[Multidrug resistance increase of tumor cells at the effect of radiation and phorbol ether depends on protein kinase C and reactive oxygen species].

The effects of phorbol ether (PMA) and ionizing radiation on multidrug resistance (MDR) of human larynx cancer cells HEp-2 and the dependences of these effects on protein kinase C (PKC) activity and reactive oxygen species (ROS) production were studied. MDR was determined by transport rate of rhodamine 123 off cells and production of ROS in cells was measured by means of 2'7'-dichlorodigidrofuorescein oxidation to fluorescent 2',7'-dichlorofluorescein. ROS production was increased in cells at PMA treatment. This increase was caused by PKC dependent activation of NADPH-oxidase because the ROS increase suppressed completely with PKC and oxidase inhibitors. It was shown that tumor cell MDR was increased 16 h after PMA (100 nM) and radiation (1 Gy) treatment. The MDR increase depends on PKC activity and ROS increase in cells at both influences since PKC inhibitor and antioxidant, lipoic acid suppressed MDR increase. The obtained data are in accordance with hypothesis about the necessity of activation both signalization and stress reaction for initiation of transcription of transport protein genes which responsible for MDR of tumor cells.

[Antitumor effect of low-intensity extremely high-frequency electromagnetic radiation on a model of solid Ehrlich carcinoma].

The influence of different exposure regimes of low-intensity extremely high-frequency electromagnetic radiation on the growth rate of solid Ehrlich carcinoma in mice has been studied. It was shown that, at an optimum repetition factor of exposure (20 min daily for five consecutive days after the tumor inoculation), there is a clearly pronounced frequency dependence of the antitumor effect. The analysis of experimental data indicates that the mechanisms of antitumor effects of the radiation may be related to the modification of the immune status of the organism. The results obtained show that extremely high-frequency electromagnetic radiation at a proper selection of exposure regimes can result in distinct and stable antitumor effects.

[Antitumor effect of natural avermectins]. / Protivoopukholevoe deistvie prirodnykh avermektinov.

The effects of the natural avermectin complex, aversectin C and individual avermectin B1 on the growth of ascitic and solid transplantable tumors in animals were studied. The results showed for the first time that both aversectin C and avermectin B1 possessed marked antitumor activity. In subtoxic doses aversectin C significantly inhibited the growth of P388 lymphoid leukemia and Ehrlich carcinoma, both ascitic and solid ones. In some administration regimens aversectin C inhibited the tumor growth by 70 to 80%. The highest effect of aversectin C was observed after its intraperitoneal administration. Avermectin B1 inhibited the growth of solid Ehrlich carcinoma and carcinoma 755.

[Analysis of 15-lipoxygenase activity in irradiated thymocytes]. / Issledovanie aktivnosti 15-lipoksigenazy v timotsitakh posle oblucheniia.

We studied the effect of gamma-radiation on 15-lipoxygenase activity in rat thymocytes. The enzyme activity was determined as the rate of linoleic acid oxidation by the protein fraction isolated from the control and irradiated thymocytes under standard conditions. We demonstrate lipoxygenase activation immediately after irradiation of thymocytes. High lipoxygenase activity is observed in the cells for no more than an hour after irradiation. No high lipoxygenase activity later indicates that its synthesis is not directly induced by irradiation. Irradiation-induced generation of lipid peroxides can be the factor of lipoxygenase activation.

[Apoptosis in P388 leukemia cells induced by specific inhibitors of 5- and 12-lipoxygenase and the product of cyclooxygenase, prostaglandin E2]. / Apoptoz v kletkakh limfoleikoza P388 pri deistvii spetsificheskikh ingibitorov 5- i 12- lipoksigenaz i produkta tsiklogenazy--prostaglandina E2.

We studied the effect of specific inhibitors of 5- and 12-lipoxygenases as well as the product of cyclooxygenase activity, prostaglandin E2, on proliferation and death of P388 leukemia cells. Inhibition of 5- and 12-lipoxygenases in the cells inhibits proliferation and induces apoptosis. The concentrations of baicalein, an inhibitor of 12-lipoxygenase, and AA861, an inhibitor of 5-lipoxygenase, causing a 50% death rate (LC50) proved to be the same, 50 microM. Excessive prostaglandin also inhibited proliferation of the cells and induced apoptosis. The LC50 for prostaglandin E2 was 4 microM. The obtained data suggest that apoptosis in P388 cells after lipoxygenase inhibition can be induced by both deficiency of lipoxygenase products and excess of prostaglandins in the cell.

[A study of the role of lipoxygenases in radiation-induced apoptosis of thymocytes. Inhibitory analysis]. / Issledovanie roli lipoksigenaz v radiatsionnom apoptoze timotsitov. Ingibitornyi analiz.

The radiation-induced apoptosis of thymocytes is suppressed by the common inhibitor of lipoxygenases nordihydroguaiaretic acid but not the inhibitors of cyclooxygenases or cytochrome P-450, which indicates the key role of lipoxygenases in apoptosis. However, the specific inhibitors of 5-lipoxygenase (AA861) and of 12-lipoxygenase (baicalein) do not suppress apoptosis and even enhance it. This effect can be explained by an increase in the yield of the 15-lipoxygenase product upon inhibition of 5- and 12-lipoxygenases. Indeed, the addition of 15-hydroxyecosotetraenic acid, a product of 15-lipoxygenase, into the incubation medium induces apoptosis in thymocytes. The results obtained suggest that 15-lipoxygenase is one of the enzymes involved in radiation-induced apoptosis of thymocytes.

[Modification of antitumor effect of vincristine by natural avermectins]. / Modifikatsiia protivoopukhlevogo effekta vinkristina prirodnymi avermektinami.

The effect of avermectins (aversectin C, aversectin C1 and avermectin B1) on the vincristine antitumor action with respect to murine transplantable tumors was studied. It was shown that both the natural avermectins mixtures and the individual avermectin B1 potentiated the antitumor action of vincristine on Ehrlich carcinoma, melanoma B16 and P388 lymphoid leukemia, including the vincristine resistant strain P388. Such an effect of the avermectins was observed only when they were administered after vincristine.

[Antitumor effect of combined treatment with ionizing radiation and vitamin B12-C complex]. / Protivoopukholevyi éffekt sochetannogo primeneniia ioniziruiushchei radiatsii s kompleksom vitaminov B12 i C.

The combined effect of ionizing radiation (0.5-4 Gy) and the vitamin B12-C complex on life-span of mice with Ehrlich carcinomas was studied. It was shown that antitumor effect of the combined treatment strictly depends on the sequence of the agent applying and on the time interval between them. For example, the combined treatment increased essentially the life-span of mice if the vitamins were used 24 h after irradiation but with the reverse order of influences, the antitumor effect was less than that of the vitamin complex only. It was supposed that the discovered regularities are due to tumor cell synchronization or division stimulation with the first influence.

[Changes in sensitivity of lymphocytic leukemia P388 cells to oxidative stress and platidiam upon tumor growth]. / Izmenenie chuvstvitel'nosti kletok limfoleikoza P388 k okislitel'nomu stressu i platidiamu po mere rosta opukholi.

We studied the effect of oxidative stress induced by hyperoxia, hydrogen peroxide, or menadione on mouse leukemia P388 cells at early (4 days) and late (7 days) stages of tumor growth. Oxidative stress proved to inhibit cell division and to induce apoptosis. Seven-day leukemia cells feature lower proliferative potential and higher sensitivity to oxidative stress and platidiam.

[Growth inhibition and induction of tumor cell death by phospholipase A2 and lipoxygenase inhibitors]. / Podavlenie rosta i induktsiia gibeli opukholevykh kletok ingibitorami fosfolipazy A2 i lipoksigenazy.

We studied the effect of arachidonic acid metabolism inhibitors in a wide concentration range on the proliferation and death of lympholeukemia cells P-388. Proliferation of the cells was estimated by metaphase frequency and the proportion of cells in S phase; cellular death was determined by their lysis, trypan blue staining, damaged nuclei, the proportion of cells with subdiploid DNA content, and DNA fragmentation. Low concentrations of phospholipase A2 and lipoxygenase inhibitors were shown to stimulate cell division, while higher concentrations inhibited it by blocking G1-S transition and inducing apoptotic cellular death. Indomethacin, a cyclooxygenase inhibitor, had no effect on proliferation and induced no cell death at concentrations up to 10 microM. Inhibitors of phospholipase A2 and lipoxygenase also inhibited tumor growth in mice.

[Cytotoxic and cytostatic effect of avermectines on tumor cells in vitro]. / [Tsitostaticheskoe i tsitotoksicheskoe deistvie avermektinov na opukholevye kletki in vitro]

Effect of natural avermectin complex (aversectin C) and separate avermectins A1, A2, B1 and B2 in the cell culture of murine myeloma Ns/o, Erlich carcinoma ascites and human larynx carcinoma Hep-2 was investigated. It was shown that aversectin C within the concentrations of 0.1 to 1.0 mcg/ml inhibited proliferation of tumor cells and induced their death. Proliferation inhibition was due to the delay of the cells cycle start (lag-phase prolongation) and blocking of mitotic cycle. Ns/o cells death had apoptosis signs: chromatin condensation and fragmentation, DNA fragmentation. It was demonstrated that only avermectin A1 has cytotoxic activity within the concentrations used, avermectins A2 and B2 had cytostatic activity, avermectin B1 showed no activity under the experimental conditions.

[Action of avermectins on lymphoid leukemia P-388 cells in vitro]. / Deistvie avermektinov na kletki limfoleikoza P-388 in vitro.

Avermectins are final products in the fermentation process with Streptomyces avermitilis. They have parasitocidic activity and are used as the main substances of insectoacaronematocides. The study of the activity of the natural avermectin complex (aversectin C) and separate avermectins A1, A2, B1 and B2 in the cell culture of lymphoid leukemia P-388 showed that within the concentrations of 0.1 to 1.0 microgram/ml aversectin C inhibited the growth of the tumor cells and induced their death. The inhibition was due to blocking the cell mitosis. The cell death was accompanied by internucleosomal degradation of the DNA nuclei i.e. the death was of the apoptosis type. The sensitivity of the cells to aversectin C was directly proportional to their initial proliferative activity. As for the separate avermectins only avermectin A1 had the cytotoxic activity within the concentrations used, avermectin A2 had the cytostatic activity and avermectins B1 showed no activity under the experimental conditions.

[Signalling during radiation-induced apoptosis of thymocytes]. / Signalizatsiia pri radiatsionnom apoptoze timotsitov.

The mechanisms of signal triggering, enhancement and transduction during radiation-induced apoptosis of the thymocytes are discussed. Apoptosis is triggered by aggregation of receptors accompanied by activation of protein tyrosine kinases. The receptor aggregation is caused by radiation-induced cross-links. The signal is transduced to the gene from protein tyrosine kinase through Ras-proteins, protein kinase C, and transcription factors. The necessity of the lipoxygenase gene expression and synthesis of this enzyme for support and enhancement of the apoptotic signal is postulated.

[Emotions, stress, smoking, alcohol consumption and cancer--the correlational and causal connections]. / Emotsii, stress, kurenie, potreblenie alkogolia i rak--korreliatsionnye i prichinnye sviazi.

Correlative and causal relationships are discussed between emotions, stress, smoking, drinking, and cancer. The following conclusions have been drawn. Emotions control the physiological stress reactions: the negative emotions initiate and maintain stress, and positive emotions stop it. A dissatisfied need provokes the development of the state of emotional stress. There are two types of emotional stress states: the active stress which is directed to "overcoming" and the passive state of "waiting till the stress is over". Individuals differ in emotionality, stress reactivity, and inclination to the active and passive emotional stress. The passive emotional stress increases the probability of cancer. This effect is caused by the development of the hormonal and neurotransmitter state, which provokes immunosuppression, DNA damage, and stimulation of hemopoiesis. Smoking and drinking are the ways of modifying the psychoemotional state. These habits as well as development of cancer are the effects of the same cause--stress. Thus, cases of correlation between smoking and drinking do not reflect the causal relationships. Only intensive smoking and drinking which lead to tissue damage can increase the incidence of cancer.

[The model of age dependent frequency of neoplasms]. / Model' vozrastno'i zavisimosti chastoty onkologicheskikh zabolevani'i.

The equation for the increase of tumor frequency with age is deduced from the supposition about the errors of DNA replication as the main cause of oncogenic mutations. The quantitative expression of the organ specificity of tumor frequency is concluded also. The age function coincide qualitative with epidemiologic date: the tumor frequency is in proportion to age with the exponents of 5 and higher. The frequency of oncogenic mutations on one DNA replication is evaluated from the equation using the statistical data of the annual sickness rate of the lip, oral cavity and throat cancer for the men and the rate of cell proliferation in this organs.

[The stimulation of cell growth in human lymphoma by ionizing radiation at low doses]. / Stimuliatsiia rosta kletok limfomy cheloveka ioniziruiushchim izlucheniem v malykh dozakh.

The effect of low-dose radiation (1-100 cGy) on the growth of lymphoma Raji cells in vitro was examined. It was shown that irradiation with doses of 2-20 cGy stimulates the cells growth. This effect was caused by shortening of the lag-phase of growth. The duration of mitotic cycle was not changed. The culture medium irradiated within this dose interval stimulates the cells growth too. It was supposed that the effect of irradiated medium was caused by long-lived products of medium radiolysis.

[The cause-effect relationships between different indices of radiation lesions of the thymocytes]. / K voprosu o prichinno-sledstvennykh sviazakh mezhdu raznymi pokazateliami radiatsionnogo porazheniia timotsitov.

The dependence of the kinetics of different thymocyte injuries of the experimental conditions was investigated. It was shown that the rate of cell death detecting by cell staining decreases with the increase of the dye molecular size. Different organic substances decrease the staining rate of the dead cells with trypan blue but increase the rate of DNA fragmentation. They change the kinetics of cell injuries development only after but not during irradiation. Development of pycnoses forestalls the DNA fragmentation. Basing on these findings the conclusion was made that the time-course of different thymocyte injuries development cannot be used for a statement what type of injuries--of plasmic membrane or cell nucleus--is initial.

[Stimulation of fibroblasts' growth in culture by low-dose ionizing radiation in acute irradiation]. / Stimuliatsiia rosta fibroblastov v kulture malymi dozami ioniziruiushchego izlucheniia pri ostrom obluchenii.

The effect of low irradiation doses (10-100 cGy) on the growth of Chinese hamster fibroblasts was examined. It was shown that the number and the mean size of colonies increased after irradiation with doses of 10-40 cGy. Dependence of the effect on dose is extremal with maximum at 10-20 cGy. Irradiation by dose of 10 cGy did not affect on the cell cycle duration but significantly shortened the las-phase of growth.

[The intercellular interactions in the interphase death of irradiated thymocytes. A study of the influence of different cells on thymocyte interphase death]. / Mezhkletochnye vzaimodeistviia pri interfaznoi gibeli obluchennykh timotsitov. Issledovanie vliiania razlichnykh kletok na interfaznuiu gibel' timotsitov.

The influence of different cells on death and pycnosis of thymocyte nuclei after in vitro irradiation has been investigated. It has been shown that the removal from the thymocyte suspension of cells, having the activity of natural killers, medullar thymocytes, and macrophages, does not influence the radiation-induced damage to cortical thymocytes. The injury of exposed thymocytes decreases, however, after incubation them with nonirradiated thymocytes or cultured cells, the efficiency of the latter being dependent on the type of cells. The data obtained may indicate that the exposed thymocytes interact with each other and exchange some factors that promote their injury.