[Molecular and cellular consequences of the Chernobyl accident].

In this paper the results of the Chernobyl accident investigation 5-10 and 24 years after are summarized. The genomic instability, adaptive response formation, genome damage and oxidative status have been investigated. The studies were performed on cells in culture, mice, children and adults living in contaminated areas and liquidators. On cells in culture after exposition in the accident zone and culturing thereafter in laboratory conditions the cell proliferative activity decrease; the late cell death, the frequency of cells with micronuclei and giant cells increasing have been observed. In the progeny of exposed cells the enhancement of radiosensitivity has been noticed. So we can suppose that in cultured cells exposition in the zone of the accident the genomic instability is induced which results in many disturbances. At the organism level in mice exposed in the Chernobyl zone the radiosensitivity increase and the decrease of endotheliocytes density in brain tissue has been observed. On the stimulated by PHA blood lymphocytes of children the increase of the frequency of cells with micronuclei more than 2 time have been noticed. In all groups investigated, the decrease of individuals with significant adaptive response was observed. In children and adults inhabitants the increase of radiosensitivity after low dose of irradiation has been noticed. 24-year after the accident it was discovered that in liquidators lymphocytes the frequency of cells with micronuclei, with chromosome type aberrations, with DNA double strand breaks have been increased; the reactive oxygen species (ROS) were decreased in comparison with the control population. We can suppose that genomic instability induced in residents of contaminated regions and liquidators long after the accident results in the genetic apparatus damage, radiosensitivity enhancement, hypoxia that represent risk factors and increase the probability of tumour and non-tumour diseases. The development of these pathological processes may happen in much more remote periods.

[The 3H-thymidine incorporation into G0 human lymphocytes induced by low doses of UVC radiation]. / Indutsiruemoe malymi dozami UVC-izlucheniia vkliuchenie 3H-timidina v G0-limfotsity cheloveka.

The 3H-thymidine incorporation in human lymphocytes of healthy donors induced by UVC radiation under doses 0.0008-60 J/m2 was investigated. It was shown that the incorporation of 3H-thymidine increases under doses in interval 0.1-20 and is constant under doses higher than 20 J/m2. Under doses in interval 0.006-0.03 J/m2 near a half of all samples had the level of incorporation increased in comparison with control samples. We connect the presence, absence or variability of this effect with individual peculiarities of cells and with different activity of cell subpopulations that are different on morphological and physiological characteristics. The hypothesis about the role of this factor in the influence of low doses of pathogenic agents (UVC and X-radiation, chemical compounds) on human lymphocytes is discussed.

[Disorders of energy metabolism in the rat brain under extreme exposures: a new method for assessing the energy state of the brain]. / Issledovanie narushenii énergeticheskogo metabolizma mozga krys pri ékstremal'nykh vozdeistviiakh: novyi metod otsenki énergeticheskogo statusa mozga.

We propose a new method to evaluate energy state of the brain based on vital assay for phosphate metabolites and intracellular pH in the brain. A proposed Z-index describes a set of correlations between phosphates involved in brain energy metabolism assayed in vivo by magnetic resonance spectroscopy on 31P nuclei. We tried to use Z-index as a quantitative test for disturbed energy metabolism. Potentialities of Z-index for evaluating rat brain energy state after extreme influences (gamma [correction of X-] irradiation and postoperative shock of the brain cortex) have been demonstrated.

[New aspects of of the effects of low intensity radiation]. / Novye aspekty zakonomernostei deistviia nizkointensivnogo oblucheniia v malykh dozakh.

In paper the new aspects of action regularity of ionizing radiation of low intensity on the biophysical and biochemical characteristics of bio-objects and populations are considered. From the point of view of breaking the connection between occurrence of damages and work of systems of restoration at low intensity irradiation, are described the dose dependence of different types--from threshold up to extreme and a plateau curve, differing among themselves only by a parity of these processes. The features of action of low intensity irradiation on bio-objects and populations--change of structure of a population, sensitivity to action of external stimulus, force of connections between the elements of regulatory systems--allow to consider the low intensity irradiation as the factor capable to cause unpredictable transition of quasistationary systems in new status.

[Sensitivity of human melanoma xenografts to nitrosoalkylurea antineoplastic agents]. / Chuvstvitel'nost' ksenograftov melanomy cheloveka k protivoopukholevym preparatam klassa nitrozoalkilmochevin.

We studied the sensitivity of human melanoma (Bro strain) xenografts to drugs of the nitrosoalkylurea (NAU) class: nitrosomethylurea (NMM), karmustin (BCNU), nimustin (ACNU), nitrulin, and ADEKO. High antitumor activity of NAM was shown when the drugs were applied not only at the early, but also at the late stages of tumor progression (tumor mass 400 and 1200 mg, respectively). The therapeutic effect of the drugs was estimated with the use of criteria characterizing the kinetics of tumor regression, increased life span, and survival of treated animals. After early administration of the drugs (Day 4 after tumor transplantation), 67% and 50% of animals survive under the influence of nitrulin and ACNU, respectively, while the rate of tumor regression increased in the sequence nitrulin < karmustin < NMM < ACNU. After late administration (11 days after tumor transplantation), NMM was most effective at increasing survival (35% of survived animals by 35 days of observation), while the rate of tumor regression increased in the sequence ADEKO < NMM < karmustin < nitrulin < ACNU.

[Kinetics of development of human melanoma xenografts in immunosuppressed animals]. / Kinetika razvitiia ksenograftov melanom cheloveka na immunosupressirovannykh zhivotnykh.

An experimental model of development of the human tumor xenografts (melanomas HCMB and Bro) in immunosuppressed phenotypically normal animals (CBA/Ca mice) was developed. Optimal conditions were established for immunodeficiency induction in the animals. Kinetics of development of the xenografts in the immunosuppressed animals was studied. The level of 0(6)-alkyl-guanine-DNA-alkyltransferase, an enzyme responsible for repair of DNA damage in the tumor cells induced by chemotherapeutic agents (nitroalkylurea), was determined.

The phenomenology and possible mechanisms of a new experimental method for accelerating postirradiation restoration of hemopoietic stem cell potential.

Extraction of bone marrow from one or several bones immediately after irradiation, with or without subsequent incubation for a short period under suitable conditions, and subsequent reimplantation into the same organism can reduce the lethal effect of irradiation in a number of species. Extraction plus a period of incubation is referred to as the reimplantation method. The effectiveness is roughly relative to the amount of bone marrow extracted and transplanted. This effect has been demonstrated by assays of 30-45-day survival and of hemopoietic stem cell potential. The effectiveness of the reimplantation method has been tested in a dose range of 6.5 to 8.5 Gy and was found to be 1.2-1.06 in terms of dose reduction factors assayed by bone marrow row cellularity 9 days after exposure and 1.18-1.09 for survival of bone marrow colony-forming units. The favorable effect of incubating irradiated bone marrow with cycloheximide on the stem cell potential has been proven by experiments using a donor-recipient method. The positive effect of the reimplantation procedure and the partial extraction procedure on the stem cell potential in irradiated mice can be shown as soon as 2 h after exposure and the procedures. The results suggest that ther exist some reserves that can be stimulated to accelerate hemopoietic restoration in a heavily irradiated organism. The recruitment of these reserves seems to be related to the response of the structures producing cytokines after lethal irradiation. In addition, repair processes may be involved in the rescue of lethally irradiated hemopoietic stem cells.

[The characteristics of the biological action of low doses of irradiation]. / Osobennosti biologicheskogo deistviia malykh doz oblucheniia.

Biochemical, biophysical and functional properties of the genetic and membrane apparatus of the cell were considered activity and regulatory properties of the membrane and cytosolic enzymes of organs and tissues of mice exposed to radiation in the wide range of doses of 6 to 1800 mGy with the radiation intensity of 4.1 x 10(-3) and 41 x 10(-3) mGy/min. It was shown that the dose-dependence of changes in the investigated properties is of non-linear polymodal (bimodal) nature. The value of the maximum and the dose at which the latter was observed depend on the object's nature, radiation intensity and time passed after irradiation. An essential factor is that sensitivity of molecules, cells, organs and animals exposed to low-dose radiation to other damaging effects changes. The explanation is given in terms of the changes in the relation between the quantity of damages and the activity of reparation systems induced by low-dose irradiation.

31P NMR in vivo study of the acute effects of different doses of gamma-radiation on rat brain phosphate metabolism.

Changes in relative levels of brain phosphates and intracellular pH at selected time intervals after total gamma-irradiation of a rat at a single dose of 6.5 or 300 Gy were studied by 31P NMR in vivo. Irradiation yielded only minor changes in the spectra. Irradiation at a dose of 6.5 Gy caused a reversible decrease in Pi and an alkaline pH shift of 0.2 units after day 1, with no change in ATP. The signal, which consisted of alpha-ATP, alpha-ADP, NAD+/NADH and diphosphodiesters, declined after day 6, possibly due to a fall in NAD+/NADH concentration. Irradiation at a dose of 300 Gy led to an increase in ATP from 10 to 13% of total phosphates after day 1. Homeostasis of brain energy metabolism was characterized by the Z-index (normalized sample correlation coefficients averaged over the correlation matrix for NMR-measured phosphomonoesters, Pi, pH, phosphocreatine, gamma-ATP+beta-ADP, alpha-ATP+alpha-ADP+NAD+/NADH+diphosphodiesters and beta-ATP). The Z value rose from -0.18 +/- 0.02 to -0.02 +/- 0.02 by day 6 or from -0.19 +/- 0.02 to -0.07 +/- 0.02 by day 1 after irradiation at a dose of 6.5 or 300 Gy, respectively. This may indicate a pathological state of brain energetics as a system and a decrease in its stability.

[Changes of radiosensitivity in animals after exposure to radiation within the territory of accident at the Chernobyl nuclear plant]. / Izmenenie radiochuvstvitelnosti zhivotnykh posle ékspozitsii v zone avarii na ChAES.

Mice exposed inside of 10-km zone around Chernobyl Atomic Station with follow-up acute irradiation were studied to find the changes in their life-span. It was found that the results essentially depend on the interval between exposition in zone and acute irradiation and space of time after irradiation.

[The biological action of low-level radiation]. / Nekotorye aspekty biologicheskogo deistviia malykh doz radiatsii.

On the basis of their own data and the literature the authors have analyzed the mechanism of biological action of low-level radiation on cells. In studying the harmful effect of gamma-radiation (10-40 cGy) on HeLa cells it was shown that damages occurred in 12 postirradiation generations. Analysis of cell distribution within the colonies has demonstrated that the share of colonies with low cell content and the number of giant cell increase. These data indicate that low-level radiation causes reproductive cell death that can occur not immediately but in later generations.

[The dose dependence of various loads using the rosette formation method]. / Dozovaia zavisimost' razlichnykh nagruzok v metode rozetkoobrazovaniia.

A method of the loading tests in rosette-formation was used to study the rosette-formation of lymphocytes and phagocytosis of neutrophils depending on different concentrations of T-activin (and levamysol) after preincubation of leucocytes in vitro with these medicines. It is shown that significant effect of the cells is observed up to the concentrations of the medicines 10(-10)-10(-13) g/l.

[The pharmacokinetics of the antitumor preparation of dimetinur]. / Farmakokinetika protivoopukholevogo preparata dimetinur.

The pharmacological disposition of 1,3-dimethyl-1-nitrosourea (dimetinur) in intact rats and animals with Walker carcinosarcoma, glioma 2211, colon adenocarcinoma was studied by the colorimetric assay using an oral drug dose of 100 mg/kg. Computer analysis of data was based on a single-compartment model using the area under the concentration-time curve (S) and the intact drug half-life (t1/2) as main pharmacokinetic parameters. The highest level of the drug (S) was observed in tumour and brain tissues on an equality with drug distribution between blood, spleen, kidney and lungs. The half-life of the dimetinur removal from blood exceeds the known values for certain active NAM type. The antitumour activity of the drug against the studied tumours correlates positively with pharmacokinetic parameters for the tumours (S and 1/tmax).

[Secretion of immunoglobulins in malignant melanoma of the skin]. / Sekretsiia immunoglobulinov pri zlokachestvennoi melanome kozhi.

The study was concerned with the dynamics of correlations between IgA, IgM and IgG levels involved in pigmented neoplasm development in 154 cancer patients and 75 healthy subjects. The dynamics was found to represent stages of tumor development rather than changes in absolute indexes of serum immunoglobulin concentrations. The nature of changes in the structure of correlations suggested a possible switch from IgM to IgG and IgM to IgA secretion, i.e. disturbances in B-lymphocyte differentiation. Said changes were observed at a certain stage of melanoma progression, namely, during metastatic spreading.

[Quantitative analysis of survival during syngeneic and semisyngeneic bone marrow transplantation: relation of the protective effect and the ability to induce secondary disease as affected by differences in the major histocompatibility locus]. / Kolichestvennyi analiz vyzhivaemosti pri singennoi i semisingennoi transplantatsii kostnogo mozga: sootnoshenie zashchitnogo éffekta i sposobnosti vyzyvat' vtorichnuiu bolezn' pri razlichiiakh po glavnomu lokusu gistosovmestimosti.

The protective effect of bone marrow (BM) with both syngeneic and semisyngeneic transplantation is an exponential function of the number of transplanted cells. The regression coefficient in the logarithmic equation represents a fraction of hemopoiesis repair units (HRU). The quantitative analysis of the remote death of recipients of the parents' BM shows that the secondary disease (SD) is caused by other than HRU cells which is in agreement with the data obtained by other methods. The fraction of BM cells that induces SD is lower than the fraction of HRU. This helps to find an optimum BM dose range within which the risk of the SD-induced death is minimized.

[Inoculability and threshold effects in transplantation of experimental tumors]. / Privivaemost' i porogovye iavleniia pri transplantatsii éksperimental'nykh opukholei.

Inoculability of various experimental tumors (spontaneous, chemically-induced, solid, ascitic and leukemic) versus the amount of inoculated tumor cells (10(0)-10(7)) was studied. With small amounts of cells (10(2)-10(3)), inoculability of some tumors appeared to be nil, while in certain long-passaged neoplasms, particularly, leukemia, as few as 5-10 cells were enough. The data obtained pointed to a threshold in experimental tumor transplantation. However, quantitative analysis failed to establish one in the tumors under study. To assure transplantation, much larger study groups, e. g. of no less than 1500 animals for a breast cancer study, are required, which is hardly practicable.