Radioprotective properties of oxolinic acid

Oxolinic acid was shown to produce a radioprotective effect on mice and a therapeutic radioprotective action on rats and hamsters. As to radioprotective efficiency, oxolinic acid is inferior to such known sulfur-containing agents as indolylalkylamines and alpha-adrenomimetics. But oxolinic acid has an important advantage over them, that is, the increase in radioresistance it induces persists for several hours. The radioprotective effectiveness of oxolinic acid prompts that it is expedient to search for new radioprotective preparations among specific inhibitors of DNA polymerase of replicative synthesis.     

Characteristics of the role of the hydroxyl group in serotonin in the pharmacological and antiradiation effect of serotonin

It was shown that omega-hydroxylation of O-alkyl serotonin derivatives can slightly improve the radioprotective and pharmacological properties of these substances but fails to remove completely the unfavourable action of O-alkylation of serotonin. There is a close correlation between the radioprotective effect of 5-oxyalkoxytryptamines and their action on blood supply of mouse spleen. The introduction of the alkoxy-group or the tertiary amino-group into omega-position removes the radioprotective effect of 5-alkoxytryptamines.     

Radioprotective action of catecholamines on a Chinese hamster fibroblast culture

The radioprotective ability of adrenaline, noradrenaline and isoproterenol in various concentrations has been studied in experiments on cultured Chinese hamster fibroblasts in vitro. Radioprotective effect of isoproterenol is pronounced at 10(-8)M concentration; adrenaline and especially noradrenaline are effective at higher concentrations. The antagonist of beta-adrenergic receptors propranolol blocks the radioprotective effect of catecholamines on cells. The beta-adrenergic mechanism of catecholamines radioprotective action on the mammals cells is under discussion.     

Radioprotective effect of nucleosides and nucleotides and the mechanism of action of adenosine

Adenosine and a majority of adenine mononucleotides have a radioprotective action; adenine and 2'-deoxyadenosine have no radioprotective effect, and that of 3',5'-cAMP only approaches the detectable level. Ribo- and deoxyribonucleosides and nucleotides of guanine, uracil, thymine, and cytosine have no protective action. Dipyridamole increases and alkylxanthines block the radioprotective effect of adenosine. So it follows that the radioprotective effect is realized via A-receptors of the plasmatic membrane external surface.     

Effect of agents for the chemical prevention of radiation sickness on the cyclic nucleotide content in the bone marrow of mice

The effect of different chemical compounds on the cAMP/cGMP ratio in the bone marrow of mice and radioresistance of animals has been studied. It has been shown that all compounds possessing radioprotective properties give rise to the cAMP/cGMP ratio in the bone marrow of mice. No changes in cAMP and cGMP level were noted after the administration of nonradioprotective substances. The maximal radioprotective effect coincide in time with the largest increase of the cAMP/cGMP ratio. The injection of radioprotectors at different doses demonstrate clearly that only at radioprotective doses the increase in the cAMP/cGMP ratio takes place. The administration of some substances 2, 15 and 60 min after the irradiation of mice shows that the radioprotective effect, though modest, was evident only in one case of elevated cAMP/cGMP ratio (the injection of 2-Mercaptoethylamine 2 min after the irradiation). Evident radioprotective effect occurs at the cAMP/cGMP ratio of about 170-200%; the ratio of about 130-140% corresponds to small radioprotection.     

Optimization of the composition of the radioprotective complex APAETP+mexamine and analysis of its action

The method of mathematical theory of experiment was used to find optimum variants of the radioprotective complex APAETP + mexamine. The character of their pharmacological interaction, depending on their dose ratio, was determined. It is suggested that it is conditioned by the specific role of different mechanisms involved in the radioprotective effect.     

The antiradiation activity and mechanism of action of dimethylaminodithiazines

A new group of radioprotective agents, dimethylaminodithiazines, was discovered. The agents are effective when used in relatively small amounts and exert a radioprotective effect rapidly with both intraperitoneal and per os injections. The role of inhibition of oxidative processes and DNA biosynthesis in the mechanism of radioprotective action of dimethylaminodithiazines is discussed.     

Radioprotective properties of indralin combined with cystamine and mexamine

The radioprotective properties of indralin when it is used in combination with cystamine and mexamine are studied in inbred mice and rats. The mice and rats are irradiated with γ rays emitted by ⁶⁰Co at doses of 9.0 and 9.5 Gy, respectively. A combined parenteral administration of indralin and cystamine in mice at doses of 25 mg/kg each is revealed to potentiate the radioprotective properties of indralin up to a level close to the ED₅₀ effect, while the separate application of these drugs in doses of 25 mg/kg each has no or a very weak radioprotective effect. Indralin (50 mg/kg) and mexamine (12 mg/kg) injected intraperitoneally in rats are found to almost completely eliminate the animal mortality caused by gastrointestinal acute radiation syndrome; the mortality in the control radiation group reaches 60% on the seventh day after the animals have been exposed to radiation at a dose of 9.5 Gy. However, if bone-marrow acute radiation syndrome develops under the above condition of super-lethal dose, the radioprotectors have a low radioprotective effect. Under the this condition, the combined application of indralin and mexamine in the same doses has 50% of radioprotective effect reached by applying these radioprotectors separately in double doses.     

Characterization of the amino acids essential for the photo- and radioprotective effects of a Bowman-Birk protease inhibitor-derived nonapeptide

The Bowman-Birk protease inhibitor has been reported to exert photo- and radioprotective activity. This effect was assigned to a cyclic nonapeptide sequence which is known to contain the amino acids responsible for the anti-chymotryptic activity of the BBI. The present study indicated that linearization of the nonapeptide resulted in a significant loss of anti-proteolytic activity, whereas the photo- and radioprotective capacity persisted. Substitution of the amino acids Leu or Ser of the nonapeptide, essential for the anti-proteolytic activity, with different amino acids, indicated that rather the hydrophobic features of the amino acids in this position than charge are critical to retain the photo- and radioprotective effect. These results suggest the existence of a bifunctional peptide sequence with anti-proteolytic and photo-/radioprotective capacity. However, the lack of correlation between the photo-/radioprotective activity and the anti-proteolytic activity within the peptides generated by modification of the linear nonapeptide argues for the existence of two closely colocalized domains within the nonapeptide responsible for photo-/radioprotection and protease inhibition.     

Mechanism of the radioprotective effect of cysteamine

The radioprotective effect of cysteamine combined with the modification of the chromatin state by sodium butyrate has been studied using V-79 and CHEL lines of Chinese hamster cells and HeLa cells. Sodium butyrate enhances the chromatin sensitivity to nucleases and removes the radioprotective effect of cysteamine as measured by the yield of cells with chromosome aberrations. As is indicated by changes in the intensity of fluorescence of the DNA-ethidium bromide complex, measured by laser flow cytometry, the protective agent decreases the binding of the dye with both irradiated and nonirradiated DNA whereas ionizing radiation and sodium butyrate increase thereof. It is concluded that the radioprotective effect of cysteamine depends in its ability to reduce the susceptibility of DNA to nucleases.     

Mechanism of the radioprotective effect of catecholamine receptor agonists. Inclusion in the radioprotective effect of different subtypes of beta-adrenoreceptors

Isoproterenol of ED50 = 0.16 mumol/kg is highly effective in protecting mice against ionizing radiation and has the high therapeutical index. There are three new indications that isoproterenol exerts its radioprotective action via beta-adrenoceptors. They are: the effect of isoproterenol is prevented by three additional beta-adrenoceptor antagonists, the isoproterenol effect is reproduced by the seven studied beta-adrenoceptor agonists of different chemical structure, and with chemical analogs which fail to stimulate beta-adrenoceptors the radioprotective effect is absent. Both beta 1 and beta 2 adrenoceptor agonists are protective agents. Mechanisms of the radioprotective action are discussed.     

Effect of hyperthermia on the radioprotective action of cysteamine and isoproterenol

Heating of mouse bone marrow cells up to 42 degrees C was shown to increase their radiosensitivity (DMF = 0.80 +/- 0.12). At this temperature, the radioprotective efficiency of cysteamine was lost completely (DMF = 0.78 +/- 0.09), and radioprotective activity of d,l-isoproterenol significantly decreased (DMF declined from 2.41 +/- 0.23 to 1.67 +/- 0.16). It is assumed that the radioprotective effect of cysteamine on mammalian cells is associated with the processes of the postirradiation DNA repair for just these processes are inhibited by heating. The mechanism of action of a beta-agonist of isoproterenol is perhaps only partially associated with DNA repair.     

Radiosensitivity during the irradiation of animals in an altered gaseous environment. A comparative study on mice and rats of the radiation-protective effect of oxygen-deficient gas mixtures

The radioprotective effect of gas hypoxic mixtures containing 5, 7, 8, 10 and 15% of oxygen on mice and rats was comparatively studied. The dependence of DMF upon oxygen concentration in the mixture was approximated by a hyperbolic function similar to the dependence of the radiomodifying effect of circulatory hypoxia caused by radioprotective agents of the indolylalkylamine series.     

Shigella antigens in early pathogenetic therapy of experimental acute radiation sickness

In experiments on gamma-irradiated hamsters it is shown that antigens, obtained from Sh. flexneri and sonnei by the sparing method, have a radioprotective therapeutic action. The antigens exhibit the immunostimulating activity which is perhaps one of the aspects of the mechanism involved in the formation of resistance to infectious complications in irradiated animals and of the favourable radioprotective effect.     

The role of endogenous glutathione in the action of sulfur-containing radio-protectors

In experiments on Ehrlich ascite tumor cells, the dependence of the radioprotective effect of beta-mercaptoethylamine and beta-mercaptopropionylglycine on the initial level of endogenous glutathione was studied. A varying degree of N-ethylmaleimide induced decrease of SH-glutathione content in the cells led to either easing or elimination of the radioprotective effect of the agents under study.     

Chemical protection against genetic effect of radiation in male mice

A study was made of the protective effect of some radioprotective agents against dominant lethal mutations (DLM) in postspermatogonial stages and reciprocal translocations (RT) in spermatogonia induced by gamma-radiation. Among the radioprotective agents used, cystaphos, a combination of cystamine and 5-MOT and a mixture of 6 components proved to be most effective against DLM, and cystaphos, gammaphos and cystamine combined with 5-MOT proved effective against RT. The degree of radioprotective efficacy was relatively low. The efficacy of cystamine in protecting against RT was higher with exposure of gonocytes of 18.5-day embryos than spermatogonia of pubertal animals. The degree of the radioprotective effect varied depending on the stage of spermatogenesis, and, in all cases, it was lower than that observed in studies of protection against lethal effects of ionizing radiation.     

Changes in the therapeutic spectrum with respect to the pharmacological and radioprotective activity after O-alkylation of serotonin and 5(2-hydroxyethoxytryptamine)

In experiments with mongrel mice, a study was made of the pharmacological activity of serotonin and its O-alkyl derivatives. It was estimated by the two indices, that is, the radioprotective properties and the influence on a local blood channel in the spleen, the modifying effect of the agents' toxicity being estimated as well. As an O-alkyl group of 5-alkoxytryptamines was elongated from one to three carbon atoms and the toxicity of the substances increased, their radioprotective effect decreased more readily than their effect on the local blood channel. The shortening of the range of the therapeutic action of the agents under study, with regard to the two pharmacological indices mentioned above, the alkyl group being lengthened, followed a logarithmic function which was more pronounced in relation to the radioprotective index (cos alpha 1/cos alpha 2 = 1.58).     

Mechanism of the radioprotective effect of catecholamine receptor agonists. Inclusion in the radioprotective effect of both subtypes of alpha-adrenoreceptors

alpha-Adrenoceptor agonists of both main groups, i. e. arylalkylamines and imidazolines, have a pronounced radioprotective effect. Their chemical analogs, which fail to stimulate alpha-adrenoceptors, do not protect mice. The effect of phenylephrine, adrenaline, and noradrenaline comes into play via alpha 1-adrenoceptors and that of clonidine, via alpha 2-adrenoceptors and also via alpha 1-adrenoceptors. Adrenoceptor agonists can probably manifest their radioprotective action via both subtypes of alpha-adrenoceptors. Possible intracellular mechanisms of the radioprotective action are discussed.     

Comparative study of the biological properties of various bacterial polysaccharides

It was shown that different polysaccharides markedly vary in their toxicity, exert a radioprotective effect when administered both 24 h and 1-4 h before irradiation, enhance and prolong the radioprotective action of S-containing radioprotective agents, and inhibit DNA synthesis in bone marrow which, in all appearance, plays a certain role in the mechanism of their radioprotective action.     

Comparative characteristics of the modification of radiosensitivity of mice and rats by a hypoxic mixture

A comparative study was made of changes in radiosensitivity of mice and rats given hypoxic mixtures (GHM) containing 6 to 15% of oxygen. The radioprotective effect of the GHM was more pronounced in mice than rats. The dependence of the radioprotective effect of the GHM on the oxygen content was well approximated by the equations: (Formula: see text). In experiments on rats, the oxygen content of 13.8% was shown to be a threshold the exceeding of which removed the modifying effect of the GHM.