these compounds are readily formed from common precursors in the environment (eg example in food during its storage or preparation) and also in vivo in the human stomach. Exposure is therefore likely to be ubiquitous. Although man may be exposed to other oesophageal carcinogens these have yet to be chemically identified, and at present nitrosamines are the sole contenders for the role of initiators of oesophageal cancer in man. Evidence suggests strongly that oesophageal cancer is initiated world-wide by nitrosamines, and promoted by secondary factors, the nature of which varies with the population concerned, notably alcohol in Europe and the USA, dietary deficiencies in China and Iran, mycotoxins in South Africa. When several risk factors coincide in one locality, the result can be a very high incidence of oesophageal cancer, with no one major cause.

Carcinogens↗
PubMed1991

Potent inhibition of oesophageal metabolism of N-nitrosomethylbenzylamine, an oesophageal carcinogen, by higher alcohols present in alcoholic beverages.

The main cause of oesophageal cancer in western countries is consumption of alcoholic beverages, the degree of risk being much greater for certain spirits than for wine or beer. Risk shows a striking correlation with the content of higher alcohols in the drinks, although the alcohols per se have not been shown to be carcinogenic in experimental animals. To test the concept that higher alcohols modulate the oesophageal carcinogenicity of nitrosamines by altering their metabolism, we studied the effect of certain higher alcohols on the metabolism of N-nitrosomethylbenzylamine by rat oesophageal mucosal and liver microsomes. In oesophagus, the alcohols were 1000 times more inhibitory than ethanol, and in liver 100 times. This suggests that enhancement of carcinogenesis may not result from an effect on nitrosamine metabolism. Higher alcohols could act by increasing the rate of replication of cells already initiated for malignancy by previous exposure to nitrosamines. Intubation of 2-methylbutanol produces a very much greater increase in oesophageal basal-cell proliferation than does ethanol.

Alcoholic Beverages↗
PubMed1988

Acute and chronic effects of diacetoxyscirpenol on cell replication in rat esophagus and stomach.

The effect of the mycotoxin diacetoxyscirpenol (DS) on the upper alimentary tract was studied on account of the association between the consumption of food contaminated by Fusaria and esophageal cancer. Previously it had been shown that a single high dose of DS induced basal cell replication in esophagus and in squamous and glandular stomach. To assess the significance of this effect in relation to the levels of exposure likely to be encountered by man and agricultural animals, it was essential to examine the dose response relationship. Also, the long-term effect of repeated intubations of DS, and of chronic feeding of DS at 10 ppm in the diet, was studied. Intubation of progressively lower doses of DS produced a decreasing effect on replication in esophagus and stomach, but at 0.06 mg/kg replication in squamous and glandular stomach was still more than in the control animals. Intubation repeated weekly for 6-8 weeks produced no detectable change in esophagus or stomach in the surviving animals which were killed at 9 months. When DS was fed in the diet, there was marked hyperplasia in the squamous stomach of two of the four animals which survived for 9 months. These results suggest that DS per se is not carcinogenic for esophagus or for stomach, and that exposure to occasional high doses does not cause persisting abnormalities in replication. However, repeated exposure to high doses would cause repeated periods of hyperplasia, and chronic exposure in some animals could result in continuing hyperplasia. Any increase in replication is likely to promote cancer by increasing the vulnerability of the gastric and esophageal mucosa to carcinogens.

Animals↗
PubMed1987

Effect of the esophageal carcinogen methylbenzylnitrosamine and of a putative potentiating factor, a trichothecene mycotoxin, on O6-methylguanine-dna methyl transferase in rat esophagus and liver.

Epidemiological evidence from China and South Africa has implicated Fusaria mycotoxins in the etiology of esophageal cancer, although treatment of animals with extracts of Fusaria cultures did not cause cancer of the esophagus. Fusaria are the major producers of trichothecenes, and animal experiments have shown that these mycotoxins can damage the esophagus but they have not been shown to cause esophageal cancer. A plausible concept is therefore that esophageal cancer is initiated by the potent environmental esophageal carcinogens, certain nitrosamines, but that the levels of exposure are too low to cause clinical cancer unless their effects are enhanced by additional risk factors. Among the most likely enhancing factors in the regions mentioned above are Fusaria mycotoxins. As trichothecenes are known to inhibit sulphydryl-dependent reactions and to inhibit protein synthesis, experiments were carried out to determine whether potentiation of cancer could be mediated via inhibition of the DNA repair protein O6-methylguanine-DNA methyl transferase (O6MG-MT). The effect of diacetoxyscirpenol (DS) on O6MG-MT was studied. Chronic or acute treatment with DS did not alter the level of O6MG-MT in esophagus, or affect the depletion which occurs after injection of methylbenzylnitrosamine, or alter the rate of reappearance of O6MG-MT. A high dose of DS induced O6MG-MT in liver. These results suggest that if trichothecenes are risk factors for esophageal cancer, the effect is unlikely to be mediated by inhibition of O6MG-MT. Induction of the repair protein in liver may be relevant in the animal toxicoses caused by consumption of trichothecenes, but is unlikely to be implicated in the etiology of liver cancer in man.

Animals↗
PubMed1987

Stimulation of DNA replication in rat esophagus and stomach by the trichothecene mycotoxin diacetoxyscirpenol.

Consumption by man of cereals contaminated by high levels of Fusaria mycotoxins has caused alimentary toxic aleukia, while chronic consumption at lower levels of contamination has been implicated in esophageal cancer in China and South Africa. Dietary treatment of animals with extracts of Fusaria cultures or with the trichothecene diacetoxyscirpenol (DS) caused esophageal hyperplasia but not cancer. The explanation could be that esophageal cancer is initiated by other factors, possibly by nitrosamines, and that Fusaria mycotoxins act either as co-carcinogens or as promoters as a result of their ability to stimulate cell replication. The effect of DS on replication in esophagus was therefore studied. As squamous stomach has a very similar histological structure to esophagus, the effect of DS on stomach was studied also. A high dose of DS given by gavage was shown by the bromodeoxyuridine-antibody technique to increase DNA replication in the basal cells of the esophagus and of the squamous and glandular stomach. For stomach, this correlated with an increased incorporation of tritiated thymidine into DNA, and an increase in ornithine decarboxylase activity. These effects had returned to normal by 7 days. The increased replication was apparently not a result of cell damage and restorative hyperplasia. It is suggested that, as has been proposed recently for butylated hydroxyanisole, DS may enhance carcinogenesis when exposure is sufficient to stimulate cell replication. This contrasts with the non-threshold action of initiating carcinogens. For man, acute exposure to the critical dose of DS probably occurs only under exceptional circumstances, as during outbreaks of alimentary toxic aleukia. Prolonged exposure to lower dose levels is more likely to be relevant.

Animals↗
PubMed1987

Sequential histological studies of rat oesophagus during the rapid initiation of cancer by repeated injection of N-methyl-N-benzylnitrosamine.

The sequence of histological changes leading to oesophageal cancer in animals after treatment with various nitrosamines has been studied previously using systems which induced cancer relatively slowly. The more potent carcinogen, N-methyl-N-benzylnitrosamine (MBzN), has been employed to induce cancer in a very much shorter time in experiments designed to detect factors which may potentiate oesophageal cancer. MBzN injected twice weekly for 4 weeks induces papillomas by 4 weeks and carcinomas by 9 weeks. The histological events occurring during the 4-week treatment period have been studied. Initially there was an increase in mitosis. After the second injection, destruction of basal cells occurred, with their complete disappearance from stretches of the epithelium, accompanied by a massive influx of inflammatory cells, and disruption of the normal architecture of the oesophageal epithelium. After 1-2 weeks the numbers of inflammatory cells decreased, concurrently with basal cell hyperplasia and dysplasia, where replicating basal cells penetrated down into the submucosa and upwards towards the lumen. Thickening of the spinous and granular layers of the epithelium and hyperkeratosis were evident, and after 30 days a macroscopically visible papilloma was present. It therefore appears that resistance develops to the toxic inhibitory effect of the carcinogen, and this allows the abnormal replication of basal cells to occur even in the continued presence of the carcinogen. The biochemical processes underlying this development of resistance are being studied, and the effects of possible potentiating factors on the sequence of events occurring during carcinogenesis are being used to test for dietary factors which may enhance oesophageal cancer.

Animals↗
PubMed1987

Effect of the trichothecene mycotoxin diacetoxyscirpenol on nitrosamine-induced oesophageal cancer and on relevant enzymes in oesophagus and liver.

To test the concept that human oesophageal cancer is initiated by nitrosamines and potentiated by consumption of food contaminated by mycotoxins produced by Fusaria, the effect of the trichothecene mycotoxin diacetoxyscirpenol (DS), alone and in combination with N-nitroso-N-methylbenzylamine (NMBzA), on rat oesophagus was studied. Chronic treatment with DS induced oesophageal hyperplasia, but simultaneous treatment with NMBzA tended to inhibit rather than to enhance carcinogenesis. The mycotoxin did not inhibit O6-alkylguanine-DNA alkyltransferase in oesophagus and produced a marked induction of repair protein in liver. Depletion of the repair protein in oesophagus brought about by injection of NMBzA was not inhibited by the mycotoxin, and its reappearance was not delayed. Intubation of DS reduced DNA synthesis in the oesophagus, while dietary treatment resulted in an increase after nine weeks. The results suggest that, while simultaneous treatment with DS reduces cancer induced by NMBzA, if there is first exposure to mycotoxin and induction of hyperplasia, and then exposure to nitrosamine, so that the carcinogen acts on a vulnerable oesophagus in which there is an increased rate of cell proliferation, the mycotoxin could well enhance carcinogenesis.

Animals↗
PubMed1986

Effect of N-nitrosamines carcinogenic for oesophagus on O6-alkyl-guanine-DNA-methyl transferase in rat oesophagus and liver.

Several O6-alkylGua adducts have been shown to be removed from DNA during its repair by transfer of the alkyl group to a cysteine residue in a specific AAP, with the formation of S-alkylcysteine. As the reaction is stoichiometric and irreversible, the AAP content of the cell can be reduced or depleted. In vivo depletion by a high dose of nitrosamine can be used to test for the formation of a repairable alkylation adduct at the O6-position of guanine. In addition, if the carcinogenic potency of a nitroso compound for a particular organ is related to the persistence of the adduct in DNA, potency would depend not on the level of alkylation attained after treatment, but on whether this was sufficient to deplete the AAP content of the organ concerned and so to slow down repair, i.e. depletion of AAP is a more relevant estimate of potency than is the initial extent of DNA alkylation. Dose-response studies on target and non-target organs showed that depletion of AAP correlated with organotropy for those nitrosamines known to methylate DNA, i.e. with NDMA for liver, and with NMBzA for oesophagus. With NDEA, the results supported the suggestion that other adducts in addition to O6-alkylGua may be involved. NMPhA, an oesophageal specific carcinogen, did not deplete AAP in oesophagus, and induced AAP in liver. This result adds to the evidence that NMPhA does not alkylate DNA.

Alkylation↗
PubMed1986

The effect of the trichothecene mycotoxin diacetoxyscirpenol on nitrosamine-induced esophageal cancer in the rat.

The fact that the only chemicals known to be potent carcinogens for the esophagus in animals are certain nitrosamines suggests that these environmental carcinogens could be a cause of human esophageal cancer. Epidemiological investigations support this concept. The level of exposure alone is not considered sufficient to account for the very high incidence of the disease in certain regions, but potentiating factors have been shown to have a dramatic effect on nitrosamine-induced esophageal cancer in animal experiments. A likely enhancing factor is consumption of food contaminated by molds, especially by Fusaria spp, a group known to produce trichothecene mycotoxins. The effect of simultaneous treatment with diacetoxyscirpenol (DS) on methyl-benzyl-nitrosamine (NMBzA)-induced esophageal cancer was studied. Feeding a diet containing DS at 10 ppm for 10 weeks caused thickening of the basal cell layer of the esophageal epithelium, but feeding DS (10 ppm) simultaneously with NMBzA (4, 8, 16 ppm) for 10 weeks, or feeding a lower dose of DS with NMBzA for a longer period, or administration of DS per os at intervals during NMBzA treatment, did not potentiate but possibly reduced esophageal tumors. Toxicity, revealed by reduced growth rate of DS-fed animals, may have inhibited carcinogenesis. In contrast to the rapid potentiating effect of zinc deficiency, DS does not appear to cause an early enhancement of esophageal cancer.

Animals↗
PubMed1984

Repair and replication of DNA in rat brain and liver during foetal and post-natal development, in relation to nitroso-alkyl-urea induced carcinogenesis.

The susceptibility of rat brain to induction of cancer by N-nitroso-N-ethyl-urea (NEU) increases dramatically from a very low level in the 12 day foetus to a maximum at the time of birth, and then decreases with age. Liver tumors are rarely induced by a single treatment with NEU at any age. If induction of cancer by nitroso-alkyl-ureas depends on replication of DNA containing the mispairing base O6-alkylguanine, susceptibility would reflect the balance between the protective effect of removal of the base by repair mechanisms and the potentiating effect of cell replication. The capacity of tissues to remove O6-alkyl-guanine from DNA depends on the amount of alkyl acceptor protein (AAP) present. To study the concept that carcinogenesis results from replication of alkylated DNA, the AAP contents and relative rates of DNA replication were studied in brain and liver of rats at various stages of development, from the 12 day foetus to the 48 week old rat. Replication in liver was approximately ten times higher than in intra-cranial contents at each stage of development studies. The AAP content was higher in the 12 day foetal brain than later, decreasing to low levels as susceptibility to NEU increased until the time of birth, and then remaining low in the adult. The peak sensitivity of brain therefore corresponds to the time at which AAP content is low and rate of DNA replication is high. With liver, AAP levels are low in the foetus, although higher than in brain, and increase after birth. The higher level of AAP in the foetal liver compared with that of brain is possibly sufficient to explain why cancer is not induced in liver in spite of the high rate of DNA replication. The results are consistent with the concept that replication of alkylated DNA is an essential event in initiation. There may be no quantitative relationship between replication and repair and susceptibility to cancer on comparison of different tissues, owing to the fact that, at the cellular level, cancer is a rare event. The amount of mispairing at replication necessary to bring it about may depend on the detailed organisation of the genome, and hence on cell type.

Age Factors↗
PubMed1984

Repair and replication of DNA in rat and mouse tissues in relation to cancer induction by N-nitroso-N-alkyl-ureas.

The high susceptibility of certain organs, for example rat brain, to induction of cancer by N-nitroso-N-alkyl-ureas, has been related to a low ability to remove O6-alkylguanine (O6AG) from DNA. It is therefore reasonable to ask why mouse brain, in which there is also a slow disappearance of O6AG from DNA after treatment with nitroso-alkyl-ureas, is not susceptible and why, in mice, thymus and lung are the main target organs. The explanation of the species difference could lie in the fact that replication of alkylated DNA is an essential event in initiation. If nitroso-alkyl-ureas had a greater inhibitory effect in some organs than in others, replication might be inhibited until after the O6AG had been removed, so preventing replication of DNA while still alkylated. This concept was tested by comparing the effect of N-nitroso-N-methyl-urea (NMU) on incorporation of [3H]TdR into DNA of relevant organs in Wistar rats and C57BL mice, and by determining ability to remove O6AG from DNA by measuring the alkyl acceptor protein (AAP) concentrations in these organs. No evidence was obtained that the AAP content was lower or inhibition of replication was less extensive in the organ of the species more susceptible to carcinogenesis than in the same organ of the less susceptible species.

Alkanes↗
PubMed1984

Repair and replication of DNA containing O6-methylguanine in fetal and adult animal tissues in relation to their susceptibilities to cancer induction by N-nitroso-N-alkylureas.

Experimental evidence and basic concepts support the view that replication of DNA containing the mispairing base O6-alkylguanine is an essential event in the initiation of cancer by simple alkylating agents. The likelihood of induction of cancer in a particular organ would depend on three factors: (1) the initial level of alkylation of DNA in that organ, (2) the rate of removal of O6-alkylguanine from DNA and (3) the extent of DNA replication during the critical period in which O6-alkylguanine is present. In systems in which the initial level of alkylation is approximately uniform in different organs, their relative susceptibilities to cancer would depend on their abilities to remove O6-methylguanine from DNA, and on the rates of replication of DNA after treatment with the carcinogen. To test this concept, repair and replication were studied in tissues with very different susceptibilities to induction of cancer by a low dose of N-methyl-N-nitrosourea, i.e., rat and mouse brain and lung, and rat brain at different stages of fetal and postnatal development. The ability of the tissue to remove O6-methylguanine from DNA was determined by incubation of tissue extracts with extraneously methylated DNA. Replication was studied by measurements of incorporation of 3H-thymidine into DNA. The outstandingly high level of replication of alkylated DNA in mouse thymus correlates with its outstandingly susceptibility to cancer induction by N-methyl-N-nitrosourea (MNU). The result of comparing repair ability and DNA replication in rat and mouse brain and lung suggest that unknown factors are involved in the resistance of the nontarget organs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

The behaviour of nuclear proteins during nitrosamine-induced carcinogenesis.

Dimethylnitrosamine given after partial hepatectomy reduces the synthesis of DNA, histone, and, to a lesser extent, of nonhistone proteins, the inhibition being general rather than for specific nuclear proteins. The extent of inhibition of macromolecular synthesis is greatest when the carcinogen is given a few hours after the operation. As a higher incidence of hepatocellular carcinoma is induced when dimethylnitrosamine is injected later, during the wave of DNA replication, it appears that inhibition of nuclear protein synthesis is not a relevant factor in carcinogenesis, unless it relates to loss of a specific non-histone protein present in small amounts. Analysis of sequentially extracted groups of non-histone proteins by 2D electrophoresis did not reveal any changes produced by treatment with dimethylnitrosamine. Animals fed a diet containing diethylnitrosamine showed an increased incorporation of amino acid into histone. Electrophoretic analysis of non-histone proteins revealed two reproducible effects of feeding the carcinogenic diet: relative to the bulk of nuclear non-histone protein, there was a reduction in the amount of a slightly basic 65000 mol. wt. polypeptide, and an increase in the level of a high molecular weight protein that was almost undetectable in material from normal rats. As these changes were not induced by partial hepatectomy of normal animals, it is possible that they are related to malignancy rather than to the associated increase in cell replication.

Animals↗
PubMed1982

The activity of 3-methyladenine DNA glycosylate in animal tissues in relation to carcinogenesis.

3-Methyladenine is one of the major products formed by reaction of a large number of environmental methylating agents with DNA in vivo and in vitro. In spite of the rapid spontaneous depurination of this base an enzyme, 3-methyladenine DNA glycosylase, has been shown to catalyse its excision. The relevance of this enzyme in carcinogenesis induced by alkylating agents was studied. Acute or chronic treatment of rats with diethylnitrosamine or with N-acetylaminofluorene caused a slight increase in glycosylase activity in liver. Experiments with liver regenerating after partial hepatectomy showed a similar increase to occur at the time of DNA replication. It could be that the increase found after treatment with carcinogens was related to the accompanying increase in cell replication, rather than being the result of a specific induction by the carcinogen. Glycosylase activity was found to be higher in the liver of the rabbit and cat than in rat or hamster liver. Organ differences (liver, kidney and brain of the rabbit) were smaller than the species differences found for enzyme activity in liver.

Animals↗