Post-irradiation Treatment with OK432 Can Prevent Radiation-induced Bone Marrow Death

Summary

The radioprotective effect of OK432, a Streptocuccus haemolyticus preparation, on bone marrow death was examined in mice. The LD₅₀ value was increased from 7·55 Gy in controls to 8·45 Gy in mice treated once with OK432 immediately after irradiation. Multiple administrations of the agent further elevated the LD₅₀ value to 9·56 Gy. The radioprotective effect was also apparent when multiple treatments were commenced as late as 72 h after irradiation.     

Protection against ionising radiation and synergism with thiols by zinc aspartate

Pre-treatment with zinc aspartate protected mice against the lethal effects of radiation and raised the LD50 from 8 Gy to 12.2 Gy. Zinc chloride and zinc sulphate were clearly less active. The radioprotective effect of zinc aspartate was equivalent to cysteamine and slightly inferior to S,2-aminoethylisothiourea (AET). Zinc aspartate displayed a similar therapeutic index to the thiols but could be applied at an earlier time before irradiation. Synergistic effects occurred with the combined administration of zinc aspartate and thiols. By giving zinc aspartate with cysteamine, the LD50 was increased to 13.25 Gy and, by combining it in the optimal protocol with AET, to 17.3 Gy. The radioprotection by zinc and its synergism with thiols is explained by the stabilisation of thiols through the formation of zinc complexes.     

Radioprotective effect of abana, a polyherbal drug following total body irradiation

Effects of 20 mg/kg body weight of abana (ABE) on radiation-induced sickness and mortality in mice exposed to 7 Gy to 12 Gy of gamma irradiation were studied. Treatment of mice with abana 1 h before irradiation delayed the onset of mortality and reduced the symptoms of radiation sickness when compared with the non-drug treated irradiated controls (double distilled water, DDW). Abana provided protection against both the gastrointestinal and haemopoietic deaths. However, animals of both the ABE+irradiation and DDW+irradiation groups did not survive up to 30 days post-irradiation beyond 11 Gy irradiation. The LD(50/30) was found to be 8.5 Gy for the DDW+irradiation group and 10.3 Gy for ABE+irradiation group. The administration of abana resulted in an increase in radiation tolerance by 1.8 Gy, and the dose modification factor (DMF) was found to be 1.2. The irradiation of animals resulted in a dose dependent elevation in lipid peroxidation, and a reduction in glutathione (GSH) concentration on day 31 post-irradiation. Treatment of mice with abana before irradiation caused a significant depletion in lipid peroxidation followed by a significant elevation in GSH concentration in the liver of mice at day 31 post-irradiation. Abana scavenged (*)OH, DPPH, ABTS(*+) and NO(*) in a concentration dependent manner in vitro. Our results indicate that the radioprotective activity of abana may be due to free radical scavenging and increased GSH level in irradiated mice.     

Protective effects of melatonin on gamma-ray induced intestinal damage

PURPOSE: To examine the protective effects of melatonin on intestinal damage induced by gamma-rays. MATERIALS AND METHODS: Six-week-old Slc:ICR male mice were used. Mice were given whole-body irradiation at various exposure doses (7-21 Gy) with (137)Cs gamma-rays (0.98 Gy/min). The mice were orally administered 1 ml of either 1% carboxymethyl cellulose sodium salt (CMC) or melatonin (1, 5, 10 or 20 mg/ml) freshly prepared as a uniform suspension in CMC before or after irradiation. The concentrations of plasma melatonin were determined by the radioimmunoassay (RIA) method. The mice were killed at 3.5 days after the exposure. The jejunum was removed, fixed in formalin and then stained with hematoxylin and eosin. The numbers of crypts per transverse circumference were counted using a microscope for 10 histological sections of each mouse. RESULTS: The intestinal damage caused by gamma-ray irradiation was prevented by melatonin correlating to dosage. The D(0) (slope of the dose-survival curve) value significantly (p < 0.05) increased from 1.55 +/- 0.19 (mean +/- SD) Gy to 1.98 +/- 0.16 Gy by orally administering 20 mg melatonin 30 min before irradiation. The radioprotective effect of melatonin continued for 6 h after the administration. CONCLUSIONS: Melatonin is judged to be a potential protector against intestinal damage associated with radiotherapy. Further experimental and clinical studies on this subject are needed to allow its use for radiotherapy.     

Radioprotective Effect of an Acute Non-specific Inflammation in Mice

Summary

Protection against 8·7 Gy whole-body γ-irradiation (lethal in 100 per cent of mice by 30 days) was observed in 90 per cent of mice bearing a one-day-old granuloma induced by polyacrylamide beads. When the inflammatory reaction was induced sooner or later a lower or null protection was obtained. A dose-effect relationship between the volume of injected beads and resulting radioprotection was established. The radioprotective effect depends only on the acute non-specific inflammation since hydrocortisone acetate injected into mice before the beads abolished this protection. This inflammatory pattern led to a dose reduction factor of 1·36 ± 0·08 (P < 0·05) for LD 50/30. A 90 per cent survival was observed in mice bearing a one-day-old granuloma when they were injected 1 h before 10 Gy with the granuloma acellular eluate (P < 0·02 compared to a 50 per cent survival observed with polyacrylamide beads alone). Substances with a molecular weight higher than 300 000 are involved in the synergistic radioprotective effect of the granuloma-eluate association.     

白藜芦醇对60Coγ射线照射小鼠氧化损伤的防护

目的研究白藜芦醇对60Coγ射线照射小鼠氧化损伤的防护作用。方法 30只♂ICR小鼠随机分成5组,正常对照组、照射对照组以及白藜芦醇低、中、高剂量(50、100、200 mg.kg-1)照射组,照射前3 d至照后第7天灌服给药,每天1次,共10次。除正常对照组外,所有小鼠60Coγ射线全身6 Gy辐照1次,照射后第7天小鼠取外周血和肝组织标本,测定血清和肝组织匀浆中超氧化物歧化酶(SOD)、谷胱苷肽过氧化物酶(GSH-Px)活性及丙二醛(MDA)含量。结果与正常对照组比较,照射对照组小鼠血清和肝组织匀浆中SOD和GSH-Px活性显著下降,MDA含量显著上升。与照射对照组比较,白藜芦醇50 mg.kg-1照射组小鼠血清和肝组织匀浆中SOD和GSH-Px活力有升高趋势,MDA含量有降低趋势;白藜芦醇100 mg.kg-1照射组小鼠血清和肝组织匀浆中SOD和GSH-Px活力显著升高,MDA含量有降低趋势;白藜芦醇200 mg·kg-1照射组小鼠血清和肝组织匀浆中SOD和GSH-Px活力显著升高,MDA含量显著降低。随着白藜芦醇给药剂量的增大,SOD和GSH-Px活力升高,MDA含量降低。结论白藜芦醇可以对60Coγ射线照射小鼠外周血和肝脏产生保护作用,防护效果与给药剂量相关,其作用机制可能与抗氧化损伤有关。     

Radiation-protective effectiveness of ATP and adenosine against high-energy protons

The radioprotective effect of ATP and adenosine was investigated on CBA and C57Bl mice hybrids F1 irradiated with 9 GeV protons. The prophylactic treatment of the animals with ATP at a dose of 350-700 mg/kg increased their survival to 63-80% for LD78-83/30 (7.5-8.0 Gy) and to 40% for LD96/30 (8.5 Gy). The administration of adenosine at a dose of 340 mg/kg, equimolar to 700 mg/kg ATP, increased their survival to 93-100% and 73%, respectively. It was found that ATP produced a favorable effect on the hemopoiesis of irradiated mice.     

c-ski对大鼠皮肤成纤维细胞抗辐射作用的影响

目的 研究原癌基因c—ski对大鼠皮肤成纤维细胞抗辐射作用的影响，并探讨其可能的机理。方法 采用Annexin—V—FITC—PI标记的方法。通过流式细胞仪检测2—8Gy的软X线照射对培养的大鼠皮肤成纤维细胞凋亡的影响；观察转染c—ski基因后细胞凋亡的变化；并采用Western blot检测c—ski对凋亡蛋白Bax、Bcl-2表达的影响。结果 软X线照射以剂量依赖的方式增加细胞凋亡，并且随着时间的延长进一步增加，大约在36h时达到峰值。转染c—ski基因使4Gy照射24h后的成纤维细胞凋亡率显著下降。转染c—ski基因48h后，Bax的表达和对照组差异无统计学意义，而Bcl-2的表达显著增加。结论 c—ski可降低成纤维细胞的辐射敏感性，促进Bcl-2的表达可能是其机理之一。     

Radioprotection in mice following oral delivery of amifostine nanoparticles

PURPOSE: Amifostine (Ethyol) is an approved cytoprotective agent prescribed to reduce certain side-effects in the chemotherapy of ovarian or non-small cell lung cancer, or in radiation treatment of head-and-neck cancer. The usefulness of this drug is further hampered, because it is not effective when given orally. The objective of this part of the project was to evaluate the radioprotective efficacy of orally active amifostine nanoparticles. MATERIALS AND METHODS: Radioprotective efficacy was evaluated by measuring the ability of the amifostine nanoparticles (equivalent to 500 mg/Kg) to inhibit whole-body gamma irradiation -induced injury in mice. All mice received acute whole-body gamma irradiation from a Cesium-137 source and the radioprotective efficacy of the formulation was determined by measuring 30-day survival at 9 Gy, bone marrow hemopoeitic progenitor cell survival at 9 Gy and 8 Gy, and intestinal crypt cell survival at 11 Gy. RESULTS: Thirty-day survival, hemopoietic progenitor cell survival, as well as the jejunal crypt cell survival were all significantly enhanced when the mice were treated orally with the amifostine nanoparticles 1 h prior to irradiation. CONCLUSIONS: These results clearly and unequivocally demonstrate that the amifostine nanoparticles developed in our laboratory provides significant protection from acute whole-body gamma irradiation injury in mice.     

西咪替丁对急性照射小鼠存活率及造血系统改变的影响

目的 观察西咪替丁对急性照射小鼠存活率及造血系统改变的影响.方法 采用137Cs γ射线全身照射小鼠,两次实验的照射剂量分别为6.0Gy和8.0Gy,剂量率均为1.01Gy/min.每次实验取健康雄性C57BL/6小鼠60只,按体重随机分为空白对照组?模型对照组?阳性药组(523)及33.3?100?300mg/kg西咪替丁组,每组10只.西咪替丁各剂量组于照射前6d灌胃给药,每天1次,照射后5h给药1次;阳性药组于照射前1d灌胃给药1次,照射后5h给药1次.检测8.0Gy照射后30d小鼠存活率,以及6.0Gy照射后30d小鼠外周血象?骨髓DNA含量和骨髓嗜多染红细胞微核率.结果8.0Gy照射后,模型对照组小鼠于第21天全部死亡,西咪替丁低?中?高剂量组30d存活率分别为50%?20%和30%;6.0Gy照射后第30天,与空白对照组比较,各照射组小鼠外周血白细胞明显降低(P<0.01),骨髓嗜多染红细胞微核率明显升高(P<0.05),骨髓DNA含量明显降低(P<0.05);与模型对照组比较,西咪替丁高剂量组外周血白细胞明显升高(P<0.01),西咪替丁各剂量组骨髓DNA含量明显升高(P<0.01,P<0.05),而骨髓嗜多染红细胞微核率明显降低(P<0.01,P<0.05)并趋于正常.结论 西咪替丁能提高急性照射小鼠30d存活率,且对其造血系统有较好的保护作用.     

富氢水对电离辐射引起胸腺细胞损伤的影响

目的 探讨富氢水对6 Gy照射小鼠胸腺细胞内活性氧水平、细胞凋亡及DNA损伤程度的影响。 方法 实验分为对照组、6 Gy照射组、6 Gy照射+富氢水组;对照组和6 Gy照射组小鼠照射前10 min灌胃正常饮用水0.5 ml,6 Gy照射+富氢水组小鼠灌富氢水0.5 ml,照射后连续灌胃,给予小鼠正常饮用水和富氢水7 d,于照射后4、7、15 d处死小鼠获取胸腺细胞。采用流式细胞术检测胸腺细胞内活性氧水平、凋亡细胞比例及磷酸化组蛋白H2AX（γ-H2AX）平均荧光强度。 结果 与对照组的小鼠比较,6 Gy照射组小鼠在照射后4、7、15 d胸腺细胞中的活性氧水平升高,早期凋亡细胞[AnnexinⅤ阳性、碘化丙啶（PI）阴性]和晚期凋亡细胞（AnnexinⅤ阳性、PI阳性）的细胞比例明显增加,γ-H2AX平均荧光强度增加。与6 Gy照射组小鼠相比,6 Gy照射+富氢水组小鼠的胸腺细胞中活性氧水平下降,早期凋亡和晚期凋亡的细胞比例降低,细胞内γ-H2AX平均荧光强度则是下降的,差异均具有统计学意义。 结论 富氢水可以有效减轻电离辐射引起的胸腺细胞损伤,为富氢水作为辐射损伤防护剂提供了实验依据。     

Chromosome protection by WR-2721 and MPG-single and combination treatments

The radioprotective action of thiol compounds 2-mercaptopropionylglycine (MPG) and S-2(aminopropylamino) ethyl phosphorothioic acid (WR-2721) was evaluated either alone or in combination on the bone marrow chromosomes of Swiss albino mice after 4.5 Gy of 60Co radiation. Single drug administration of WR-2721 at 300 mg/kg body weight resulted in a 50% reduction in the yield of aberrant cells at 24 hours post irradiation, while the other single drug doses were less effective. The combination of the two drugs increased the effect in the sense that 150 mg/kg WR-2721 with 20 mg/kg MPG gave equal protection as 300 mg/kg WR-2721 given alone. Moreover, on day 14, when WR-2721 produced an increase in the precent aberrant cells the above combination brought down the value to normal. It appears that MPG neutralizes to some extent the toxic effect of WR-2721, without impairing the protective efficiency.     

Modification of survival and hematopoiesis in mice by tocopherol injection following irradiation

The LD50/30 of CD-1 female mice increased from 6.6 Gy to 7.0 Gy when 2.5 mg of dl-alpha-tocopherol was injected immediately post irradiation. Increased survival was associated with increased numbers of hematopoietic colony forming units (CFU). Endogenous spleen colonies were found in greater numbers in the tocopherol-treated mice after irradiation. The vitamin, however, must be injected within five hours following irradiation to have this effect. The increased numbers of CFU in tocopherol-treated mice may be due to a stimulation of recovery or repair processes. Split-dose studies suggest that most repair of sublethal damage in hematopoietic stem cells take place within seven and nine hours following irradiation. Tocopherol injection appears to enhance the recovery manifested in the split-dose assay. There is also evidence that tocopherol-treatment caused an earlier onset of mitotic activity in CFU after irradiation. The increased number of spleen colonies in tocopherol-injected mice is not due to an altered CFU seeding efficiency associated with an altered spleen microenvironment. Tocopherol injection did not affect the shoulder of the stem cell survival curve using exogenous spleen colony assays of bone marrow-derived or spleen-derived hematopoietic stem cells. There appears to be a decrease in Do in the higher dose region (4.3 Gy) of the bone marrow exogenous SCA survival curves for the vehicle-injected and the non-injected groups; however, the tocopherol-injected group showed no evidence of change in radiosensitivity up to the highest dose used (5.0 Gy). Data may be interpreted to suggest that the therapeutic effect of tocopherol may involve repair of hematopoietic stem cell damage in the higher dose range of bone marrow syndrome.     

A radioprotective effect of calcium chloride in combination with cystamine, mexamine, and hypoxemic hypoxia in mice.

A mild protective effect of a solution of CaCl2 (3.21 g%) injected in a volume of 0.2 ml i.p. 30 minutes prior to irradiation was demonstrated in experiments with male mice in the strain C 57 B1/10. The pre-irradiation administration of CaCl2 increased the LD50/30 by approximately 60R as compared with control animals, to which an isoosmotic NaCl solution was injected. A more pronounced decrease of the post-irradiation mortality of the animals was reached by combined administration of CaCl2 with chemical protectors- cystamine or mexamine administered in relatively low s.c. doses, as well as by a combination of CaCl2 with the protective action of hypoxemic hypoxia. Under the conditions of combined protection, the administration of CaCl2 increased LD50/30 by approximately 100 to 130R. A higher rate of formation of endogenous spleen hematopoietic colonies was observed in the animals protected by calcium. Possible mechanisms of the radioprotective effect of calcium on the level of the hematopoietic stem cells are discussed.     

Radioprotection in mice following oral delivery of amifostine nanoparticles

Purpose: Amifostine (Ethyol^®) is an approved cytoprotective agent prescribed to reduce certain side-effects in the chemotherapy of ovarian or non-small cell lung cancer, or in radiation treatment of head-and-neck cancer. The usefulness of this drug is further hampered, because it is not effective when given orally. The objective of this part of the project was to evaluate the radioprotective efficacy of orally active amifostine nanoparticles.

Materials and methods: Radioprotective efficacy was evaluated by measuring the ability of the amifostine nanoparticles (equivalent to 500?mg/Kg) to inhibit whole-body gamma irradiation -induced injury in mice. All mice received acute whole-body gamma irradiation from a Cesium-137 source and the radioprotective efficacy of the formulation was determined by measuring 30-day survival at 9?Gy, bone marrow hemopoeitic progenitor cell survival at 9?Gy and 8?Gy, and intestinal crypt cell survival at 11?Gy.

Results: Thirty-day survival, hemopoietic progenitor cell survival, as well as the jejunal crypt cell survival were all significantly enhanced when the mice were treated orally with the amifostine nanoparticles 1?h prior to irradiation.

Conclusions: These results clearly and unequivocally demonstrate that the amifostine nanoparticles developed in our laboratory provides significant protection from acute whole-body gamma irradiation injury in mice.     

Protective effects of melatonin on γ-ray induced intestinal damage

Purpose: To examine the protective effects of melatonin on intestinal damage induced by γ-rays.

Materials and methods: Six-week-old Slc:ICR male mice were used. Mice were given whole-body irradiation at various exposure doses (7–21 Gy) with ¹³⁷Cs γ-rays (0.98 Gy/min). The mice were orally administered 1 ml of either 1% carboxymethyl cellulose sodium salt (CMC) or melatonin (1, 5, 10 or 20 mg/ml) freshly prepared as a uniform suspension in CMC before or after irradiation. The concentrations of plasma melatonin were determined by the radioimmunoassay (RIA) method. The mice were killed at 3.5 days after the exposure. The jejunum was removed, fixed in formalin and then stained with hematoxylin and eosin. The numbers of crypts per transverse circumference were counted using a microscope for 10 histological sections of each mouse.

Results: The intestinal damage caused by γ-ray irradiation was prevented by melatonin correlating to dosage. The D₀ (slope of the dose-survival curve) value significantly (p < 0.05) increased from 1.55 ± 0.19 (mean ± SD) Gy to 1.98 ± 0.16 Gy by orally administering 20 mg melatonin 30 min before irradiation. The radioprotective effect of melatonin continued for 6 h after the administration.

Conclusions: Melatonin is judged to be a potential protector against intestinal damage associated with radiotherapy. Further experimental and clinical studies on this subject are needed to allow its use for radiotherapy.     

卡拉胶寡糖对放射损伤的防护作用

目的 探讨卡拉胶寡糖对受6．0Gy X射线照射小鼠的辐射防护作用。方法采用6MV X直线加速器一次全身照射BALB／c小鼠，3个卡拉胶寡糖组照射前连续14d和照射后继续给药7d。观察小鼠30d存活率、外周血白细胞总数、胸腺指数和脾脏指数、脾脏NK细胞活性和腹腔巨噬细胞吞噬功能。结果卡拉胶寡糖组小鼠30d存活率比照射对照组提高75％～90％；而且卡拉胶寡糖能加速小鼠外周血白细胞的恢复，明显提高胸腺指数和脾脏指数，激活脾脏NK细胞的杀伤活性，增强巨噬细胞吞噬功能。结论卡拉胶寡糖对受照射小鼠有明显的辐射防护作用。     

抗辐射药物2,2-二甲基四氢噻唑及胱胺有机酸盐的研究

为了改善２，２－二甲基四氢噻唑盐酸盐（ＤＭＴＤ）的理化性质及提高辐射防护效价。方法合成了ＤＭＴＤ和胱胺的各种有机酸盐，对９．０３Ｇｙ６０Ｃｏγ射线一次全身照射的小鼠，照前给药，评价它们的辐射防护效果。结果大部分化合物具有不同程度的防护效果，其中ＤＭＴＤ酒石酸盐２５０ｍｇ／ｋｇ，照前一小时腹腔注射，存活率比单独照射对照组提高４０％；胱胺琥珀酸盐２５０ｍｇ／ｋｇ，照前１５分钟腹腔注射，存活率净增加７７．５％。结论胱胺琥珀酸盐的辐射防护效果显著，值得进一步研究     

Use of the adaptive classifier for determination of LD50 in the acute radiation disease

In experiments on female Wistar rats a new method for the determination of LD50 is demonstrated and compared with the classical probit method using the same experimental animals. The method is applicable for the computation of LD50 and analogical quantities in man, too. The method is based on the application of an adaptive logical circuit (ADALINE) trained for the dichotomous prognostic classification of irradiated individuals quod vitam according to a set of clinical and laboratory indicators registered on the third day after irradiation. After the training procedure has been finished, the classifier makes possible an individual prognosis of survival or death. The analogue output signal according to which the classification is performed changes continually from negative to positive values and exhibits S-shaped relation to the radiation dose. Its zero value corresponds to the position of LD50 on the abscissa. For the construction of the searched function, i.e. for the optimum approximation of experimentally obtained values of the output signal, the method of the changeable polyhedron was applied belonging to the optimalization numerical methods used in the regulation technics. The computed value of LD50 was 7.80 Gy in rats very closely corresponding with the value 7.61 Gy determined by means of the classical probit method.     

凉血活血颗粒对急性放射病-肺损伤的保护作用

目的 研究凉血活血颗粒对急性放射病-肺损伤小鼠模型的保护作用.方法 采用5.5Gy60Coγ射线一次性全身照射小鼠,制成急性放射病-肺损伤动物模型.小鼠在照前45min至照后30d,给药组以不同剂量的凉血活血颗粒灌胃给药,正常对照组及模型组用等体积蒸馏水灌胃,均为1次/d.观察照后小鼠的一般情况,照后10 d每组抽取6...