Decrease in Bcl-2 Protein Level during the Development of Lewis Carcinosarcome.

We studied the development of Lewis carcinoma and possible antitumor effect of preliminary administered antioxidant anphen. The tumor was intramuscularly transplanted to C57Bl×DBA mice (7×106 cells per mouse). According to immunoblotting results, the content of anti-apoptotic Bcl-2 protein steadily decreased starting from post-transplantation day 11. In few days, its content decreased by 15-20% and soon the animals died. After administration of anphen, the content of Bcl-2 decreased more rapidly than in the control. Atomic force microscopy revealed a decrease in the mean volume of erythrocytes and then increase in this parameter at the terminal stage of tumor growth. These findings suggest that anphen does not affect the tumor growth rate and mouse lifespan, but enhances apoptosis of blood cells of animals with Lewis carcinoma at the terminal stages of tumor growth.

Effect of Promising Antitumor Phenolic Antioxidant Anphen Sodium on the BCL-2 Family Proteins.

The proapoptotic effect of anphen (the effect on the level of the antiapoptotic protein Bcl-2) was investigated by immunoblotting. Incubation of Lewis carcinoma cell suspension with anphen at a concentration of 10-6 M for 0-3 h caused a 80% reduction in the level of the Bcl-2 protein and its homodimer. In vivo, when administered for 4 days to outbred mice, anphen (10-4 M) induced a decrease in the level of the Bcl-2 homodimer in the spleen cells by 20% and an increase in the content of the Bad protein (apoptosis activator) and the Bcl-XL protein. The antitumor effect of anphen may be due to blocking the hydrophobic pocket of the Bcl-2 protein.

[Effect of oregano essential oil on the engraftment and development of Lewis carcinoma in F1 DBA C57 black hybrid mice].

The effect of a low uptake dose of oregano essential oil with drinking water for three months (Origanum vulgare L.) on the degree of Lewis carcinoma engraftment and some parameters of oxidative stress has been studied in vivo using F1 DBA C57 Black hybrid mice. Oregano essential oil has been established to possess an anticancer activity. The degree of tumor engraftment decreased by 1.8 times, its size decreased by 1.5 times, and the development of tumor was significantly suppressed in sick mice under the effect of oregano essential oil. It was found that the uptake of essential oil did not affect the intensity of lipid peroxidation in the brain of mice and resulted in a significantly (by 36%) decreased content of secondary lipid oxidation products in the liver as shown in a reaction with thiobarbituric acid as compared to control subjects. The activity of antioxidant enzymes was found to increase after three months of essential oil uptake (by 1.5-3 times) as compared to the control group. This effect of essential oil supports the presence of bioantioxidant properties in this essential oil.

[The effect of volatile antioxidants of plant origin on leukemogenesis in mice].

The effect of savory essential oil added with drinking water (150 ng/ml) or with feed (2.5 microg/g) on the lifetime of AKR mice and the parameters of oxidative stress in animal blood were investigated. It was found for the first time that long-term administration of an essential oil in low doses increased the average lifetime of mice by 20-35% and was accompanied by a decrease in the hemolysis level and the content of lipid peroxidation products in erythrocytes of mice, as well as alteration in the structural state of their membranes and stabilization of polyunsaturated fatty acids level in mice liver cells.

[Effect of antioxidant beta-(4-hydroxy-3,5-ditertbutylphenyl) propionic acid (phenosan) on the development of malignant neoplasms].

The effect of different doses of synthetic antioxidant beta-(4-hydroxy-3,5-ditertbutylphenyl)propionic acid (phenosan) on the development of spontaneous leukemia in AKR mice was studied. The drug efficiency was determined from the survival curves, animal life spans, and the incidence of leukemia. Phenosan exhibited a pronounced antitumor activity at therapeutic (10(-4) mol/kg, 4 administrations) and ultra-low (10(-14) mol/kg, 4 administrations) doses. The dose of 10(-4) mol/kg proved most efficient to increase the life span of the shortlived subpopulation, while the dose of 10(-14) mol/kg increased the life span of the long-lived subpopulation. The ultra-low dose of the drug seems promising as a prophylactic agent.

[Effect of low-level irradiation on incidence rate and development of malignant neoplasms].

Low-level irradiation (1.2-2.4 cGy, dose-rate 0.6 cGy/day) leads to a significant acceleration of the development of spontaneous leukosis in AKR mice: decrease in the average and the maximum life-span of animals leukosis-carriers (by 20 and 120 days, respectively) and an increase in the leukosis incidence rate (%). The introduction of antioxidant phenozan (beta-(4-hydroxy-3,5-ditertbutylphenyl) propionic acid) results in a considerable antileukosis effect: the average life-span increases by more than 40 days and the leukosis incidence rate decreases by 6%.

[Effect of low doses of low-intensity irradiation on the incidence and progress of spontaneous leukosis in AKR mice]. / Vliianie nizkointensivnogo oblucheniia v malykh dozakh na vozniknovenie i razvitie spontannogo leikoza u myshei linii AKR.

Development of spontaneous leukosis in AKR mice is accelerated by irradiation with low doses (1.2-2.4 cGy, dose-rate 0.6 cGy/day): the leukoses incidence rate increases, deaths of the animals from leukosis occurs earlier, shortening the average and maximum life-spans of the animals. The dynamics of changes in the mass of organs of the immune systems (thymus and spleen) shown extrema. The moment of reaching the extremum correlates with the maximum rate of animals' deaths.

[Spontaneous leukosis as a model for an investigation of low and very low physical and physico-chemical effects on oncological process]. / Spontannyi leikoz -- model' dlia izucheniia éffektov malykh i sverkhmalykh doz fizicheskikh i fiziko-khimicheskikh vozdeistvii na opukholevyi protsess.

Kinetic investigation of spontaneous leukosis in AKR mice have been carried in connection with a number of indices: changes in the mass of principal organs of the immune systems (thymus, spleen, lymphatic nodes), liver, alterations of haematological data (the sum of leukocytes, the percentage composition of blood cells, the quantity of undifferentiated cells), changes of physico-chemical conditions in cells (NMR-investigation). The dynamics of some of these indices and also life-spans of animals with leukosis after irradiation with doses 1.2-2.4 cGy (dose-rate 0.6 cGy/day) have been investigated. The enhancement of the frequency of leukosis and shortening the average and maximum life-spans of irradiated mice has been found.

[1H-NMR spectroscopy of the cell membranes of thymus lymphocytes in AKR mice]. / 1H-IaMR spektroskopiia kletochnykh membran limfotsitov timusa myshei AKR.

360 MHz 1H NMR was used to monitor the changes of AKR mice thymus lymphocytes in cases of spontaneous and transplantable leukemia and vincristine administration. A comparison of relative signal intensities of methyl and methylene fatty acid chains protons and phosphatidylcholine headgroups protons enables to monitor leukemia development and vincristine effect. Spin-lattice relaxation curves of the same protons of leukemic thymi lymphocytes are well fitted by biexponential functions, bringing evidence for two regions with different lipid mobility.

[Changes in levels of p53 protein, immunoglobulin L-chains, and iron complexes in mice of leukosis strain AKR following low dose irradiation]. / Izmenenie soderzhaniia belka p53, L-tsepei immunoglobulinov i kompleksov zheleza pri obluchenii malymi dozami myshei leikoznoi linii AKR.

Changes in the content of protein p53 (regulator of the cell cycle) L-chains of immunoglobulins, and iron complexes (Fe2+) during the development of spontaneous leukosis in AKR mice and upon irradiation of animals with a dose of 1.2 cGy were studied by ESR spectroscopy, electrophoresis, and immunoblotting. It was found that irradiation leads to an increase in the incidence of leukoses in males by 7% and a decrease in life duration of females. A decrease in the content of protein p53 and L-chains in immunoglobulins in males and females was observed; however, in females, the decreases was less pronounced because the content of these proteins in females is naturally decreased. In mice irradiated with low doses at the age of three- to four months, a decrease in the amount of iron complexes at a later age (seven- to eight months) was registered. These data suggest that there is a relationship between the induction of protein p53 and the content of immunoglobulin L-chains in the blood serum of animals.

[Kinetic patterns of the development of transplantable AKR leukemia]. / Kineticheskie zakonomernosti razvitiia perevivaemogo leikoza AKR.

Under study was the kinetics of the development in primary passages of AKR leukemia transplanted by different number of cells. The indices of the leukemic process (the spleen, lymph nodes, the liver, thymus, blood leucocytes) vary with time in extreme curves. The leukemia transplantability is reduced from 100% to 24% with lessening of the transplant from 10(4) to 10(1) cells. The latent period duration and the survival of mice are linearly related to the transplanted cells number logarythm.

[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.

[Changes in fatty acid composition in the brain and liver in aging mice of high cancer risk AKR strain and effect of savory essential oil administration on leukemic process].

Age-related alterations of fatty acid composition in liver and brain of AKR mice was investigated. The effect of savory essential oil (Satureja hortensis L.), added with drinking water on fatty acid composition in these organs and the processes of lipid peroxidation in erythrocytes were estimated. It was found that during aging the percentage of saturated fatty acids and polyunsaturated fatty acids decreased while monounsaturated fatty acids increased. The development of leukemia was accompanied by the increase of saturated and polyunsaturated fatty acids percentage and a decrease of monounsaturated fatty acids amount. In the liver aging caused the increase in the percentage of saturated fatty acids, the decrease of monounsaturated fatty acids, while the amount of polyunsaturated fatty acids was not changed. Leukemia (after 8 month) was accompanied by the increase of percentage of monounsaturated fatty acids and the decrease in the amount of oleinic and docosohexaenic acids. The intake of savory essential oil was accompanied by intensification of polyunsaturated fatty acids synthesis in mice liver and reduction of lipid peroxidation products content.

Quantitative investigation of the changes in the cell composition of the spleen during the growth of Worker's carcinosarcoma.

The weight of the spleen and its cell composition as a function of the weight of the tumor was studied during the development of Worker's carcinosarcoma. The progression of the dependence is presented in the appropriate mathematical form. It is shown that with development of the process of tumor enlargement, erythro- and myelopoiesis are intensified in the spleen. The overall quantity of erythroblastic elements reaches a maximum value when the weight of the tumor reaches 30 g and subsequently remains at the same level. The kinetic curves of the changes in the number of lymphocytes in the spleen and also their graphical dependence on the weight of the tumor are of an extreme character. At late stages in the development of the tumor, the number of cells of the granulocyte type begins to increase.

Kinetics of changes in lymphoid organ weight and the cellular composition under leukosis of the latter, inoculated with different amounts of cells.

The authors studied the kinetic pattern of weight change in lymph glands, spleen, thymus, and their cellular composition during the development of mouse reticulosarcomatosis and Shvets' leukosis when the transplant contained different numbers of tumor cells. They found that during the development of reticulosarcomatosis, the weight of lymph glands and their content of lymphocytes and plasmocytes undergo enormous changes; the weight of the spleen and its content of lymphocytes increase gradually while the kinetic curve of plasma cell changes presents two maxima. During the development of Shvets' leukosis, the weight of spleen and lymph glands and their lymphocyte content change enormously while the number of plasmocytes rises exponentially. In every case, the authors determined a definite dependence of the reaction of lymphoid organs on the size of the transplantate.

Block copolymers of ethylene oxide and propylene oxide (pluronics) as immunomodulators and antitumour agents.

Block copolymers of ethylene oxide and propylene oxide (pluronics) are nontoxic water-soluble membranotropic surfactants available as polymers with various compositions, molecular masses, number, and arrangement of blocks. In vivo experiments are reported which demonstrate that these polymers and their functional derivatives stimulate the production of anti-sheep-erythrocyte antibodies in mice. The introduction of reactive (hydroperoxide) groups into the polymers by chemical modification or by solubilization of low-molecular-mass hydroperoxides alters the properties of these immunostimulators. In vitro experiments revealed that these modified polymers enhance the activity of natural killer cells without reducing their viability. It is proposed that the immunomodulatory properties of pluronics and their derivatives play an important role in the antitumour activity of these substances in vivo.

[The immunomodulating properties and antitumor activity of block copolymers of ethylene oxide and propylene oxide (proxanols)]. / Immunomoduliruiushchie svoistva i protivoopukholevaia aktivnost' bloksopolimerov okisi étilena i okisi propilena (proksanolov).

Influence of block copolymers of ethylene and propylene oxides (proxanols) on the human natural killer activity was studied. Proxanols had no effect on the lymphocytes viability and increased their cytotoxic activity against target cells K 562 in vitro. Certain antitumor properties of proxanols were demonstrated in vivo (especially for ascitic tumors). The proxanols activity was chiefly determined by the membranotropic properties of its main polymer chain.