Four series of experiments on C57Bl/6 mice were conducted involving local irradiation (20 Gy) of transplanted Lewis carcinoma and administration of the betaleukine radiomodificator (recombinant human interleukine-1β) 24 h before and immediately after the exposure. The criteria determining the effect of betaleukine on carcinoma growth were the delay of growth after exposure and the growth rate after the effect was restored compared with the corresponding characteristics in the intact and exposed controls. The administration of betaleukine did not lead to a shortening of growth delay nor to an increased growth rate. In one series of experiments, however, growth delay was significantly prolonged, while the growth rate tended to decrease. In the same experiment, the carcinoma growth rate in the intact control was the lowest among all other mice. It was concluded that the model of transplantation tumor in mice is promising for assessing the applicability of radioprotective substances in chemoradiation therapy.

The antimutagenic effect of three antiradiation drugs (betaleukin, indralin, and riboxin) was studied for the model of acute R-irradiation of mice, using a micronucleus test on polychromatic erythrocytes (MN-PCE) of bone marrow. The drugs were administered, respectively, 2 h, 10, and 30 min before the start of irradiation at a dose of 1 Gy. All drugs decreased the mutagenic effect 24 h after irradiation, but the antimutagenic effect of riboxin was not statistically significant. The Dose Reduction Factor (DRF) for the MN-PCE index for betaleukin, indralin, and riboxin was 2.5, 1.9, and 1.4 (present study) and was significantly higher than the DRF for 30-day survival (published data). Thus, the antimutagenic effect of the three drugs has been revealed. These data are important for understanding the mechanism of their protective action. An applied approach can be useful for screening new antiradiation drugs.

In experiments on SPF mice, the authors evaluated the radio-protective effectiveness of the recombinant Flagellin, developed at the Institute of High-Purity Preparations (St. Petersburg), administered at a wide range of doses of 0.004–2 mg/kg for 30 min prior to X-ray irradiation in the dose range of 7–10 Gy. The effectiveness of Flagellin was evaluated in terms of 30-day survival rates of the mice, the average life expectancy, and according to the DMF criterion for bone marrow death. The DMF values were 1.24–1.23–1.22 at the level of LD 16 , LD 50 , and LD 84 . ED 50 approximately equals 25 μg/kg. The dose-response effect of Flagellin was evaluated to reach a plateau at a dose of 0.2 mg/kg.

The antimutagenic activity of anti-radiation drugs betaleukin, flagellin, indraline and riboxin with different mechanisms of action was studied in short-term and chronic experiments in mice in vivo. All drugs showed antimutagenic properties in bone marrow cells, as well as hepatoprotective effect. The greatest effect under the used experimental conditions was noted for betaleukin and the new anti-radiation drug flagellin.

Изучена антимутагенная активность противолучевых препаратов разного механизма действия: беталейкина, флагеллина, индралина и рибоксина в краткосрочных и хроническом экспериментах на мышах in vivo. Все препараты проявили антимутагенные свойства в клетках костного мозга, а также гепатопротекторное действие. Наибольший эффект при используемых условиях эксперимента отмечен для беталейкина и нового противолучевого препарата флагеллина. The antimutagenic activity of anti-radiation drugs betaleukin, flagellin, indraline and riboxin with different mechanisms of action was studied in short-term and chronic experiments in mice in vivo. All drugs showed antimutagenic properties in bone marrow cells, as well as hepatoprotective effect. The greatest effect under the used experimental conditions was noted for betaleukin and the new anti-radiation drug flagellin.

We studied the mutagenic effect of X-ray irradiation in doses of 0.5, 1, and 1.5 Gy on female (CBA×C57Bl/6)F1 mice. The mutagenic effect (assessed by the parameter “frequency of bone marrow polychromatophilic erythrocytes with micronuclei”) linearly depended on the dose of X-ray irradiation in the range of up to 1 Gy and reached the plateau at 1.5 Gy. The fraction of polychromatophilic erythrocytes was 45, 45, and 46% under control conditions (without exposure) and exposure to the irradiation in the doses of 0.5 and 1 Gy, respectively. Irradiation in a dose of 1.5 Gy induced a slight inhibition of erythropoiesis. These data confirm the hypothesis on possible death of highly aberrant erythrocyte precursors after irradiation in high doses.

В опытах на мышах F1(CBA ? C57Bl) проводили оценку профилактической противолучевой эффективности различных радиомодификаторов по ранним клеточно-тканевым радиационным эффектам при пролонгированном -облучении животных с низкой мощностью дозы и поиск индикаторов медикаментозно повышенной радиорезистентности по показателям экспрессии генов белков теплового шока и р53 в костном мозге. Противолучевой эффект был обнаружен только у беталейкина. Беталейкин оказывал разнонаправленное (стимулирующее и ингибирующее) воздействие на экспрессию генов белков теплового шока, не коррелировавшее с противолучевым эффектом препарата. Беталейкин оказал раннее и преходящее ингибирующее действие на экспрессию р53. Обсуждается перспективность исследования беталейкина как радиомодификатора длительного действия и р53/NF- B сигнальных путей как индикаторов эффективности радиомодификаторов.

Different radiomodificators (cytokine betaleukine, antioxidant phenoxan, antigipoksant limontar and nucleoside riboxin) were investigated on mice for evaluating their radiation protective capacity against prolonged (21 h) exposure at a dose of 12.6 Gy at a low dose rate of 10 mGy/min. Bone marrow cellularity and endogenic CFUs were used as evaluation criteria 9 days after exposure. Simultaneously, expression of the heat shock proteins of 25, 70 and 90 kDa in unexposed mice bone marrow was studied 2, 24 and 48 h after injections. Betaleukine only had a positive significant effect in both tests in the variants of 50 mcg/kg and 3 mcg/kg when administered 2 h and 22 h before exposure, correspondingly. Effects of betaleukine HSPs on expression were both stimulating and inhibiting, that was in contradiction with a constant positive effect in 5 experiments on exposed mice for each betaleukine variant. It argues against the vital role of HSPs in the betaleukine antiradiation effect. In 2 experiments with high temperatures betaleukine administered at a dose of 50 mcg/kg evoked a very high HSP-70 gene expression after 24 h, and mice exposed to irradiation at that time in a parallel experiment showed an increased radiation effect. It corresponds to the idea that HSPs serve a stress indicator.

We have evaluated the treatment effectiveness of Leucostim and Neupomax in dogs exposed to radiation at lethal doses of 3 and 3.5 Gy, correspondingly, by testing the dynamics of the blood cell number, first of all, leucocytes and neutrophiles, and the 45-day survival. Supportive therapy for all the dogs, including the control ones, consisted in antibiotic treatment during the acute period of 7-24 days. It was shown that both pre-parations administered consecutively for about 17-21 days after irradiation positively influenced the dynamics of all blood cells but predominantly impacted the neutrophile number dynamics. The latter ones manifested a higher nadir level and an earlier onset of restoration in the G-SCF treated dogs in comparison with the control ones. The tendency to a positive influence on the survival has been shown in Neupomax-treated dogs exposed to 3.5 Gy of radiation (plus about 40%). The results of the experiments were in good accordance with the data by foreign authors who used Neupogen. This allows a conclusion that home-produced G-SCF preparations can replace their foreign analogues.

Recombinant human thrombopoietin (rh TPO) has been investigated as a means of acute radiation disease urgent treatment in the experiments on 24 mongrel dogs. The animals were exposed to total acute gamma-irradiation at the doses of 3.5 Gy (exceeding LD50/45 under our conditions) and 3 Gy. All the dogs including control ones received antibiotics Ampicillin and Gentamicin twice a day during the acute period from the 7th to the 21st day. TPO was injected one time s/c or i/v at the doses of5 or 10 mkg/kg 1.5-2 h after exposure. TPO at a dose of 5 mkg/kg was ineffective. TPO at a dose of 10 mkg/kg had a positive effect on the kinetics of blood forming units, especially platelets (nadir, restoration rate) in terms of the 45-day survival. As a result, in TPO groups, nadir averaged at both exposure doses on leucocytes (1.3-1.4) x 10(9)/l vs (0.70-0.75) x 10(9)/l in control groups and on thrombocytes (102-112) x 10(9)/l vs (44-33) x 10(9)/l in control ones. Despite the low number of animals in experimental groups, the results permit to regard rhTPO as a worth-while urgent therapeutic means for the acute radiation damage treatment and preventing thrombopenia.

In the experiments on F1 (CBA x C57BL) and BALB mice irradiated by 137Cs gamma-rays, preparations of unglycosilated G-SCF such as Neupogen and their domestic analogs Leucostim and Neupomax were investigated. The tests such as 9-day bone marrow cellularity (BMC) and endogenous CFUs, the neutrophile number restoration, the 30-day survival index have shown that all three preparations have an approximately equal effectiveness relating to acute radiation disease treatment and granulopoiesis stimulation after a 5-10 day consecutive administration following irradiation of mice at lethal and sublethal doses. We have come to the conclusion that Leucostim and Neupomax can be regarded as adequate substitutes for Neupogen.

Объект исследования – оценка в экспериментах на облученных мышах противолучевой и гемостимулирующей эффективности препаратов рекомбинантного человеческого гранулоцитарного колониестимулирующего фактора (рч Г-КСФ), отечественных – лейкостима и нейпомакса в сравнении с импортным – нейпогеном. Исследования проведены на мышах F1 (CBA ? C57Bl) и мышах линии BALB. Животных подвергали острому тотальному облучению на гамма-установке ИГУР в широком диапазоне доз 4.0–9.5 Гр. Курсовые (5–10-суточные) введения всех трех препаратов оказали выраженное противолучевое и гемостимулирующее действие по показателям клеточности костного мозга, селезеночных эндоколоний, дифференциальной лейкограммы, а также по показателю 30-суточной выживаемости. Сравнение лейкостима и нейпомакса с нейпогеном по показателям противолучевой и гемостимулирующей эффективности существенной разницы не выявило. Полученные результаты позволяют сделать вывод о том, что лейкостим и нейпомакс могут быть адекватной заменой нейпогена.