[Characteristics of the carcinogenic action of methyl(acetoxymethyl)nitrosamine and DNA repair in rats of different ages]. / Osobennosti kantserogennogo deistviia metil(atsetoksimetil)nitrozamina i reparatsii DNK u krys raznogo vozrasta.

A pattern of DNA methylation and carcinogenesis has been studied in young (3 month-old) and old (14 month-old) female rats following a single intravenous injection (13 mg/kg) of methyl(acetoxymethyl)nitrosamine (DMN-OAc). The incidence of various tumours as well as the incidence of tumours in some peculiar sites were found to be similar in young and old DMN-OAc-treated rats. The life time of old rats was less than that in young animals; the average period of tumour detection was also shorter in old rats. In both young and old animals the highest concentrations of methylated purines were found in lung and kidney DNA. However, the level of DNA methylation in old rats was higher than in corresponding tissues of young animals. Efficiency of O6-meG repair in methylated template DNA was found to be the highest in liver extracts of 1- and 12-month-old rats. Further, by the age of 2 years, the activity of O6-meGT decreased. The findings suggest that different age periods could be characterized by different efficiency of DNA alkylation, synthesis and repair.

[The carcinogenic effect of 5-bromodeoxyuridine and its amplification by x-rays in rats]. / Kantserogennyi éffekt 5-bromodezoksiuridina i ego usilenie rentgenovskim oblucheniem u krys.

5-bromodeoxyuridine (BUdR) injected to rats in the neonatal period is shown to produce a pronounced carcinogenic effect which brings about the appearance of various benign and malignant tumours. Exposure of females to X-ray total-body irradiation (1.5 Gy) was followed by intensification of the carcinogenic effect of BUdR. Assuming that this pyrimidine analog reacts solely with DNA substituting thymidine during DNA synthesis and induces point mutations due to tautomerization, the data obtained demonstrate the possibility of tumour induction by a selective DNA perturbation.

[The effect of benz(a)pyrene on the thermal characteristics of DNA in vivo and in vitro]. / Vliianie benz(a)pirena na templovye kharakteristiki DNK in vivo i in vitro.

Thermal properties of DNA-benz(a)pyrene complex and chromatin within liver cells in BALB/c mice and Macaca fascicularis monkeys after benz(a)pyrene administration were studied using a highly sensitive differential scanning microcalorimeter designed for investigations of dilute biopolymer solutions and complex biological systems. It was shown that benz(a)pyrene (BP) had different efforts on DNA in vivo and in vitro. It was established that at a molar ratio r < 0.03 BP/DNA bp, benz(a)pyrene served as a stabilizing but at higher concentrations as a destabilizing factor of DNA. It was found that BP damaged liver DNA stronger than bone marrow and spleen DNA of a given animal in vivo. Based on analysis of heat redistribution at the heat absorption stages corresponding to denaturation of inactive and active chromatin, we concluded that BP is capable of causing specific breaks in the DNA chain of inactive chromatin and unfolding the whole domain-loop of chromatin, which should lead to uncontrolled genome activation and, therefore, to carcinogenesis.

[DNA methylation characteristics of different fetal and maternal body tissues in rats administered 1,2-dimethylhydrazine]. / Osobennosti metilirovaniia DNK razlichnykh tkanei ploda i materinskogo organizma krys pri vvedenii 1,2-dimetilgidrazina.

A high rate of DNA methylation in the liver and large colon mucosa was registered 6 hrs after dimethylhydrazine (SDMH) treatment of rats with 19-day gestations. However, in fetal liver, a low concentration of methylated guanine (7-methyl guanine) derivatives was found, while in large colon and brain, these substances were not detected at all. It is suggested that the resistance of embryonal tissues to the transplacental effect of SDMH is due to the underdeveloped enzymatic system of the fetus.

[Transplacental blastomogenesis in mice under conditions of the detoxifying function of the mother's body]. / Transplatsentarnyi blastomogenez u myshei v usloviiakh vykliucheniia detoksitsiruiushchei funktsii materinskogo organizma

The experiments on mice of line SHR have shown that in animals, delivered by Cesarean section I hour following intrauterine injection of 40 mg/Kg of DMBA in mothers (a period of maximum concentration of the carcinogen in the tissues of foetuses) and sacrificed one year later, carcinogenesis proceeded much more intensively than in mice, which after transplacental DMBA exposure continued their intrauterine development for 6 hours longer, i.e. till complete disintegration of DMBA. An enhancement of the transplacental carcinogenic effect was manifested in a reliable increase of the total frequency of the appearance of different neoplasms, in more frequent development of lung, ovary and mammary tumors, and also in the appearance of malignant lung tumors-adenocarcinomas. A considerable enhancement of the transplacental blastomogenic effect in these mice was due to exclusion of the detoxication function of the maternal organism.

[Effect of age on carcinogenesis in female rats induced by methyl (acetoxymethyl) nitrosamine]. / Vliianie vozrasta na kantserogenez, indutsirovannyi u samok krys metilatsetoksimetilnitrozaminom.

A single intraperitoneal injection of methyl-acetoxymethyl-nitrosamine produced tumors in 85.7% of 3 month-old female rats and in 62.5% of 14 month-old ones matched by 26.5% in controls. Intestinal tumors developed most frequently. Also, tumors of the pituitary, thyroid, breast, uterus as well as leukemia were detected. Multiple intestinal tumors were more frequent in the young age group (1.43 and 1.00), tumor-free interval in older animals being 217 days longer. Studies on DNA alkylation and repair were carried out using intraperitoneal injections of 14C-methyl-acetoxymethyl-nitrosamine. Young animals showed higher levels of methylpurines in organ tissues other than those of small intestine 3 hrs after treatment. The rate of methylpurine excretion in young rats was higher, too. However, liver tissue of old rats showed a higher rate of O6-methylguanine repair than that in younger ones.

[The age-related dynamics of the activity of the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase in different organs of rats]. / Vozrastnaia dinamika aktivnosti fermenta reparatsii DNK O6-alkilguanin--DNK alkiltransferazy v razlichnykh organakh krys.

Concentrations of O6-alkylguanine-DNA alkyltransferase (AT) which repairs a procarcinogenic DNA adduct O6-alkylguanine formed following exposure to carcinogenic N-nitroso compounds were measured in the liver, kidney and peripheral blood leukocytes of male L10 rats aged 1, 4, 14, 22 and 36 months. In the liver, peak AT level was observed at the age of 14 and 22 months. No age-related differences were established for kidney and leukocytes. The highest concentration of AT was registered in the kidney while the lowest--in leukocytes. The study revealed stoichiometric transfer of O6-methylguanine methyl group to cysteine residue of AT. No positive correlation was established between individual tissue AT levels in different animals. The highest level of total protein and the lowest concentration of DNA were observed in the liver and kidney of 14-22 month-old rats. The data obtained provide an explanation for relative resistance of 1-2 year-old rats to hepatotropic nitrosamine and suggest that the level of AT in a given tissue is not predictive of its activity in other tissues.

[Blastomogenesis in mice due to postnatal effect of N-nitrosoethylurea and x-ray irradiation]. / Blastomogenez u myshei pri postnatal'nom vozdeistvii N-nitrozoetilmocheviny i rentgenovskogo oblucheniia.

N-nitrosoethylurea (NEU) is found to show an intensive transplacental carcinogenic effect inducing in mice different neoplasms, mainly lung adenomas. Postnatal x-ray irradiation of control animals resulted in the occurrence of ovarian tumors in some female mice. Delivary and feeding of the progeny would lead to the development of mammary gland tumors in a number of control female animals. Postnatal exposure to x-rays of mice exposed to transplacental effect of NEU resulted in the increased incidence of lung neoplasms, mainly adenocarcinomas.

[Effect of N-nitrosoethylurea dosage and postnatal x-ray irradiation on transplacental blastomogenesis in mice]. / Vliianie dozy N-nitrozoetilmocheviny i postnatal'nogo rentgenovskogo oblucheniia na transplatsentarnyi blastomogenez u myshei.

In transplacental exposure to nitrosoethylurea in a dose of 2 mg/Kg the frequency of occurrence of different neoplasms in mice would not change as compared with a dose of 20 mg/Kg. However, in a dose of 2 mg/Kg the time of lung tumor development was prolonged. Postnatal roentgen irradiation increased the incidence of lung adenomas and ovarian tumors in female mice, exposed in embryogenesis to NEU effect in a dose of 2 mg/Kg; male mice showed a somewhat delayed development of tumors. In animals, subjected to NEU effect transplacentally in a dose of 20 mg/Kg, postnatal roentgen irradiation resulted in the appearance of lung adenocarcinomas, tumors of other lacolizations being developed neither in female nor in male mice.

[Alkylation of liver DNA purines in rats of different age treated with diethylnitrosamine]. / Alkilirovanie purinov DNK pecheni krys raznogo vozrasta, podvergnutykh vozdeistviiu diétilnitrozamina.

24 hrs after oral administration of 14C-diethylnitrosamine (DENA) at a dose of 280 mg/kg into male rats the level of 7-ethyl guanine was similar in both young and old (3 and 14 months, respectively) animals whereas the level of O6-ethylguanine was increased 2-fold higher in old animals. The rate of 7-ethylguanine and O6 ethylguanine elimination from liver DNA was higher in the young rats. The rate of incorporation of 3H-thymidine into liver DNA was decreased in the old animals. Administration of DENA (280 mg per kg) 50 hrs before the injection of the labelled thymidine inhibited its incorporation into the liver DNA in the young rats and did not alter the process in the old rats. The data obtained suggest an important role of age-dependent decrease in proliferative processes in liver tissue of the old rats in the response to carcinogenic effect of DENA.

[Inactivation of O6-alkylguanine-DNA alkyltransferase in the liver of rats during administration of methylated DNA]. / Inaktivirovanie O6-alkilguanin-DNK alkiltransferazy v pecheni krys pri vvedenii metilirovannoi DNK.

Intraperitoneal administration of 6.5 mg of methylated DNA, O6-methylguanine concentration being 11.5% that of guanine, to 3 month-old noninbred male rats was followed by a 5-fold decrease in the activity of O6-alkylguanine-DNA alkyltransferase (AT) within the first hour. The said enzyme is responsible for DNA O6-alkylguanine repair and plays a key role in mutagenic, carcinogenic and cytostatic effects of some alkylating agents. Within 24 hours, AT activity returned to normal to be followed by a significant increase. A correlation between the degree of inhibition of AT activity and dose of methylated DNA was established. Untreated DNA did not produce an inhibitory effect.

[Distribution and mechanism of the carcinogenic action of 1,2-dimethylhydrazine in rats]. / Raspredelenie i mekhanizm kantserogennogo deistviia 1,2-dimetilgidrazina u krys

The radioactivity of blood, bile, urine and contents of isolated intestinal segments was measured at various periods after 3H-1,2-dimethylhydrazine (3H-DMH) and 3H-1,2-diethylhydrazine (3H-DEH) subcutaneous administration. These experiments have revealed that DMH metabolites entered the intestine both with bile and directly through the intestinal wall. The DMH metabolites entering the bowel as glucuronides are cleaved with beta-glucuronidase of bacterial origin, and as a result of this the alkylation of enterocytes nucleic acids and protein takes place. In totally hepatectomized animals no methylation of enterocyte macromolecules was noted. DEH fails to penetrate the intestinal wall and to alkylate biomolecules of enterocytes, when administered parenterally or per os. Some possible DMH metabolic pathways are discussed, and the dynamics of DNA and protein methylation is analysed in the light of these proposed pathways.

[The individual characteristics of the excretion of benzo(a)pyrene metabolites in rats]. / Individual'nye osobennosti ékskretsii metabolitov benz(a)pirena u krys.

Assessment of individual peculiarities of carcinogen metabolism in the body opens up new vistas in predicting individual sensitivity to these agents. The authors developed a spectrofluorometric [correction of spectrofluorescence] technique to assay concentrations of carcinogenic benzo(a)-pyrene (BP) metabolite (7,8-BP) and a product of its detoxication (3-BP) in excreta of male rats who had been given a single dose of 200 mg/kg of benzo(a)pyrene intraperitoneally. Ten-thirty times daily variations in individual levels of both metabolites were accompanied by less variation in their total amount. Parameters of BP metabolism perhaps can be used for predicting individual risk of BP-induced tumor development.

Assessment of benz(a)pyrene pollution in the flood area of the Luga river. / Otsenka zagriazneniia benz(a)pirenom lugovykh ploshchadei v poime r. Lugi.

Benz(a)pyrene pollution levels have been identified in the soils and vegetation of the flood plains of the River Luga, Leningrad Region. Maximum pollution exceeding background levels 2-10 times (11.02-52.71 mkg/kg) was detected in the soils around the towns of Luga and Kingisepp. The benz(a)pyrene levels in the vegetation (2.04 mkg/kg) were below background values. No significant correlation was established between the concentrations of pollution in the soil and vegetation. Our data suggest that the area of the mid-course of the River Luga should be preserved as a natural habitat of the plants of the Poaceae family.

[Acceleration of the metabolism of carcinogens in the maternal body and embryos]. / Uskorenie metabolizma kantserogenov v materinskom organizme i v embrionakh.

Outbred mice on the 19th-21st day of pregnancy were injected intravenously 3,4-benzpyrene (BP) in the dosage of 15 mg/kg or 9,10-dimethyl-1,2-benzanthracene (DMBA) in the dosage of 40 mg/Kg in control groups, and moreover preliminary injected BP (24 hours before) in experimental groups. The BP concentration of embryos and the maternal liver 15 minutes following the injection of the basic dose of the carcinogen in increased dosage of preliminary exposure first would decrease, reach the minimum, in preliminary dosage equal to 0.75 mg/Kg, and then would increase up to values observed in control experiments with the dosage of 30 mg/Kr 7.5-15 mg/Kg, and then it would fall again in the dosage of 30 mg/Kg. The preliminary injection of BP in the dosage of 0.75 mg/Kg produced a sharp fall in the carcinogen concentration in embryos and the maternal organism during the first moment of observation (after 5 minutes), but it failed to influence the rate of subsequent decrease of the substance level. An explanation of the two effects observed is suggested based on the assumption that there exist two enzymatic systems metabolizing BP: one-premanently present in the liver and the other-induced by the carcinogen. The preliminary BP injection did not influence the concentration of DMBA.

[Spontaneous tumors in rats from the Rappolovo Breeding Nursery of the Academy of Medical Sciences of the USSR]. / Spontannye opukholi u krys razvodki pitomnika "Rappolovo" AMN SSSR.

The authors report the data on the incidence of neoplasms in rats of the "Rappolovo" nursery breeding (USSR Acad. Med. Sci.) and their offsprings during 4 sequential generations kept in the vivarium of the N. N. Petrov Research Institute of Oncology of the USSR Ministry of Health. The frequency of spontaneous tumors in 213 male and 230 female rats was 25.8 and 35.7% accordingly. Totally, male animals developed 65 tumors, females--114. over 80% of all neoplasms developed in animals older than 18 months. The frequency of neoplasms of separate localizations in males and females was as follows: the hypophysis--7.0 and 12.6% correspondingly; the mammary gland--0.5 and 11.7%, the thyroid (thyroidal epithelium) - 1.4 and 3.0% and (light cells) 5.6 and 8.3%; the adrenal cortex--0.5 and 1.3%; the hematopoietic system --7.0 and 5.6%; parasitic sarcomas of the abdominal cavity --5.6 and 3.0%; the skin --0.4 and 0.4%; soft tissues --0.9 and 0%; the liver--0.4 and 0.4%; the kidneys --0.4 and 0.4%. Moreover, one male showed seminal vesicle tumor, and females-solitary neoplasms of the pancreas and salivary gland, the dura mater, the ovary and uterus. Significant differences were revealed in the frequency of spontaneous neoplasms in separate rat generations.

[A comparative study of the individual characteristics of the excretion of metabolites of benzo(a)pyrene and its carcinogenic effect in rats]. / Sravnitel'noe izuchenie individual'nykh osobennostei ékskretsii metabolitov benz(a)pirena i ego kantserogennogo éffekta u krys.

Nineteen outbred LIO rats received a single intraperitoneal injection of 200 mg/kg benzo(a)pyrene (BP) in sunflower oil. Levels of excretion of a BP activation product 7.8-BP-dihydrodiol and deactivation product 3-hydroxy-BP showed significant individual variations. Half the animals developed intraperitoneal sarcoma at various stages of the experiment. A direct correlation between urine 7.8-BP-dihydrodiol excretion level and tumor latency was established. The value of metabolite excretion level monitoring for making individual prognosis of BP carcinogenic effect is discussed.

[The individual characteristics of the activity of the DNA-repair enzyme O(6)-alkylguanine-DNA alkyltransferase in the stomach of monkeys exposed to the gastric carcinogen N-ethyl-N1-nitro-N-nitrosoguanidine]. / Individual'nye osobennosti aktivnosti fermenta reparatsii DNK O(6)-alkilguanin-DNK alkiltransferazy zheludka obez'ian, podvergnutykh vozdeistviiu gastrokantserogena N-étil-N1-nitro-N-nitrozoguanidina.

Variations in the activity of a DNA repair enzyme 0(6)-alkylgianine-DNA alkyltransferase (AGT) were studied in gastric mucosa samples obtained from 15 M. fascicularis monkeys chronically exposed to a gastrocarcinogen N-ethyl-N'-nitro-N-nitrosoguanidine. Marked interindividual difference in the enzyme activity before and in the course of the exposure was observed. The value of AGT activity assay to predict individual susceptibility to alkylating carcinogens is discussed.

[Rat liver mitochondrial DNA treated with 1,2-dimethylhydrazine]. / Issledovanie mitokhondrial'noi DNK pecheni krys, obrabotannykh 1,2-dimetilgidrazinom.

Primary structure of 5'-end 16S RNA gene of mitochondrial DNA (mDNA) isolated from rat liver tissue within 20 hrs after treatment with 1,2-dimethyl hydrazine, was analyzed. The preparations studied did not contain mutations induced by the drug. The region of mDNA analyzed appears not to be a preferential target for mutagenic effect of 1,2-dimethyl hydrazine unber these experimental conditions.

[The dependence of the nitrosation activity of the gastric juice in humans on their age and the type of pathological status of the gastric mucosa]. / Zavisimost' nitroziruiushchei aktivnosti zheludochnogo soka liudei ot vozrasta i tipa patologicheskogo sostoianiia slizistoi obolochki zheludka.

The study involved two groups of patients aged 6-14 and 40-60 years, and identification of different conditions of gastric mucosa. The study has established a correlation between the nitrosation activity and acidity of gastric juice and the pathological condition of the gastric mucosa. Enhanced nitrosation activity was observed in samples with a pH under 4.0. That activity was at its lowest in cases of normal gastric mucosa, and at its peak--in high-acidity superficial and erosive gastritis. In cases of superficial gastritis with similar levels of acidity, the nitrosation activity of gastric juice for different amines in children was 2-4 times that in adults. The difference in nitrosation levels for different amines tended to diminish with the decrease in the basicity of the amine in question. A linear correlation was observed between the free-radical activity of gastric juice samples and nitrosation activity (correlation coefficient, k = 0.72).