Current Status of Targeted Radioprotection and Radiation Injury Mitigation and Treatment Agents: A Critical Review of the Literature.

As more cancer patients survive their disease, concerns about radiation therapy-induced side effects have increased. The concept of radioprotection and radiation injury mitigation and treatment offers the possibility to enhance the therapeutic ratio of radiation therapy by limiting radiation therapy-induced normal tissue injury without compromising its antitumor effect. Advances in the understanding of the underlying mechanisms of radiation toxicity have stimulated radiation oncologists to target these pathways across different organ systems. These generalized radiation injury mechanisms include production of free radicals such as superoxides, activation of inflammatory pathways, and vascular endothelial dysfunction leading to tissue hypoxia. There is a significant body of literature evaluating the effectiveness of various treatments in preventing, mitigating, or treating radiation-induced normal tissue injury. Whereas some reviews have focused on a specific disease site or agent, this critical review focuses on a mechanistic classification of activity and assesses multiple agents across different disease sites. The classification of agents used herein further offers a useful framework to organize the multitude of treatments that have been studied. Many commonly available treatments have demonstrated benefit in prevention, mitigation, and/or treatment of radiation toxicity and warrant further investigation. These drug-based approaches to radioprotection and radiation injury mitigation and treatment represent an important method of making radiation therapy safer.

[Sun protection factor 50+ : Pro and contra]. / Lichtschutzfaktor 50+ : Pro und Kontra.

The use of sunscreens with sun protection factors beyond 50 is controversial. In order to avoid misleading the consumer, several countries have already decided not to declare SPF beyond 50 on sunscreen products. Arguments against high SPF include the following: the risk of imbalanced protection, which could increase the risk of damage caused by longer-wave ultraviolet radiation; imparting a false sense of safety, which could lead to the extension of sun exposure times; health risks from higher concentrations of filter substances; and the only marginally higher blockade provided by high SPF sunscreens. On the other hand, it has been realized that the functional SPF of sunscreens remains far behind the declared SPF in the practical application and, therefore, the use of higher SPF in sensitive individuals and during strong UV exposure could make sense.

[The classification of radiation protective agents as the reflection of the present state and development perspective, of current radiation pharmacology].

Pharmacological drugs which can reduce the radiation damage to the organism when applied in the nearest time before or after exposure to radiation can be referred to as radiation protective agents. The classification of radiation protective agents, which has been well established to date, is a reflection of the history of the formation and current state of radiation pharmacology: the most significant historical landmarks in the screening of radiation protective agents among different groups of pharmaceutical preparations and the formation of the theoretical knowledge about the mechanism for their radiation protective effects. It consists of: (1) radioprotectors which realize their radiation protective effect at the physical, chemical and biochemical levels in the course of the energy absorption of ionizing radiation via partial neutralization of the "oxygen effect" as a radiobiological phenomenon; (2) radiomitigators, which realize their effect at the system level by accelerating the post-radiation recovery of radiosensitive tissues through an activation of proinflammatory signaling pathways and an increase of secretion of hematopoietic growth factors, are used in the early period after exposure to radiation prior to the development of clinical manifestations of acute radiation damage as drugs of emergency and early treatment for radiation injuries; (3) radiomodulators--pharmaceutical drugs and food nutritional supplements which elevate the resistance of the organism to adverse environmental factors, including mutagenic effects of exposure to low-dose ionizing radiation, by means of modulating the gene expression through "substrate" maintenance of adaptive changes resulting in an increased antioxidant protection of the organism; (4) pharmaceutical drugs to protect against the incorporation of technogenic radionu- clides into the organism; (5) pharmaceutical drugs to prevent (arrest) manifestations of the primary response to radiation.

[Actual problems of searching and studying radiation countermeasures].

The state of radiation counterdrug elaboration has been analyzed. The main criterion of estimation is how various possible radiation incidents are provided with radiation countermeasures. The latter are differentiated in 3 principal groups: radioprotectors, radiomodificators (these are able to have a positive effect when administered preliminary, before the exposure, or provide a delayed nonspecific protection after the exposure--urgent therapy) and hemopoietic growth factors demanding course administration. It should be underlined that the list ofofficinal radiation countermeasures is rather short. The most dynamic now are investigations aimed at developing a home preparation of recombinant human interleukine-1beta named betaleukine, and the preparation CBLB502, a modified microbe polypeptide elaborated in the USA. Also elaborated is a scheme of emergency exposure treatment. It includes urgent administration of the cytokine combination (betaleukine and thrombopoietin) with subsequent supportive therapy and a hemopoietic growth factors course. In the case of medical radiation- and chemotherapy the preparations betaleukine and thiol compound amifostine are used rather seldom. Official countermeasures for protection against low dose rate prolonged exposure are still absent. The problem of an indicator/marker of the radioresistance induced by a radioprotector or radiomodificator still remains unsolved. Reliable indicators/markers are needed to provide the 2nd stage of clinical trials of radioprotectors/modificators.

Animal models and medical countermeasures development for radiation-induced lung damage: report from an NIAID Workshop.

Since 9/11, there have been concerns that terrorists may detonate a radiological or nuclear device in an American city. Aside from several decorporation and blocking agents for use against internal radionuclide contamination, there are currently no medications within the Strategic National Stockpile that are approved to treat the immediate or delayed complications resulting from accidental exposure to radiation. Although the majority of research attention has focused on developing countermeasures that target the bone marrow and gastrointestinal tract, since they represent the most acutely radiosensitive organs, individuals who survive early radiation syndromes will likely suffer late effects in the months that follow. Of particular concern are the delayed effects seen in the lung that play a major role in late mortality seen in radiation-exposed patients and accident victims. To address these concerns, the National Institute of Allergy and Infectious Diseases convened a workshop to discuss pulmonary model development, mechanisms of radiation-induced lung injury, targets for medical countermeasures development, and end points to evaluate treatment efficacy. Other topics covered included guidance on the challenges of developing and licensing drugs and treatments specific to a radiation lung damage indication. This report reviews the data presented, as well as key points from the ensuing discussion.

[Radiation protectors within the radiation safety system for extended duration exploration missions].

Radiation environment in extended duration exploration missions is scrutinized in the context of the probability of the risks of deterministic and stochastic effects of radiation. Though the probability of severe radiation damage due to solar flare is very low, nonetheless it is requisite that the crew must be provided with appropriate, including pharmacological safeguards. The current nomenclature of radiation protectors composes short-term agents against acute radiation damage. Among the others, preparation B-190 is distinguished by particularly high effectiveness and universal action, and good tolerance even when organism is exposed to the extreme factors of space flight Regimen of B-290 therapy alone and with combination with aminothiol preparations have been developed to render treatment following multiple solar events. Effectiveness of radioprotectors can be increased substantially by local shielding of the abdomen and pelvis. The most promising nonspecific stimulators of total resistance of organism are riboxin (inosin) and combined preparation aminotetravit as well as vitamins tocopherol and retinol. Therapy combining B-190 with riboxin and aminotetravit is also under discussion. Cytokine neipogen is also viewed as a candidate agent for early therapy. Concern is raised about possible development of chronic oxidative stress in long-duration exploration missions. Highlighted is the significance of adequate nutrition supplemented with fresh vegetables as a source of the most valuable bioflavonoids. Antioxidants L-selenomethionine and melatonin proved their effectiveness against heavy nuclei of galactic radiation. An open issue is how to make natural antioxidants beneficial to oxidative stress control and attenuation of low-intensity galactic radiation.

[Modern possibilities of medicinal prophylaxis and early therapy of radiation injuries].

Medical antiradiation protection is one of the key factors determining fighting capacity of armies. The basis of medical protection in the countries of the NATO is made with the preparations used up to an irradiation (radioprotector WR-2721) and at the first time after radiating influence. The Russian system of antiradiation protection includes radioprotectors, drugs for prophylaxis and treatment of syndrome of primary reaction to an irradiation, means of early therapy of radiation injure, preparations for sorption and elimination of radionuclides, got in an organism.

[Current problems of chemical radiation protection of organisms]. / Sovremennye problemy protivoluchevoi khimicheskoi zashchity organizmov.

The classification has been proposed for antiradiation protective agents which are divided into four groups: I. Radioprotectors; II. Adaptogens; III. Absorbents; IV. The means of Rehabilitations. Radioprotectors in turn are subdivided into myelo-, entero- and cerebroprotectors. Adaptogens act as stimulators of radioresistance. These are natural protectors which are perspective for chemical protection under low-level ionizing irradiation. Natural protectors influence regulatory systems of exposed organisms, mobilize endogenous background of radioresistance (EBR), immunity and intensivity the total non-specific resistance of organism (TNRO). Natural protectors (extracted from cells, plants, animals) are low- or nontoxic and can be used with food. Absorbents, the means of protection from internal irradiation, are subdivided into the drugs which prevents incorporation of radioiodine by thyroid gland and absorption of radionuclides (137Cs, 90Sr, 239Pu, 241Am) in the digestive tract. The main features which distinguish radioprotective drugs of different mechanisms on human organisms are presented. The main which different programs of reability on invalids-Chernobyl.

[Classification of radiation protective agents as a basis of modern radiation pharmacology]. / Klassifikatsiia sredstv profilaktiki luchevykh porazhenii kak formirovanie kontseptual'nogo bazisa sovremennoi radiatsionnoi farmakologii.

The consistency of the classification of prophylactic antiradiation drugs have been given consideration as history of their discovery, theory of the radioprotection mechanisms and their use in applied medicine. To prophylactic antiradiation drugs can be related to the drugs of having capable of decreasing radiation injuries burden while administrated before or immediately after radiation. The ones consists of radioprotectors with short-term of long-term action, drugs stimulating radioresistance, the ones suppressing symptoms of primary radiation reaction, the ones of early detoxication, the ones for absorbtion and elimination of radionuclides from an organism.

Space radiation concerns for manned exploration.

Spaceflight exposes astronaut crews to natural ionizing radiation. To date, exposures in manned spaceflight have been well below the career limits recommended to NASA by the National Council of Radiation Protection and Measurements (NCRP). This will not be the case for long-duration exploratory class missions. Additionally. International Space Station (ISS) crews will receive higher doses than earlier flight crews. Uncertainties in our understanding of long-term bioeffects, as well as updated analyses of the Hiroshima. Nagasaki and Chernobyl tumorigenesis data, have prompted the NCRP to recommend further reductions by 30-50% for career dose limit guidelines. Intelligent spacecraft design and material selection can provide a shielding strategy capable of maintaining crew exposures within recommended guidelines. Current studies on newer radioprotectant compounds may find combinations of agents which further diminish the risk of radiation-induced bioeffects to the crew.

[A new classification of prophylactic antiradiation agents]. / Novaia klassifikatsiia profilakticheskikh protivoluchevykh sredtsv.

A new classification has been proposed for prophylactic antiradiation drugs, which are divided into three groups: radioprotectors, stimulators of radioresistance and the means of protection from internal irradiation. Depending on organs (systems) for the protection of which they are designed, radioprotectors in their turn are subdivided into myelo-, entero- and cerebroprotectors; stimulators of radioresistance (depending on the optimal regimens of their use to develop a higher resistance of the organism) are subdivided into drugs that are effective in single and repeated (course) use; the means of protection from internal irradiation are subdivided into the drugs that prevent incorporation of radioiodine by the thyroid gland, and into the drugs preventing absorption of radionuclides in the digestive tract. The main features that distinguish radioprotectors from stimulators of radioresistance are presented. The former are characterized by such properties as exhibiting the effect exquisitely when prophylactically administered in doses close to those of maximal tolerance, greatest effect against shortterm (pulse) irradiation, rapid development and short duration of the radioprotective action period, reduction in the effect in repeated use, etc. Stimulators of radioresistance rank below radioprotectors in their effect against short-term irradiation, however, unlike the latter, they exhibit their protective effect against a long-term (low dose rate) exposure as well under the conditions of both prophylactic and therapeutic use; their radioprotective action is more prolonged, they are distinguished for their low toxicity and lower the risk of delayed sequelae of irradiation, etc. Examples of the most typical members of each group of prophylactic antiradiation drugs are cited, data are presented which characterize their radioprotective activity, the role and place in the system of antiradiation protection of troops and population.

[Photoprotection by drugs]. / La photoprotection médicamenteuse.

Medicinal photoprotection is indicated in photosensitive skin diseases and photodermatoses. Vitamin PP and para-aminobenzoic acid can be tried in benign estival polymorphous light eruptions. Carotinoids are efficient in erythropoietic protoporphyria and useful in idiopathic polymorphous light eruptions and in remanent photosensitization. Immunodepressants may be used against remanent photosensitization.

Radioprotection of DNA by biochemical mechanisms.

The title of this presentation should be understood as having two facets: the preservation of genetic information and function by protecting the DNA from the deleterious effects of radiation by reducing the degree of damage, is one important task. Yet another, which may be as important, is the utilization of biochemical entities whose function is to repair damages which have already been formed in DNA, thus enhancing the protection of living cells.

[The mechanisms of the action of radioprotectors of different chemical classes in the intestinal syndrome]. / O nekotorykh mekhanizmakh deistviia radioprotektorov raznykh khimicheskikh klassov pri kishechnom sindrome.

Some thiazole, triazole, thiadiazine, and heterylalkane derivatives increased the lifespan of gamma-irradiated (9-14 Gy) mice up to 6-22 days (as opposed to 4.1 days in the irradiated control). The efficacy of chemical agents within the dose range mentioned above was mainly associated with protecting intestinal epithelium stem cells the number of which was 4-9 times as large as that of nontreated animals. There was a moderate (40-50%) decrease in oxygen consumption under the effect of the most active radioprotectors.

Chemical protection against ionizing radiation.

Some of the problems related to chemical protection against ionizing radiation are discussed with emphasis on: definition, classification, degree of protection, mechanisms of action and toxicity. Results on the biological response modifyers (BRMs) and on the combination of nontoxic (i.e. low) doses of sulphydryl radioprotectors and BRMs are presented.