[Efficiency of evaluating the carcinogenicity of chemical substances in short-term tests and the SAR model].

The efficiency of estimating the carcinogenic activity of chemical substances was compared for five short-term tests and structure-activity relationships (SAR) analysis. The sample included 84 substances with known biological testing results obtained by the Ames test, bacterial SOS chromotest (SOS), chromosome aberration (CA) cytogenetic test, sister chromatid exchange (SHE) test, and gene mutation (GM) test with mammalian cells in vitro and by carcinogenicity assays in rodents in vivo. Structural descriptors were selected using an original database, which included the structural formulas of substances with known carcinogenic activity in rodents. Original software was created to generate and select the descriptors that statistically coincided with carcinogenic activity. The descriptors that were associated exclusively with carcinogenic substances from the database and the tests that produced positive results exclusively with carcinogens were used to evaluate the carcinogenic activity of the substances. A combination of three short-term tests (Ames, SOS, and CA tests) and the SAR model proved to identify carcinogenicity for more than 60% of carcinogens.

Modification of DNA repair by human interferons.

We have found a new biological function of interferons, namely, their capacity to protect human cells from the action of some physical and chemical mutagens. To evaluate the protective effect of interferons the following criteria were applied: formation of sister chromatid exchanges (SCE) and chromosomal aberrations (CA), as well as viability of cells and intensity of DNA repair synthesis. Pretreatment of cells with natural interferon decreased the number of sister chromatid exchanges and chromosomal aberrations, induced by different mutagens, and increased the intensity of DNA repair synthesis. This is attributed to the ability of interferon to enhance certain phases of DNA repair. In the case of photomutagenic action of 8-methoxypsoralen (8-MOP) on the lymphocytes, when monoadducts (MA) only, or both monoadducts and interstrand cross-links (ICL) are formed, the antimutagenic effect of interferon is exhibited only with respect to ICL. Unlike the natural interferon, the recombinant alpha 2-interferon failed to have any effect on the lymphocytes of clinically healthy donors exposed to gamma-radiation. In the repair- deficient cells (Marfan's syndrome) the protection of natural interferon against the action of 4-nitroquinoline-1'-oxide and gamma- radiation was found to be reduced significantly and that of alpha 2-interferon was not manifested at all. Thus, the capacity of interferons to alter the DNA repair, conceivably, depends on the type of interferon and on the cell genotype.

[On the mechanism of adaptive response in human cells]. / K mekhanizmu adaptivnogo otveta v kletkakh cheloveka.

There was investigated one of the mechanisms of adaptive response, related to chromosome aberrations induced by gamma-rays, in lymphocytes of healthy donors and donors with hereditary diseases (Marfan's syndrome and homocystinurea) whose cells are repair-deficient. 3H-thymidine treatment was used as an adaptive dose in G1-period of cell cycle and 8-methoxypsoralen (8-MOP), activated with UV-light, was used as a challenge agents. Cells of healthy donors and cells of patients with Marfan's syndrome had normal adaptive response in relation to gamma-irradiation and photomutagenic action of 8-MOP. There was no induction of adaptive response in realation to gamma-irradiation and 8-MOP photomutagenic action in cells of patients with homocystinurea. The cells from donors characterised with normal repair system and lack of adaptive response 8-MOP photomutagenic action wasn't modified by 3H-thymidine. We have found parallelism of adaptive response protective effect against chromosome aberrations, induced by UV activated 8-MOP and gamma-rays in repair proficient cells of healthy donors and repair deficient cells of patients with Marfan's syndrome. These data lead us to conclusion that mechanism of adaption, at least in some cases has no connection with repair process modification.

[The quantitative analysis of micronucleus induction in human lymphocytes cultured in vitro (preconditions for making modified micronucleus assay)]. / Kolichestvennyi analiz induktsii mikroiader v limfotsitakh cheloveka, kul'tivirovannykh in vitro (predposylki dlia sozdaniia modifitsirovannogo mikroiadernogotesta).

The new modification of the method of micronucleus (MN) detection without cytochalasin-B is used in this paper. The code name of the method is called "method of micronucleus detection in mononucleated cells". The basis of this method is that it makes possible to analyze MN and chromosome aberrations (CA) at the same slides. To confirm the true supposition of the authors about correlation between MN quantity and chromosome/chromatid type aberrations so called "coefficient of transformation" was calculated and it was 7.9 +/- 0.41 for the chromosome type aberrations and over 67.2 +/- 30.2 for chromatid type aberrations. Mutagenic action of gamma-irradiation and 8-methoxypsoralen (8-MOP), activated with long-wave UV-light was estimated for the first cell cycle mitosis. When compared in straight experiments results of gamma-induced MN were received by two methods: the method of cytokinesis-block (commonly used) and by the suggested method, the "coefficient of transformation" of CA into MN was 3.6, when cytochalasin-B was used and 6.7 without using it. The total data give a possibility to make a new cytological micronucleus test for mutagens revealing. As we think the modified test is more simple, more reliable less laborious and less expensive.

[New mechanisms of antimutagenic effect of interferon]. / Novye mekhanizmy antimutagennogo deistviia interferona.

A study was made of the antimutagenic effect of natural lymphoblastoid interferon and alpha 2-recombinant interferon against initial damages to DNA induced by 8-methoxypsoralen, activated by UV-light, in human peripheral blood. The crosslinking and uncrosslinking 8-methoxypsoralen monoadducts were shown to make different contribution to the biological effects in cells, that is, chromosome aberrations and sister chromatid exchanges. Both of the investigated interferons exhibited their protective effect with respect to crosslinking monoadducts only. The antimutagenic action of interferon was implemented by a non-repair way. It is suggested that the scavenging of active radicals is a possible mechanism of the protective action of interferon.

[The anticlastogenic effect of ascorbic acid in relation to the damages induced in human lymphocytes by the photomutagenic action of 8-methoxypsoralen and by ammonium molybdate]. / Izuchenie antiklastogennogo éffekta askorbinovoi kisloty po otnosheniiu k povrezhdeniiam, indutsirovannym v limfotsitakh cheloveka fotomutagennym deistviem 8-metoksipsoralena i molibdenatom ammoniia.

In experiments with cultured human lymphocytes anticlastogenic effect of ascorbic acid (AA) with respect to photomutagenic action of 8-methoxypsoralen (8-MOP) and ammonium molibdenate (Mo) was studied. It was found that AA effectively protected from mutagenic action of Mo. Effective protection of cells from 8-MOP monoadducts and DNA interstrand links was also observed.

[The radioadaptive response in the lymphocytes of schizophrenia patients]. / Radioadaptivnyi otvet v limfotsitakh bol'nykh shizofreniei.

Radioadaptive response in cells from three patients was studied by induction of structural chromosome aberrations. Radioadaptive response was revealed in lymphocytes of all three patients. Coefficient of protection was 59.0% and did not differ from this after cell pretreatment with interferon. It is suggested the similarity or identity of mechanism of radioadaptive response and of interferon antimutagenic action which was implemented by non-repair way.

[Radioadaptive response in lymphocytes of children living in territories polluted by radionuclides as a result of the accident at the Chernobyl power plant]. / Radioadaptivnyi otvet v limfotsitakh detei prozhivaiushchikh na territoriiakh, zagriaznennykh radionuklidami v rezultate avarii na Chernobyl'skoi AES.

The radioadaptive response and antimutagenic action of lymphoblastoid interferon in the human blood lymphocytes of the children from polluted after Chernobyl accident Bryansk region were studied. Cells pretreated with tritiated thymidine with 2 Gy of gamma-rays at 20 h of culture after PHA-stimulation on seven of the ten donors result in lack of radioadaptive response. On testing some of them (4 donors) no protective adaptive response was found, others (3 donors) pretreated with tritiated thymidine gave sensibilization. Significant decrease in interferon antimutagenic activity in lymphocytes with disturbed adaptive response was also found. It has been proposed that there is similarity or identity of mechanism of radioadaptive response and of non-repair component of interferons antimutagenic action.

[Directed modification of the damaged DNA region in inducing structural chromosomal mutations]. / Napravlennaia modifikatsiia povrezhdennogo uchastka DNK v induktsii strukturnykh mutatsii khromosom.

The method of directed modification of damaged DNA regions elaborated recently in our laboratory made it possible to conduct a direct experimental study of mutagenicity of two single-stranded breaks located within the isolocus of sister chromatids, in strands of the same polarity. The efficiency of induced mutagenesis was shown to be very high when the experimental technique was employed allowing single-stranded DNA breaks to occur in this position with high probability. It should be noted that the fraction of interstitial deletions and rearrangements of chromosomes of the exchange type were predominant in the spectrum of induced mutations. It is concluded that the coincidence of two breaks in the strands of the same polarity in the isolocus of sister chromatids is realised into chromosome aberrations with high probability.

[Natural and recombinant interferons provide different protection of human cells with impaired repair system (Marfan syndrome) against mutagens]. / Prirodnyi i rekombinantnyi interferony neodinakovo zashchishchaiut kletki cheloveka s narushennoi sistemoi reparatsii (sindrom Marfana) ot vozdeistviia mutagenov.

It was shown that pretreatment of human cells with interferons (IF) of different origin has an unequal protective effect under the action of various mutagens with different activity. The protective effect of IF was estimated using the test of sister chromatid exchanges. Natural leucocyte alpha IF is highly effective in healthy human cells and in those of patients having Marfan syndrome. The latter are characterised by disorder in DNA repair under the action of 4-nitroquinoline-1-oxide (4-NQO), 8-methoxypsoralen and gamma-rays. Recombinant interferon (alpha 2) displayed no activity against gamma-rays in cells of healthy donors and patients with Marfan syndrome. Nor was it effective in the cells of patients in the experiments with 4-NQO. The absence of correlation between the ability of IF to protect the cells and their influence on the rate of cell proliferations was established.

[A defense mechanism of human cells in the radioadaptive response and antimutagenic activity of interferon has common paths]. / [Mekhanizm zashity kletok cheloveka pri radioadaptivnom otvete i antimutagennoi aktivnosti interferona imeet obshchie puti.

The radioadaptive response was assessed by the chromosome aberration test in lymphocytes of humans with hereditary diseases of connective tissue, which were earlier characterized as repair-deficient: Marfan syndrome (SM), Elers-Danlos syndrome (E-D), and homocystinurea (HCU). The radioadaptive response was observed in cells of patients with Marfan syndrome and Elers-Danlos syndrome but not in cells of patients with homocystinurea. Parameters of cell protection against gamma-irradiation at radioadaptive response were similar to those obtained in cells pretreated with interferon. These data indicate, first, the possibility that repair pathways and the radioadaptive response are independent and second, that there are common pathways of protection upon radioadaptive response and the antimutagenic action of interferon.

[Distribution of spontaneous and 8-methoxypsoralen-induced sister chromatid exchanges along the length of the 1st chromosome of Chinese hamster cells]. / Raspredelenie spontannykh i indutsirovannykh 8-metoksipsoralenom sestrinskikh khromatidnykh obmenov po dline pervoi khromosomy kletok kitaiskogo khomiachka.

Distributions of spontaneous, induced by monoadducts and induced by crosslinks sister chromatid exchanges (SCE) along the first chromosome of Chinese hamster cells are nonrandom. All experimental distributions have low frequency of SCE in centromeric and telomeric regions. It can be explained by specific structural organization of the chromosome. However, there are some differences between experimental distributions. Distribution of SCE induced by crosslinks differs from that of spontaneous SCE. Distribution of SCE induced by monoadducts, unlike other distributions, has an increased frequency of exchanges in the q11 region. This region contains several narrow closely disposed G+ bands. It is possible that monoadducts lead to increasing SCE frequency on G+-G- junctions. Distribution of SCE induced by crosslinks resembles random distribution, except centromeric and telomeric regions. These results lead to conclusion that the mechanisms of formation of spontaneous, induced by monoadducts and induced by crosslinks SCE differ from each other.

[A comparison of the efficacy of the anticlastogenic action of interferon and of the radiation-adaptive response]. / Sravnenie éffektivnosti antiklastogennogo deistviia interferona i radioadaptivnogo otveta.

Human lymphocytes, in the in vitro culture, exposed to X-rays (0.05 Gy) or treated with lymphoblastoid interferon (50 IE/ml) in phase G1 were less susceptible to induction of chromosome aberrations, of a chromosome type, by subsequent gamma-radiation (2 Gy) than those exposed to 2 Gy radiation only. The anticlastogenic effect of the pretreatment with interferon was considerably higher than that of preirradiation with X-rays which might be the result of the pleiotropic action of interferon in a cell.

[Mechanism of the antimutagenic action of interferon: the capacity to protect the human cellular repair system]. / K mekhanizmu antimutagennogo deistviia interferona: sposobnost' zashchishchat' sistemu reparatsii keltok cheloveka.

It has been shown that premutagenic treatment with leukocytic interferon (10, 100 IU/ml) of human peripheral blood lymphocytes cultivated in vitro at the G1-stage of the mitotic cycle results in different cell response to gamma-radiation in doses of 0.5, 1, 2, 4 Gy according to chromosome aberration. The antimutagenic effect failed to be attained with the doses 0.5 and 1 Gy, being maximal at the dose 2 Gy. According to sister chromatid exchanges (SCE) cell pretreatment with interferon leads to a reduction in the effect of gamma-radiation at the dose 2 Gy to the level obtained in the cells after exposure to interferon. In experiments with 4-nitroquinoline-I-oxide, there was a significant decrease in the number of SCE in interferon-treated cells.