The use of the aquarium fishes Danio rerio and Poecilia reticulata as highly sensitive species for testing the carcinogenicity of chemical compounds

Aquarium fishes Danio rerio and Poecilia reticulata are recommended as test-objects for testing carcinogenic chemical agents. 30 compounds were tested for their action on these objects. The analysis of the incidence of induced tumors, period of their appearance and Iball index shows high sensitivity of the aquarium fishes to the carcinogenic action. Data are presented on the dynamics of experimental carcinogenesis, morphology of induced tumours, as well as on modifications of carcinogenesis (the role of environmental temperature, age, dose, exposition, etc.). Advantages and limitations of the "fish model" are compared with those found in the experiments carried on mammals.     

Effect of synthetic polymers on the formation of carcinogen-protein antigens in the early stages of carcinogenesis

Polymers of different chemical structure were studied for their effect on the production of carcinogen-protein antigens (CPA) at early stages of benzidine-induced carcinogenesis in mice. Polyacrylic acid (out of the four polymers studied) was found to exert the most pronounced inhibitory effect on the CPA production mainly in the liver.     

Effect of electrostimulation of the hypothalamus on the immunological reactivity of rats with 7,12-dimethylbenz[a]anthracene-induced tumors

Experiments on Wistar male rats established that electrostimulation of the area of the posterior hypothalamic nuclei 2.5 months after administration of 7,12-dimethylbenz(a)anthracene into the femur muscle restrained to a considerable extent the inhibitory effect of the carcinogen on the immune reactivity. The reactivity was estimated by the amount of antibody-forming and rosette-forming cells in the spleen, thymus, lymph nodes and by the activity of DNA synthesis in the cells of these organs. The effect of hypothalamus electrostimulation may be a determinant in the mechanism of the inhibitory action of chemical carcinogenesis.     

Experimental models of 2-stage carcinogenesis

The regularities observed in the experiments carried out by the two-stage scheme (initiation-promotion) are considered. Apart from the mouse skin in which these regularities are established, the phenomenon of initiation-promotion is reproduced on the epithelial tumours of the liver, bladder, colon, thyroid, mammary gland, epithelial and mesenchymal tumours of the uterus. The following properties of the promoters are listed: lack of mutagenicity; weak carcinogenicity towards the target organ; threshold of the promoting effect; cessation of carcinogenesis after the promoting treatment has been stopped; organotropism. Approaches and principles of chemical compound testing for cocarcinogenic and promoting activity are considered.     

Action of carcinogenesis promoters on the adhesive force of cells in the liver, lung and thyroid gland in rats and mice

The short-term effects of the carcinogenesis promoters on the adhesive force of cells are compared with the data from literature on their ability to exert a promoter action on the carcinogenesis development in the same organs during prolonged introduction after an initiator. The ability of substances to decrease the adhesive force in the tissue below the resistance threshold is established to correlate with its promoter activity. The coincidence of tissue specificity of both effects and active doses of substances is observed.     

Molecular mechanisms of the transformation of protooncogenes into oncogenes

The problem of cellular protooncogene activation is considered. This stage during carcinogenesis is evaluated as critical in the whole process of neoplasia development. Four possible principal pathways of protooncogene activation are discussed: oncogene amplification; chromosomal translocations; insertions and transpositions of genetic material; point mutations. Two ideas in carcinogenesis based on the oncogene conception have attracted special attention: the "dose hypothesis" emphasizing the importance of the quantitative changes of oncoproteins and the idea of the qualitative alterations of protooncogenes.     

Mathematical model of the immunostimulation of tumor growth

A mathematical model of immune system that takes into consideration the subpopulation of suppressor lymphocytes was proposed. The possibility of stable balance in the process of carcinogenesis is shown. The prospects of mathematical formalization of the immune processes are discussed.     

Characteristics of genotoxic and carcinogenic action of metals

The data on carcinogenic activity of certain metals and their compounds to humans and experimental animals are reviewed. Cellular uptake and intracellular distribution of metal compounds, metal-induced genotoxicity in different short-term tests are described. Specific lesions of DNA produced by carcinogenic metals, the influence of metal ions on the cell growth, DNA replication and DNA repair involved in mutagenesis and oncogenesis are under discussion. Mechanisms of metal carcinogenesis are studied to a less extent as compared with organic carcinogenesis.     

Changes in the epidermal growth factor receptors in the liver cells of rats in N-nitrosodiethylamine-induced hepatic carcinogenesis

A sharp decrease in the number of epidermal growth factor receptors (EGF-R) in the rat liver plasma membranes had been found at different stages of diethylnitrosamine-induced carcinogenesis. The complete loss of high-affinity binding sites for EGF did not prevent EGF-dependent autophosphorylation of EGF-R. Hepatocytes from the rat liver tumors in the primary culture had two classes of EGF-R: high and low affinity ones, though their number had been twice less than in the normal hepatocytes. The dynamics of internalization and down-regulation of EGF-R was very similar in the primary culture of transformed and normal hepatocytes. It testifies that there are some factors of microenvironment in the liver during carcinogenesis which cause the loss of EGF-R (down-regulation) and a decrease of their affinity (activation of protein kinase C). A possible autocrine or paracrine nature of these factors is discussed.     

Effect of disordered thyroid function on the realization of the transplacental carcinogenic action of N-nitrosomethylurea in 1st- and 2d-generation rats

The F1 rats subjected to the influence of N-nitrosomethylurea (NMU) in dose of 20 mg/kg on the 21 day gestation as a result of postnatal disturbances of the thyroid function induced by long administration of thyroxin (3 mg/100 g, daily), methylthiouracil (MTU; 0.1% solution in tap water) or thyroidectomy have shown a decreased incidence of the nervous system tumours, but not of the kidney tumours, i. e. sites typical of NMU transplacental carcinogenesis. At the same time the NMU transplacental effect increased thyroid carcinogenesis, induced by the MTU postnatal application, which manifested in the increased incidence of malignant tumours of this site. The carcinogenic effect was observed in F2 rats, while some of them developed tumours of the nervous system (14.9%) and kidney (8.5%) but with lower incidence than in F1 (35.4; 14.1%, respectively). The same modifying factors (thyroxin, thyroidectomy, MTU) employed under the same conditions produca similar effect on carcinogenesis in F2 animals.     

Changes in the supramolecular structure of chromatin and pepsinogen synthesis in the gastric mucosa of rats undergoing N-methyl-N'-nitro-N-nitrosoguanidine-induced carcinogenesis

A model of gastric tumour induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in rats made it possible to detect essential alterations of chromatin-DNA-protein complexes, that is a weakening of the DNA-protein linkage. The changes appear at early stages of carcinogenesis and persist in induced adenocarcinomas of the stomach. Simultaneously an inhibition was established in pepsinogen synthesis during MNNG carcinogenesis, which reflects a damage in expression of functionally important genetic information. This fact shows a molecular-genetic connection between the process of the gastric mucosa malignization and a disturbance of physiologically important tissue-specific gene functions.     

Characteristics of the inhibition of thymus endocrine function and synthesis of substances with thymosin-like activity caused by thymostimulin and splenin during DMBA-induced mammary gland carcinogenesis in rats

The contents of thymic hormones and endogenous substances with thymosin-like activity (TLA) was studied under conditions of administering thymostimulin and splenin during DMBA-induced carcinogenesis in rat mammary glands. It has been established that during latent carcinogenesis there is an inhibition of thymic endocrine function which persists in tumour-bearing animals. Injections of thymostimulin and splenin induce synthesis of substances with TLA, accompanied by an inhibition of blastoma development.     

Change in the protein kinase activity of glandular stomach mucosa in rats during malignant transformation

Changes in the activity of protein kinases in the glandular stomach mucosa of rat were studied in the case of carcinogenesis induced by N-methyl-N'-nitro-N'-nitrosoguanidine. No essential changes in the activity of cAMP-dependent protein kinase (histone kinase) were found in the mucosa as well as in tissues of the developed tumours of the rat glandular stomach. The activity of cAMP-independent protein kinase (casein kinase) increased significantly 3 months after the beginning of the carcinogen administration and at the late stages (after 12-15 months) it was decreased considerably both in the glandular stomach tumours and in the stomach mucosa without the characters of the malignant growth. It is supposed that changes in the activity of casein kinase in the stomach mucosa at the late carcinogenesis stages are associated with the neoplastic transformation and precede the appearance of morphological characters of the malignization.     

Ornithine decarboxylase activity and polyamine contents in 1,2-dimethylhydrazine-induced carcinogenesis of the intestines in rats

The ornithine decarboxylase (ODC) activity and concentration of polyamines have been studied in small and large intestine during 1,2-dimethylhydrazine-induced carcinogenesis in rats. Changes in the polyamine biosynthesis consisting both in enhanced ODC activity and an increase of the intracellular content of putrescine, spermidine and spermine. Process of the polyamine synthesis activation proceeds in two phases: the most expressed and similar changes in polyamine metabolism factors have been observed at early (the 1st month) and late (the 5th-6th months) stages of carcinogenesis. It is supposed that intensification of the polyamine synthesis is a typical feature of malignization in the gastrointestinal tract.     

Biochemical and molecular biology characteristics of gastric carcinogenesis in humans and animals

The data on the changes in the isoenzyme spectrum of pepsinogen-pepsin inversely correlating with the development and retaining of the malignant condition of gastric mucosa in human and animals are reviewed. The results of the molecular-genetic studies of gastric carcinogenesis, in particular the role of protooncogenes--oncogenes in this process are presented.     

Changes in the content of pepsinogen messenger RNA in the gastric mucosa of rats during N-methyl-N'-nitro-N-nitrosoguanidine-induced carcinogenesis

Pepsinogen mRNA is shown to be the major fraction of rat poly (A)+RNA. It codes polypeptide with molecular weight of about 45 kD. Changes in the pepsinogen mRNA content at the early stage of carcinogenesis are nonspecific and are due to the toxic effect of MNNG. Steady shifts in the quantity of pepsinogen mRNA are found between the 1st and 3d months. Pepsinogen mRNA content decreases down to the half of the normal one between the 3d and 6th months. A quantity of RNA capable to be a template for pepsinogen synthesis is reduced by more than 90% in the MNNG induced tumour. The pepsinogen production defect in gastric mucosa neoplasia is mainly due to pepsinogen mRNA synthesis damage.     

1,2-dimethylhydrazine induction of epithelial tumors of the kidneys in CBA strain mice

The results of experiments on the 1,2-dimethylhydrazine (DMH) induction of epithelial renal tumours in CBA male mice are presented. The dose-response study shows a sharp increase (from 5 to 75%) of the epithelial renal tumour incidence in the range of 2, 4 and 8 injections of DMH. Higher doses induce a decrease of the tumour incidence due to the early death caused by other tumours. DMH is shown to be the most powerful renal carcinogen in mice. Serial sacrifice of mice after 5 injections of DMH is a convenient model for the study of renal carcinogenesis in mice. Main histological types of epithelial renal tumours are illustrated.     

The role of modifying factors in the carcinogenic effect of asbestos and asbestos-containing dusts

The modifying role of adsorption activity, fibre size, fibrogenicity, carcinogens of other classes and of some noncarcinogenic compounds in asbestos carcinogenesis have been considered. It is supposed that the modifying factors play a dominant role in asbestos blastomogenicity. The removal of these factors is an important method for tumours prophylaxis in asbestos workers.     

The role of protein kinase C in tumor growth

A review of recent papers dealing with the role of protein kinase C (PK C) in regulation of normal and tumour cell proliferation contains the data on the interaction of PK C with the tumour promoters and oncoproteins as well as the data which characterize changes of the PK C activity in tumour cells and during carcinogenesis. Probable mechanisms of the PK C influence on the functioning of the growth factors receptors are discussed. It is proposed that one of the PK C functions which is substantial for induction of the mitogenic signal is the polyamine synthesis stimulation. Participation of PK C in the tumour promotion may play a key role in multistep processes of the carcinogenesis.     

Differences in the antigenic structure of chromatin from the liver and hepatoma cells in the rat

Differences in antigenic structure of chromatin from normal and tumour cells were studied using rabbit antibodies against chromatin of the rat liver, Zaidela ascite hepatoma and solid hepatoma 27 cells. It is shown that carcinogenesis is accompanied by loss of a part of normal liver antigens. All the antigens which are not indicated in solid hepatoma were not detected in ascite tumour too. The latter is deficient in some antigens common for the normal liver and solid hepatoma cells. Chromatin of both hepatomas contains antigens which are not detected in liver chromatin. Hepatoma 27 contains also antigens detected in this tumour only. At least some antigens of tumour cells are not found in regenerating liver and in liver cells of newborn rats. Antigenic properties of liver cells chromatin in old (30 months) rats approach to those of hepatoma cells chromatin.