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At least 19 recordsLinked to original sources
PubMed1975

Evaluation of a new model to detect bladder carcinogens or co-carcinogens; results obtained with saccharin, cyclamate and cyclophosphamide.

A sensitive rat model has been designed to detect potential weak bladder carcinogens or co-carcinogens. The test compound is given to animals which have received a single initiating, but non-carcinogenic, dose of N-methyl-N-nitrosourea (MNU). The model has been used to investigate two compounds currently under suspicion as weak bladder carcinogens, namely sodium saccharin and sodium cyclamate, and one compound known to be cytotoxic but not carcinogenic for the bladder epithelium namely cyclophosphamide. For comparison, these three compounds were also tested as solitary carcinogens in animals not pre-treated with MNU. At the very high dose levels used, sodium saccharin and sodium cyclamate were weak solitary carcinogens producing 4/253 and 3/228 bladder tumours respectively, and the first of these tumours did not appear for more than 80 weeks. When tested in the MNU/rat model more than half the animals receiving either sodium saccharin or sodium cyclamate developed bladder tumours from 10 weeks onwards. By contrast, cyclophosphamide failed to produce any tumours when tested either as a solitary carcinogen or in the MNU/rat model. It must be emphasized that the doses of saccharin and cyclamate used were far higher than those consumed by man, including diabetics, and these results should not be directly extrapolated to man without careful consideration of many other factors including negative epidemiological findings. The theoretical basis of the model is discussed and also the relevance, in terms of environmental human exposure, of detecting compounds which have a synergistic effect with other known bladder carcinogens. It appears that this model can be used to detect a carcinogenic or co-carcinogenic potential in compounds which are organotropic for the bladder more rapidly and with fewer animals than if the compounds are tested as solitary carcinogens by more conventional methods. It is suggested that it could be used to detect those compounds which require further investigation.

Administration, Oral↗
PubMed1978

[Nuclear DNA synthesis rate and labelling index: effects of carcinogenic and non-carcinogenic chemicals on its behaviour in the organism of growing CBA-mice. The thymidine-incorporation-screening-system (TSS) (author's transl)].

During the last few decades there has been an extraordinary accumulation of man-made chemicals in the human environment. There is a growing consensus in oncology that a large proportion of human cancers are environmental in origin by exposure of man to such carcinogenic chemicals. These chemicals in the majority of all cases have not been tested to prove their carcinogenicity. Testing of new chemical compounds is needful prior to their introduction into commerce, foods, agriculture or the working places to prevent human cancer. To test such a large number of possibly carcinogenic chemicals, economical and rapidly practicable bioassays are necessary. In the following we compare some well known bioassays with our autoradiographic thymidine-incorporation-screening-system and other assays based on biochemical quantification of DNA synthesis as parameter for identification of carcinogenic substances. The partial inhibition of the whole DNA synthesis in a proliferating cell population after treatment with toxic and carcinogenic chemicals is an early common response especially in hepatectomized animal, livers caused by the effects of those substances. However, by quantitative evaluation of the nuclear DNA synthesis rate as a basic parameter using autoradiographs of kidney and liver of juvenile growing CBA-mice, it is possible to differentiate carcinogenic from non-carcinogenic chemicals by means of silver grain counting after 3H-TdR incorporation. Contrarily the "whole DNA synthesis" expressed by the percentual 3H-labelling index of kidney and liver did not permit such a differentiation in our experimental arrangement. We could demonstrate that carcinogenic compounds of different chemical classes partially inhibit the nuclear DNA synthesis rate significantly over a time period longer than 24 hours. The tested non-carcinogenic compounds did not show this suppressive effect on the nuclear DNA synthesis rate.

Animals↗
PubMed1978

Effects of carcinogenic and non-carcinogenic chemicals on plasma esterases in BALB/c mice.

Esterase profiles of plasma from female BALB/c mice treated with a variety of carcinogenic and weakly- or non-carcinogenic chemicals were analyzed. Mice treated with the potent carcinogens diethylnitrosamine, dinitrosopiperazine, dipropylnitrosamine, dimethylhydrazine, urethane, and dimethyldinitrosopiperazine had similarly altered plasma esterase profiles after 7 days' exposure to the chemicals. The alterations consisted of increased activity in 4 esterase bands. The increased activity persisted in some of the bands after cessation of carcinogen exposure. Exposure to high concentrations of the weakly- or non-carcinogenic compounds nitrosohydroxyproline, nitrosomethoxymethylamine, 1-nitroso-4methylpiperazine,nitroso-2,6dimethylpiperidine, and ethyl methanesulfonate caused no obvious plasma esterase alterations. Ingestion of carbon tetrachloride resulted in increased activity in one esterase band with concomitant decrease in a second band. Analysis of serum from test mice for levels of serum glutamic oxaloacetic transaminase, alkaline phosphatase, lactate dehydrogenase-lactate substrate, and D-gamma-glutamyl transpeptidase did not differentiate between mice treated with selected carcinogens and those treated with non-carcinogens and/or carbon tetrachloride.

Animals↗
PubMed1976

Carcinogen-induced DNA repair in nucleotide-permeable Escherichia coli cells. Analysis of DNA repair induced by the carcinogens N-acetoxy-N-2-acetylaminofluorene and 7-bromomethyl-benz(a)anthracene.

Upon exposure to the carcinogens N-acetoxy-N-2-acetylaminofluorene and 7-bromomethyl-benz[a]anthracene, which bind covalently to DNA, ether-permeabilized (nucleotide-permeable) Escherichia coli wild-type cells responded with DNA excision repair. This repair was missing in mutants carrying defects in genes uvrA, uvrB and uvrC, whereas it was present in uvrD and several rec mutants. Enzymic activities involved were identified by measuring repair polymerization and size reduction of denatured DNA. 1. An easily measurable effect in E. coli wild-type cells was carcinogen-induced repair polymerization. When initiated by N-acetoxy-N-2-acetylaminofluorene or 7-bromomethyl-benz[a]anthracene, it depended upon an ATP-requiring step; CTP, GTP or UTP did not substitute for ATP. DNA repair synthesis was inhibited by p-chloromercuribenzoate and quinacrine. In uvrA, uvrB and uvrC mutants no carcinogen-stimulated DNA synthesis could be detected, indicating that steps involved in pyrimidine dimer excision are also involved in chemorepair. In recA, recB and recC mutant cells, repair synthesis was stimulated by the carcinogens to a normal extent. This evidence excludes the ATP-dependent recB,C deoxyribonuclease and recA gene products as playing an important role in carcinogen-induced excision repair. polA1 cells showed drastically reduced levels of rapair polymerization, indicating that DNA polymerase I is the main polymerizing enzyme. 2. As determined by DNA size reduction in alkaline sucrose gradients, the arylalkylating carcinogens caused endonucleolytic cleavage of endogenous DNA in wild-type cells. This incision step was most effectively performed in the presence of ATP; UTP, CTP and GTP were only slightly effective. Incision was inhibited by p-chloromercuribenzoate and quinacrine. When exposed to the arylalkylating carcinogens, uvrA, uvrB and uvrC mutant cells did not perform the incision step in the presence of ATP, suggesting the involvement of the respective gene products in the initiation of chemorepair.

Acetoxyacetylaminofluorene↗
PubMed1979

Measurement of DNA-excision repair in suspensions of freshly isolated rat hepatocytes after exposure to some carcinogenic compounds: its possible use in carcinogenicity screening.

When suspensions of freshly isolated rat hepatocytes were exposed to a number of carcinogenic compounds, it was possible to measure an increased UDS by a rapid procedure via liquid-scintillation counting. For a number of carcinogenic compounds and some of their non-carcinogenic structural analogues a good correlation between the carcinogenic property and the ability to induce UDS was demonstrable. Out of 12 carcinogenic compounds, belonging to several different chemical classes, 10 gave rise to an increased UDS, whereas only 2 compounds, the polycyclic aromatic hydrocarbons benzo[alpha]pyrene and benz[alpha]anthracene, did not. All 4 noncarcinogenic compounds tested were negative. Possibly this method can be of value as a routine screening test, in combination with other short-term test systems, thus improving the predictive value of screening in vitro with respect to carcinogenicity.

Animals↗
PubMedDate not supplied

Testing of chemicals for carcinogenic activities and some problems related to the assessment of carcinogenic risks to men.

It is recognized that many human cancers are influenced by environmental factors. Therefore, testing of chemicals for carcinogenic activities represents an important part of comprehensive toxicological examinations. Procedures to be employed in bioassays for carcinogenicity will be discussed. Short-term tests should be utilized as screening methods to select suspected chemicals which should or must be further tested in long-term animal experiments. Animal tests can predict carcinogenicity in man. Any substance which is shown conclusively to cause tumors in animals should be considered carcinogenic and therefore a potential hazard for man, but tests on experimental animals cannot provide irrefutable proof of the safety or carcinogenicity of a substance for the human species. Therefore, some of the problems related to the assessment of carcinogenic risks by chemicals will be discussed.

Animals↗
PubMed1978

Further improvements in the hepatocyte primary culture DNA repair test for carcinogens: detection of carcinogenic biphenyl derivatives.

DNA repair in hepatocyte primary cultures was induced by simultaneous treatment with the carcinogen and [3H] thymidine for 18 h beginning immediately after attachment of cells. The unscheduled DNA synthesis elicited by carcinogens was determined by counting grains with an automatic grain counter. In 5 biphenyl derivatives, a correlation was found between carcinogenicity and the ability to induce DNA repair. Hence, the method offers promise as a means of screening chemical carcinogens.

Biphenyl Compounds↗
PubMed1977

Selection of an in vitro carcinogenicity test for derivatives of the carcinogen hexamethylphosphoramide.

The demonstration that hexamethylphosphoramide (HMPA) possesses potent carcinogenic properties has raised doubts about the safety of exposure to other phosphoric amides. In order to define a suitable short-term test with which to evaluate such analogues, the response of the Salmonella typhimurium mutation assay of Ames and cell transformation assay of Styles to HMPA and 3 selected analogues has been studied. These analogues were the related leukaemogen phosphoramide, the putative non-carcinogen, phosphoric trianilide and N.N'N''-trimethylphosphorothioic triamide, a compound of unknown and hitherto unpredictable properties. While both tests found the trianilide negative, the Ames test failed to detect phosphoramide as positive and gave an erratic and predominantly negative response to HMPA. In contrast, the transformation assay found both phosphoramide and HMPA positive. This test response profile indicates that the transformation assay is the preferred test with which to evaluate analogues of HMPA for potential carcinogenicity. Some structural requirements for potential carcinogenicity within this class of compounds are tentatively deduced.

Anilides↗
PubMed1975

Carcinogen-induced DNA repair in nucleotide-permeable Escherichia coli cells. Induction of DNA repair by the carcinogens methyl and ethyl nitrosourea and methyl methanesulfonate.

Ether-permeabilized (nucleotide-permeable) cells of Escherichia coli show excision repair of their DNA after having been exposed to the carcinogens N-methyl-N-nitrosourea (MeNOUr), N-ethyl-N-nitrosourea (EtNOUr) and methyl methanesulfonate (MeSO2OMe) which are known to bind covalently to DNA. Defect mutations in genes uvrA, uvrB, uvrC, recA, recB, recC and rep did not inhibit this excision repair. Enzymic activities involved in this repair were identified by measuring size reduction of DNA, DNA degradation to acid-soluble nucleotides and repair polymerization. 1. In permeabilized cells methyl and ethyl nitrosourea induced endonucleolytic cleavage of endogenous DNA, as determined by size reduction of denatured DNA in neutral and alkaline sucrose gradients. An enzymic activity from E. coli K-12 cell extracts was purified (greater than 2000-fold) and was found to cleave preferentially methyl-nitrosourea-treated DNA and to convert the methylated supercoiled DNA duplex (RFI) of phage phiX 174 into the nicked circular form. 2. Degradation of alkylated cellular DNA to acid solubility was diminished in a mutant lacking the 5' leads to 3' exonucleolytic activity of DNA polymerase I but was not affected in a mutant which lacked the DNA polymerizing but retained the 5' leads 3' exonucleolytic activity of DNA polymerase I. 3. An easily measurable effect is carcinogen-induced repair polymerization, making it suitable for detection of covalent binding of carcinogens and potentially carcinogenic compounds.

Carcinogens↗
PubMed1978

Relevance of short-term carcinogenicity tests to the study of the carcinogenic potential of urban air.

It is now accepted that screening for carcinogens in animals is expensive and demonstrates carcinogenic potential rather than actual carcinogenicity in man. A number of short-term tests which depend on mutagenicity, stimulation of DNA repair, ability to produce chromosome damage or other actions, and which correlate at least to some extent with carcinogenic potential, have been devised. These have the advantages of being rapid and cheap. Some can be carried out by using human cells. They may have advantages in the context of air pollution since they are sensitive down to very low dose levels and since they can deal with complex mixtures. Combinations of such tests may be of more value than any single test. Their particular value may be as a preliminary screening procedure in a tiered testing programme which may have high predictive efficiency.

Air Pollutants↗
PubMed1978

Growth stimulation following serum transfer from carcinogen-treated donors to normal rats: a new aspect of early carcinogen actions.

Especially in their early phase of action carcinogens are strong inhibitors of cell proliferation. This is an apparent contradiction to the promoting activity of oncogens in the process of carcinogenesis. Because of obvious similarities between restorative and neoplastic growth processess on the tissue level we have studied the possibility, whether such similarities do exist also with regard to stimulatory activities in the serum. To overcome the non-specific inhibitory effect of a carcinogen, the serum of 2-acetylaminofluorene (AAF) treated male Sprague-Dawley rats was transferred to normal recipients. The results demonstrate that the proliferation of the same tissues (hepatocytes, adrenocortical cells, thymocytes) as in liver regenerating animals were stimulated by the serum of the carcinogen-treated rats. Whether the observed short-term effect corresponds to the so-called promoting activity of the carcinogen(s) is discussed. Nature and origin of the humoral stimulator(s) are still unknown.

2-Acetylaminofluorene↗
PubMed1978

Potentially carcinogenic analogues of the carcinogen hexamethylphosphoramide: evaluation in vitro.

Experiments conducted in vitro are described which indicate that a family of specifically substituted phosphoramides may share the carcinogenic properties displayed by the structurally novel carcinogen, hexamethylphosphoramide (HMPA). Most of the analogues tested only gave a positive response in vitro when using a substantially modified liver homogenate activation system (S-9 mix). The analogy drawn in our earlier paper between this new class of potential carcinogens and the nitrosamine carcinogens, has been strengthened. The following compounds gave a positive response in the cell transformation assay of Styles: hexamethylphosphoramide (HMPA), hexamethylphosphorous triamide, hexamethylphosphorothioic triamide, tripiperidinophosphine oxide, phosphorothioic trimorpholide and diethoxymorpholinophosphine oxide (DEMPA).

Amides↗
PubMed1978

Concanavalin A agglutination of bladder cells of rats treated with bladder carcinogens; a rapid new test to detect bladder carcinogens.

N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), which is a potent, specific bladder carcinogen in rats, and its related compounds were orally administered to rats for 1 week. The bladder cells were isolated by the treatment with EDTA and sonication and they were subjected to agglutination assay by concanavalin A (Con A). Bladder cells obtained from rats treated with BBN, N-butyl-N-(3-carboxypropyl)nitrosamine (BCPN), N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN) and N-butyl-N-(2-hydroxyethyl)nitrosamine (BHEN) were agglutination-positive, while those cells treated with N-tert-butyl-N-(4-hydroxybutyl)-nitrosamine (t-BBH) and N-butyl-N-(3-hydroxypropyl)nitrosamine (BHPN) were negative. Results obtained by this method were highly correlated with the known carcinogenicity of BBN and its analogues. Therefore, this method could be used for rapid screening of bladder carcinogens.

Animals↗
PubMed1979

Carcinogenic effect of N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine, a postulated proximate pancreatic carcinogen in Syrian hamsters.

N-Nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) proved to be a potent carcinogen in Syrian golden hamsters. The compound is an in vivo metabolite of N-nitrosobis(2-hydroxypropyl)amine, N-nitrosobis(2-oxopropyl)amine (BOP), and N-nitroso-2,6-dimethylmorpholine and a postulated proximate pancreatic carcinogen in hamsters. As with BOP, HPOP induced a higher incidence of pancreatic ductular adenocarcinomas than did N-nitrosobis(2-hydroxypropyl)amine and N-nitroso-2,6-dimethylmorpholine, and these neoplasms showed a great tendency for invasion and metastasis. Also, HPOP induced tumors of the forestomach, liver, gallbladder, kidneys, and vagina (as did BOP). However, HPOP [unlike BOP, but like N-nitrosobis(2-hydroxypropyl)amine and N-nitroso-2,6-dimethylmorpholine] led to tumor development in the nasal cavity, larynx, trachea, intestine, Harderian gland, lips, and flank organ. The possible mechanisms of HPOP carcinogenicity are discussed.

Animals↗
PubMed1979

The early effects of chemical carcinogens on adult rat hepatocytes in primary culture: I. Quantitative changes in intracellular enzyme activities following a single dose of carcinogen.

The effects of exposure of adult rat hepatocytes to chemical carcinogens have been studied using a short-term maintenance culture system. Scanning microdensitometry was used to quantitate the observed changes in enzyme activity. The dose-response curves showed a biphasic response for all 4 enzymes studied (glucose-6-phosphate dehydrogenase, succinate dehydrogenase, NADPH oxidase and gamma-glutamyl transpeptidase) there being decreased enzyme activities at the higher dose levels used, possibly indicating cytotoxicity. The enhancement of enzyme activity at low dose levels was due to generalised increases occurring in every cell, rather than to selection of a cell species particularly high in enzyme activity. A culture period of 24 h was necessary for the complete adaptation of the cells to the culture environment as evidenced by the response of intracellular glucose-6-phosphate dehydrogenase activity to carcinogen treatment. These findings are discussed in relation to previously reported in vivo studies.

Animals↗
PubMed1992

Theoretical mechanisms for synthesis of carcinogen-induced embryonic proteins: XXVI. Evolutionary significance of carcinogen-induced embryonic gene activity.

Besides the major theme of this series of writings--that chemically derepressed embryonic genes are fundamental to the mechanisms of carcinogenesis, there appear to be other significant aspects to this process. Yeast cells have the ability to differentially respond to carcinogens and non-carcinogens by the activation of embryonic type genes that are also found in mammals. This strange relationship is interpreted here as being due to certain phylogetically conserved genes from yeasts existing also in mammals that are used in both organisms for the same process. For example, a protooncogene found in yeast cells or embryonic cells serves for rapid mitosis. Also yeast mating type genes have high homologies to homeotic domains and therefore may be prototype genes of homeotic genes, which are embryonic type genes in animals.

Biological Evolution↗
PubMed1976

Carcinogen-induced DNA repair in primary rat liver cell cultures; a possible screen for chemical carcinogens.

Primary rat liver cell cultures were exposed to a direct acting carcinogen, methyl methanesulfonate, and procarcinogens requiring metabolic activation, aflatoxin B1 and B2. DNA damage by these agents was evidenced by the induction of DNA repair, measured as unscheduled DNA synthesis. The sensitivity of these cultures to the potent porcarcinogen aflatoxin B1 indicates that this system may be adapted for screening suspected chemical procarcinogens, and for investigating the relationship between metabolic activation of procarcinogens, DNA damage, DNA repair, and carcinogenicity.

Aflatoxins↗