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The effectiveness of fractionated exposure to gamma- and neutron radiation in their separate and combined use on the growth and functional morphology of mutant p53 sarcoma M-1 in rats was studied. Investigation techniques included immunostaining of PCNA and mutant p53 expressing cells, determination of mitotic activity and apoptotic death of tumor cells, as well as computer analysis of microscopic images. The antitumor efficacy of different types of radiation is shown to be determined by different levels of apoptosis induction, reduced proliferation and cellularity. Neutron radiation of the impulse generator has a marked damaging effect on the vasculature and the development of tumor necrosis. Fractionated irradiation at equal daily doses led to the decrease in the relative effectiveness of radio-inactivation of tumor cells. After 9 fractions of irradiation, the calculated value of the RBE of fast neutrons normalized to the input dose of 1 Gy by the coefficient of tumor growth inhibition, a reduced proliferative activity of PCNA and induced apoptosis of tumor cells was 3.4, 3.7 and 3.1, respectively. In the mode of daily superfractionation with splitting the dose in two fractions, the effectiveness of the combined exposure corresponded to the additive effect of gamma- and neutron radiation with a tendency toward synergism. There are reasons to believe that high resistance of sarcoma M-1 to the ionizing radiation impact is due not only to a fraction of hypoxic cells, but also the mutant status of p53 gene.

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Cancer stem cells (CSC) found in multiple tumor types and cancer cell lines were shown to be more resistant to low-LET radiation in comparison to other cancer cells. Therefore, CSC are supposed to determine the long-term effect of cancer therapy. Research into the CSC sensitivity to high-LET radiation is of great interest because of the advances in hadron therapy. The aim of this investigation is to compare CSC and other cancer cell sensitivity to the low- (60Co gamma-rays) and high-LET (neutron) radiation. To identify CSC, we used the low cytometry-based side population (SP) technique based on the CSC capacity to produce the efflux of the vital dye Hoechst 33342. SP and non SP cells were sorted and exposed to gamma and neutron radiation at doses of 1-10 Gy and 0.1-4.7 Gy, correspondingly. We applied the colony-formation test to examine the SP and non SP survival rate after irradiation. It was shown that the sensitivity of SP to gamma-irradiation was lower than that of other cells: D0 average values (+/- SE) made up 2.3 +/- 0.3 Gy and 1.4 +/- 0.2 Gy, correspondingly (p = 0.047). The survival rate of SP and non SP did not differ after neutron irradiation. The values of relative biological effectiveness of neutron radiation relative to gamma-radiation at the D10 level were 2.6 for SP and 2.1 for other cells. The obtained results justify for the first time a high efficiency of application of neutrons in radiotherapy from the point of view of CSC elimination.

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The irradiation with mixed gamma-neutron radiation was carried out at the pulse nuclear reactor on fast neutrons BARS-6 in a regimen of one pulse (100 micros) and in a regimen of continuous irradiation during 60 minutes. Was shown, that the irradiation of mice with pulse radiation was 1.3-1.8 times more effective in the induction of the chromosome aberrations in bone marrow cells in comparison with the continuous regimen of irradiation. At the same time, other biological tests (yield of chromosome aberrations in human lymphocytes, decreasing the number of cells in thymus) demonstrated that pulsed and continuous regimens have almost equal biological effectiveness.

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Solutions of the ferrous sulfate, of the albumin and of the suspension of liposomes were irradiated by mixed gamma-neutron radiation (fission spectrum neutrons, contribution of gamma-component to the absorbed dose up to 20%) at the pulse reactor BARS-6 with single-pulse (duration 100 micros) or continuous radiation (duration 60 min). It was shown, that after the pulse irradiation the concentration of the malonic dialdehyde in liposomes was in 3-4 times higher than after the continuous radiation at equal absorbed doses (p < 0.05). On the contrary, the irradiation of the liposomes suspension as well as of the solutions of the ferrous sulfate and of the albumin in a mode of single-pulse or of continuous mode did not reveal the statistically significant differences in the production of Fe3+ ions and of peroxides of the albumin for two mode of the radiation action.

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The effect of pulsed neutron radiation was studied in comparison with continuous neutron radiation and continuous gamma-radiation. Animal survival and induction of metallothionein (MT) synthesis in liver and kidney of mice exposed to equivalent doses were chosen as criteria for evaluation of radiation effects. It was found that the level of MT in liver and kidney of mice exposed to neutron radiation decreased 24 hours after irradiation and then continued decreasing in kidney for 48 hours after irradiation. This is evidence of more intensive free-radical processes initiated by pulsed neutron radiation. At the same time, RBE values of pulsed neutrons did not differ significantly from that of continuous neutron radiation.

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The authors discuss the technological problems associated with the use of fast neutrons in radiotherapy of cancer patients and outline the approaches to the solution of these problems. The state of the art is assessed. Physical and radiobiological prerequisites for the use of fast reactors for radiotherapy of patients with malignant tumors are analyzed. Results of clinical use of BR-10 reactor at the Medical Radiology Research Center, Russian Academy of Medical Sciences, are presented. Experimental and clinical findings indicate that the results of radiotherapy may be appreciably improved if a novel perspective source of fast neutrons, a nuclear reactor, is used.

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A brief review of up-date problems of neutron radiobiology, related to neutron therapy development and setting up of radiation safety standards for neutrons, is present. The main attention is paid to the effects of combined gamma-neutron irradiation, peculiarities of reactor neutrons biological action and new approaches in neutron capture therapy. On the basis of own and literature data the results of cellular and whole-body studies as well as the applicability of biophysical modelling for description and interpretation of experimental data are discussed.

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Experiments were made on rats with transplantable sarcoma-45 and sarcoma M-1. Dose correlation was established during a study of hyperglycemic radiomodifying action. Glucose injection at a dose of 6-17.5 g/kg was shown to enhance irradiation action. Glucose injection below or above these doses might cause worse radiotherapy results or even the death of animals. The best effect was obtained with small-size tumors. Large tumors (over 2 cm3) were less sensitive to hyperglycemia combined with irradiation. Skin radioprotective action of hyperglycemia before irradiation increased with an increase in a dose. The authors proposed a method of radioprotective action of hyperglycemia on normal tissues, enhancing simultaneously the antitumor effect of irradiation.

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The paper is devoted to a study of acute radiation reactions of the depilated thigh skin of outbred rats after their irradiation at various doses with gamma quanta and neutrons of a BR-10 reactor with the mean energy of 0.85 MeV. A scale, developed for the assessment of a degree of severity of radiation reactions permitted quantitative interpretation of the obtained results. The RBE of neutron irradiation was 4.2.

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The paper is concerned with the results of investigation of antitumor effectiveness (rats, sarcoma M-1) of neutron radiation of a BR-10 reactor with the mean energy of 0.85 MeV, correlated with the effect of 60Co gamma radiation (Luch-1). RBE in single local tumor radiation with neutrons was 4.5, being higher than RBE based on acute skin radiation reactions over a tumor (4.0). For this case FTA is over I (1.13) but slightly lower than after dose fractionated irradiation (1.18). Experimental data indicate the necessity of extending the clinical use of reactor neutrons and a profound study of the effects after neutron irradiation, particularly in dose-fractionated regimens.

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Proceeding from an analysis of the literature and their own data on radio- and thermodifying properties of hyperglycemia the authors have proposed a scheme of polyfactor therapy of malignant tumors including the following succession of exposures under clinical conditions: irradiation (the 1st fraction)--a chemotherapeutic drug--hyperglycemia--hyperthermia--irradiation (the 2nd fraction). The interval between exposures should be the least, best of all exposures should follow one another in a quick succession. Using the experimental data for determination of methods of therapy of transition and metastatic tumors of the upper respiratory tracts, satisfactory clinical results were obtained with regard to survival and the absence of local radiation reactions.

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Distribution of 57Co-bleomycetin in organs and tissues of rats with experimental short-term hyperglycemia was studied. Hyperglycemia was induced by intraperitoneal administration of 40 per cent glucose solution in doses of 1 to 10.4 g/kg. The labeled antitumor antibiotic was also administered intraperitoneally (0.2-0.8 MBq per animal). The data on both the external radiometry in the area under the animal limb and the radiometry of separate organs and tissues showed that hyperglycemia markedly altered pharmacokinetics of the labeled antibiotic and retarded its elimination. With respect to the lungs it even increased the drug tropism and accumulation. This information may be useful in radionuclide diagnosis and therapy in particular of lung cancer. The time course of glucose concentration in blood was not an adequate criterion of hyperglycemia influence since the influence of hyperglycemia on retarding the drug elimination was also observed when the level of glucose in blood did not differ from the initial one.

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Experimental studies on rats with sarcoma 45 showed that antitumor efficacy of bleomycetin could be markedly increased by inducing short-term hyperglycemia. It was noted that the theoretical value of the additive effect of these factors was lower than the experimental one. This is in favour of the synergistic mechanism of bleomycetin action under conditions of hyperglycemia.

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Comparative investigation of the time course of the release of acid phosphatase and cathepsin D from cancerous tissue after exposure to ultra-high-frequency hyperthermia and radiation (2-8 Gy) has demonstrated that the maximal effect was attained after thermal (42 degrees C) exposure for 15 min as compared to that after 30- and 60-minute hyperthermia and ionizing radiation at a dose of 8 Gy.

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Repeated local exposure (6 sessions) of rat sarcoma 45 to ultrahigh-frequency hyperthermia (41.5--42.5 degrees C in the tumor for 30 minutes per session) and x-ray radiation (a single dose of 8 Gy) irrespective of the succession of their application enables complete resolution of the tumor to be attained at the logarithmic stage of its growth.

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