INTENSITY OF OXIDATIVE PROCESSES IN BLOOD AND LEVEL OF APOPTOSIS IN BLOOD LYMPHOCYTES IN RADIOLOGISTS/X-RAY TECHNOLOGIES EXPOSED TO SMALL DOSES OF IONIZING RADIATION. / ІНТЕНСИВНІСТЬ ОКИСНИХ ПРОЦЕСІВ В КРОВІ ТА РІВЕНЬ АПОПТОЗУ В ЛІМФОЦИТАХ КРОВІ У РАДІОЛОГІВ/РЕНТГЕНОЛОГІВ, ЯКІ ЗАЗНАЮТЬ ВПЛИВУ МАЛИХ ДОЗ ІОНІЗУЮЧОГО ВИПРОМІНЮВАННЯ.

OBJECTIVE: to determine the presence of changes in peripheral blood parameters, characterizing its redox state, and the level of apoptosis of lymphocyte in radiologists/x-ray technologies who, due to their official duties, are exposed to small doses of ionizing radiation. OBJECT AND METHODS: The work was performed on blood samples of 45 professionals radiologists/x-ray technologies and 52 conventionally healthy individuals (control group). The content of malondialdehyde and sulfhydryl groups of proteins and peptides (-SH) in blood plasma was determined; catalase enzyme activity and the ratio of pro-antioxidant processes in hemolysates, the level of superoxide anion-radical (О2-) generation, the total production offree radical compounds (reactive forms of oxygen and nitrogen) and the level of apoptosis of peripheral blood lymphocytes (PBL). RESULTS: The content of malondialdehyde in the blood of professionals was increased by 1.49 times and the contentof -SH was decreased by 1.67 times compared to conventionally healthy individuals. An increase in the level of О2-production by 1.56 times was observed for PBL. The obtained results indicate a shift in the ratio between antioxidant and pro-oxidant processes towards the latter, which is confirmed by a 1.49-fold increase of this index. The levelfor PBL apoptosis was reduced by 1.35 times. For professionals, against the background of increased generation of О2-, a reliable direct correlation was observed between the indicator of apoptosis and the total production of free radical compounds, and between the latter and the level of apoptosis of lymphocytes, which was not noted for the conventionally healthy individuals group. CONCLUSION: A change in the ratio between pro- and antioxidant processes in the blood was found for professionals who are in contact with sources of ionizing radiation, which indicates the possibility of the development of oxidative stress, and the consequence of a reduced level of apoptosis of lymphocytes may be the danger of accumulating genetic damage in these cells.

ROLE OF CONTEMPORARY IMAGING METHODS IN RADIOTHERAPY PLANNING AND MONITORING OF GYNECOLOGICAL CANCER PATIENTS (REVIEW). / РОЛЬ СУЧАСНИХ МЕТОДІВ ВІЗУАЛІЗАЦІЇ У ПЛАНУВАННІ ПРОМЕНЕВОЇ ТЕРАПІЇ ТА МОНІТОРИНГУ ОНКОГІНЕКОЛОГІЧНИХ ХВОРИХ (огляд літератури).

Radiotherapy (RT) and radiation oncology are of essential role in the clinical treatment of cancer patients. The widely available imaging modalities such as diagnostic ultrasound, computer-assisted tomography, and contrast-enhanced MRI are used in clinical practice for diagnostics and management planning. Moreover, these methods are also used to monitor the treatment upon RT. However, some diagnostic issues cannot be sufficiently resolved by the simple use of standard morphological imaging. Thus, positron emission tomography is gaining an increasing clinical relevance in the management of cancer patients undergoing RT, as it allows to visualize and quantify the tumor features at a molecular level, such as tumor metabolism or receptor expression, beyond simple morphological patterns shown by the conventional imaging. This review focuses on the recent and current advances in imaging techniques, including PET imaging, in the diagnostics and planning of RT in some cancers, namely in cervical cancer.

RELEVANT BIOCHEMICAL INDICES OF BLOOD RADIOSENSITIVITY IN GYNECOLOGICAL CANCER PATIENTS. / RELEVANTNI BIOKhIMIChNI POKAZNYKY RADIOChUTLYVOSTI KROVI ONKOGINEKOLOGIChNYKh KhVORYKh.

OBJECTIVE: identification of the relevant biochemical indices of blood radiosensitivity in endometrial cancerpatients under the test irradiation in a wide range of doses. MATERIALS AND METHODS: Peripheral blood samples were drawn for assay in the newly diagnosed endometrial cancer patients (study group, n = 42) and healthy donors (control group, n = 27). A set of biochemical values was reviewed to identify and justify the prognostic markers of cell radiosensitivity in the tumor environment featuring gradual development of oxidative stress, namely the intensity of superoxide anionradical (О2) generation, pro/antioxidant ratio (PAR), and malondialdehyde (MDA) content. Predictive values were selected through the construction and analysis of «doseresponse¼ dependencies of the studied parameters during Xray test exposure in a dose range of 0.5-3.0 Gy. Nature of the dose curves was determined using linear and linearquadratic regression models. RESULTS: The 3.2 times higher MDA content was found in blood plasma of endometrial cancer patients compared to the control group, namely (60.87 ± 4.93) µM/g of protein versus (18.93 ± 2.05) µM/g of protein (р ≤ 0.05). The raise in MDA content along with increase in the test radiation dose (in a range of 0.5-3.0 Gy) was approximated by the linear regression model Y = 67.44 + 12.52D, R2 = 0.85. A 1.29-1.74fold increase in the mean group value depending on the radiation dose was recorded (р ≤ 0.05). Effects of lowdose irradiation (0.5 Gy) were differentiated as (85.03 ± 8.9) against the initial MDA level of (60.87 ± 4.93) µM/g of protein. There was an increase in the intensity of О2 generation in blood lymphocytes and elevated PAR value in hemolysate from endometrial cancer patients compared to healthy donors by 1.34 and 1.30 times (р ≤ 0.05) respectively, which indicated the intensification of prooxidant processes in patients. The interindividual peculiarities of the blood reactionresponse to radiation were revealed according to parameters depending on the initial values, which characterize them only as additional prognostic biomarkers in radiation treatment planning for gynecological cancer patients. CONCLUSIONS: It has been proven that the linear nature of dose dependence of MDA content in blood plasma of endometrial cancer patients and response to lowdose irradiation of are the basic criteria for recognizing MDA as a relevant prognostic biochemical indicator of radiosensitivity of healthy cells from the tumor environment. The content of MDA in blood plasma of gynecological cancer patients should be taken into account in order to identify the subjects with a high risk of radiation complications.

CONTEMPORARY APPROACHES TO PROGNOSTICATION AND MANAGEMENT OF PELVIC RADIATION INJURIES IN GYNECOLOGICAL CANCER PATIENTS. / SUChASNI PIDKhODY DO PROGNOZUVANNIa TA LIKUVANNIa PROMENEVYKh UShKODZhEN' ORGANIV MALOGO TAZU PISLIa RADIOTERAPIÏ KhVORYKh ONKOGINEKOLOGIChNOGO PROFILIu.

BACKGROUND: Rapid development of radiotherapeutic techniques and implementation of radiation therapy (RT) nanotechnologies in practice, taking into account principles of radiobiology, ensures that the planned dose will bedelivered to the target volume with minimal irradiation of healthy tissues while maintaining the guaranteed RTquality. Therefore, further advance of RT involves not only implementation of the new technologies in radiationpractice, but also the intensive developments in fields of radiation medicine and clinical radiobiology. OBJECTIVE: search for optimal models of the high-energy (HDR - high dose rate) brachytherapy (BT) using the 192Irsource in comparison with effects of the reference gamma radiation from 60Co, thereby, to increase the effectivenessof chemoradiation therapy (CRT) of gynecological cancer patients (GCPs) with minimal radiation loads on criticalorgans and tissues in the tumor environment. The radiobiological study was aimed to determine the feasibility ofusing the transmembrane potential (TMP) and intensity of reactive oxygen species (ROS) production in peripheralblood lymphocytes (PBL) as predictors of radiosensitivity of non-malignant cells from the tumor environment or itsbed in order to minimize the RT complications in GCPs. MATERIALS AND METHODS: Patients (n = 115) with cancer stages II-III, T2-3N0-1M0 were managed with comprehensiveconservative treatment. Three groups of patients were selected depending on the applied HDR BT method against abackground of the administered chemosensitizing agents. Blood samples of GCPs (n = 24) before the RT initiationand of apparently healthy individuals (AHIs, i.e. the control group, n = 18) were taken for the radiobiologicalresearch. RESULTS: Review of the direct results of 60Co or 192Ir sources use in HDR BT and of the follow-up data showed theincreased tumor positive response in the main study groups after CRT course by respectively 16.6 % and 20.1 % incomparison with 60Со HDR BT administration. Concerning local reactions it was noted that grade II radiation reactions were almost absent in the main groups. According to the results of radiobiological studies, it was establishedthat TMP level in PBL of GCPs was 1.36 times higher than in AHIs. CONCLUSIONS: Thus, the emerging of late radiation injuries depended on the accuracy of of individual computer planning and correct reproduction of the planned RT course, timely correction of treatment programs, use of a complexof rational medical prophylaxis, severity of tumor process and concomitant disorders, as well as on the used type ofHDR radiation sources (192Ir and 60Co). Changes in TMP values and intensity of ROS production in PBL of GCPs in comparison with AHIs, and the high values of these parameters in PBL of individual patients are a rationale to specifythem as additional indicators characterizing the possibility of radiation complications before the RT planning.

ROLE OF RADIOPROTECTORS IN MINIMIZATION OF STOCHASTIC EFFECTS OF RADIATION INCIDENTS.

The real threat of emergency situations in Ukraine dictates the need to take into account the experience of previous radiation accidents, during which a significant part of the population was exposed to low-dose radiation. In such a case clinical manifestations of irradiation were mostly absent, while the danger of stochastic (carcinogenic) effects remained. Therefore, at present, the strategy of radiation protection of the population should be aimed at revising and choosing effective and low-toxic anti-radiation means. The main criterion for the development of stochastic consequences of exposure is radiation-induced genome instability, which is a promoter of carcinogenesis. The use of radiomitigators, which are able to weaken the harmful effect of ionizing radiation on critical highly radiosensitive systems of the human body, is promising. Our research showed the radiomitigative effect of inosine in cultured human T-lymphocytes on the genetic level with the significant decrease in the frequency of gamma-induced chromosome aberrations. The results experimentally justified an expediency of use of radiomitigators in the conditions of an emergency situation to minimize the occurrence and development of stochastic effects in population.

FEATURES OF OXIDATIVE METABOLISM AND GENETIC DISORDERS IN PERIPHERAL BLOOD LYMPHOCYTES OF PATIENTS WITH PRIMARY CERVICAL CANCER.

BACKGROUND: The combination of chemo- and radiotherapy used as main treatment of locally advanced cervical cancer (CC) may lead to side effects in healthy cells, which undermine the effectiveness of treatment and quality of life. The assessment of damage level in healthy radiosensitive cells from the tumor environment before the treatment is important in order to predict and prevent remote side effects of radiation. AIM: To study the oxidative metabolism and genetic disorders in peripheral blood lymphocytes (PBL) of primary CC patients in order to evaluate the possibilities of predicting radiation complications based on the molecular and biological properties of PBL. MATERIALS AND METHODS: Peripheral blood samples were collected from 13 primary CC patients T1-4N0-1M0-1, and PBL were routinely isolated. The oxidative metabolism (mitochondrial trans-membrane potential, superoxide anion radical (О2•) generation, reactive oxygen species (ROS) production in PBL as well as the level of SH-groups in plasma and pro/antioxidant ratio in hemolysates were examined. The development of genetic instability was determined by estimation of DNA double-strand breaks (DNA-DSB), frequency and spectrum of chromosome aberrations and apoptosis. RESULTS: The marked increase in the intensity of О2• generation in PBL (1.5-fold), depletion of SH-groups content (1.6-fold) and a shift in the pro-antioxidant balance (1.4-fold) towards its prooxidant component were observed in the blood of primary CC patients as compared to healthy individuals. These oxidative stress related events were accompanied by an increase in the level of DNA-DSB (2.1-fold), apoptosis (3.5-fold) and frequency of cells with chromosome aberrations (3.9-fold). On the contrary, significant decrease in mitochondrial trans-membrane potential (2.0-fold) and ROS generation in PBL (4.0-fold) were detected. CONCLUSION: Preliminary data indicate a violation of redox processes regulation, a shift in the pro-antioxidant balance towards its pro-oxidant component, accompanied by an increase in the level of DNA damage, development of genetic instability and apoptotic death of blood lymphocytes in primary CC patients.

Effects of brachytherapy on cytogenetic parameters and oxidative status in peripheral blood lymphocytes of gynecologic cancer patients.

BACKGROUND: The state-of-the-art brachytherapy technologies with high-dose sources of 60Co and 192Ir within contemporary treatment protocols for cancer patients allow achieving maximum dose distribution in the clinical target and with minimum radiation exposure of surrounding organs and tissues. For minimization and overcoming the early and late radiation complications, development of respective radiobiological criteria along with perfecting of physical and technical characteristics of the ionizing radiation sources are required. AIM: To study the effect of 192Ir radiation on the chromosomal aberrations and prooxidant/antioxidant status of blood lymphocytes in gynecological cancer patients. MATERIALS AND METHODS: The patients (n = 45) with endometrial, cervical and secondary cancer of vagina were enrolled in the study. For brachytherapy, the irradiation of vaginal mucosa was conducted using "GammaMed plus" device for contact radiation therapy with 192Ir source. Prior to irradiation and in 20-24 h after brachytherapy session, the venous blood samples were obtained and peripheral blood lymphocytes (PBL) were cultured for cytogenetic analysis. The prooxidant/antioxidant status was determined in hemolysates by the method of hydrogen peroxide-induced chemiluminescence. RESULTS: The average level of spontaneous chromosome aberrations in PBL of the patients was (7.8 ± 0.4) per 100 metaphases, which is more than twice higher than the upper limit of the average population values. The frequency of chromosome aberrations in PBL of patients after brachytherapy session was (15.3 ± 1.0) per 100 metaphases. An increased intensity of O2- generation by PBL after brachytherapy session was also noticed. CONCLUSION: Local irradiation at a dose of 6 Gy featuring the first dose fraction of brachytherapy induces extra chromosomal aberrations in PBL of gynecological cancer patients and intensifies prooxidant processes in the blood.

Can SARS-CoV-2 change individual radiation sensitivity of the patients recovered from COVID-19? (experimental and theoretical background).

R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology of the National Academy of Science of Ukraine has been studying the mechanisms and specificities of individual radiation sensitivity (IRS) formation in professionals who work in the field of ionizing radiation, cancer patients and representatives of other population groups. Our data based on the use of G2-test in in vitro irradiated blood lymphocytes in late G2-period of cell cycle indicated an increased carcinogenic risk in professionals with high IRS. We suggest that the COVID-19 pandemic could make significant adjustments in the formation of IRS in professionals who have survived the disease and continue to work with ionizing radiation (IR). Increased systemic inflammatory activity, which persists for a long time in COVID-19 patients, in combination with low-dose range irradiation (professionals who continue to work with IR) and with local irradiation in the high-dose range (radiation therapy for cancer patients) may affect IRS. Repeated determination of IRS in professionals who have had COVID-19 infection, using chromosomal G2-radiation sensitivity assay will answer the question: can SARS-CoV-2 coronavirus affect the IRS? The proposed hypothesis of the radiosensitivity evolution needs further experimental validation using a set of radiobiological indices to clarify the mechanism of IRS formation following COVID-19 infection. The detected changes (increase) of human IRS after COVID-19 must be taken into account for personalized planning of radiotherapy of COVID-19 cancer patients.

IRIDIUM-192 RADIOTHERAPY BENEFITS IN THE MANAGEMENT OF GYNECOLOGICAL TUMORS. / PEREVAGY IONIZUIuChOGO VYPROMINIuVANNIa IRYDIIu-192 U PROMENEVOMU LIKUVANNI ONKOGINEKOLOGIChNYKh ZAKhVORIuVAN'.

BACKGROUND: Application of the most advanced radiation technologies of brachytherapy featuring the high dose ratesources i.e. 60Co and 192Ir within contemporary management protocols for gynecological cancer provides maximum dosedistribution in the clinical target along with minimal radiation exposure on surrounding organs and tissues. It involvesirradiation of large spaces with delivery of high therapeutic doses at the tolerance bound of «critical¼ organs (bladder,rectum) and tissues. Thus minimization of the early and late radiation complications, life span extent and quality oflife increase remain just the issues in contemporary radiation oncology requiring therefore the elaboration of radiobiological criteria along with substantiation of physiсо-engineering properties of the radiation sources. Taking intoaccount the basic radiobiological patterns will ensure a definitive further progress in the field of radiation oncology. OBJECTIVE: to study and compare the biological effects of 192Ir with the effects of the reference gamma radiation 60Coand increase the effectiveness of brachytherapy using a 192Ir source. MATERIALS AND METHODS: Radiobiological dosimetry on the basis of a test system of peripheral blood lymphocytesfrom the gynecological cancer patients with subsequent cytogenetic analysis of radiation-induced chromosomeaberrations was performed to study and compare the biological effects of 192Ir and reference 60Со γ-radiation, and toenhance the efficiency of 192Ir brachytherapy. RESULTS: Radiation markers, i.e. dicentric chromosomes with an accompanying paired fragment prevailed in thespectrum of radiation-induced damage. Variability of individual cytogenetic parameters of peripheral lymphocytesupon the first fraction of irradiation at the same dose of 5 Gy indicated an individual sensitivity of patients to the192Ir γ-irradiation. Comprehensive conservative treatment with adjuvant radiotherapy was applied to the patients(n = 98) having got secondary vaginal cancer stage II-III, T2-3N0-1M0. The high dose-rate (HDR) brachytherapy using 192Ir radiation sources was applied in the main study group (n = 37), HDR brachytherapy using 60Co radiation sourceswas applied in the control group (n = 35). CONCLUSION: The HDR brachytherapy with 192Ir and 60Co sources on the up-to-date technology intensive devices provides a high accuracy of dose distributions when irradiating the malignant neoplasms with minimized radiationexposure to the «critical¼ tissues. Treatment results are improved therefore. The use of 192Ir radiation sources compared with 60Co ones resulted in an increased throughput of treatment, enhanced tumor regression, and reduced incidence of radiation effects on the critical organs. Currently we perform the radiobiological studies on somatic cellsfrom cancer patients at the genetic, biochemical, biophysical, and cytological levels in order to receive a biologicalindication of radiation damage under the impact of 192Ir isotope. Continuation of clinical trials with radiobiologicalsupport will provide an opportunity to predict the early and late radiation complications and thus to provide a personalized approach in brachytherapy of cancer patients using the 192Ir sources of γ-rays.

Early and late radiation effects in healthy tissues of oncologic patients under therapeutic irradiations. / RANNIE I POZDNIE LUChEVYE ÉFFEKTY V ZDOROVYKh TKANIaKh ONKOLOGIChESKIKh BOL'NYKh PRI TERAPEVTIChESKOM OBLUChENII.

The objective of the article is summarize the literature regarding on the patterns and mechanisms of the formation of early and distant radiation reactions of healthy cells due to the therapeutic irradiation of cancer patients. Particular attention is given to the modern views on the molecular mechanisms of the processes of various repair systems (DDR, BER, NER, MMR, etc.) whose ineffectiveness is associated with radiation induced instability of the genome of healthy cells and the etiology of secondary tumours of radiation genesis in cancer patients as a result of radiation therapy. Solving the problem of individual radiation sensitivity of an organism of cancer patients will help to reduce the frequency of early and late radiation complications.

Chornobyl catastrophe: cytogenetic effects of low dose ionizing radiation and their modification.

Among the long-term effects of the Chornobyl disaster the greatest concern of international medical and scientific community is given to the established fact of excess of the spontaneous level of cancer incidence in the exposed population. According to mo-dern concepts, the accumulation of chromosome aberrations, especially in radiosensitive cells, could be potentially oncogenic, and low doses of ionizing radiation could be promoters of the radiation-induced carcinogenesis. The results of our studies have shown that such substances as thymalin, inosine, ascorbic acid, caffeine could modify radiation-induced cytogenetic effects in peripheral blood lymphocytes of healthy individuals and exert protective or sensitizing action dependent on their concentrations, cell radiosensitivity, dose of irradiation, and relative biologic effectiveness of ionizing radiation. This article is part of a Special Issue entitled "The Chornobyl Nuclear Accident: Thirty Years After".

Anty radiation means: classification and mechanisms. / PROTIVOLUChEVYE SREDSTVA: KLASSIFIKATsIIa I MEKhANIZMY.

The objective of the article is to analyze and summarize the literature regarding the mechanisms of action of anti radiation agents. Depending on their purpose, the modern classification includes radioprotectors, radiomitigators and radio modulators. Attention is drawn to the fact that many traditional radioprotectors, due to the high toxic ity, are ineffective under the conditions of prolonged radiological exposure with low dose rate. We look at the purine and organoselenium connections as perspective preventative measures. We study the radioprotective drugs that activate repair systems, based on the model of human peripheral blood lymphocytes and analysis of chromo some aberrations, which are biomarkers of radiation damage to the body. These drugs are recommended to be used for the representatives of certain priority groups of the Ukrainian population that has an increased risk of radia tion induced tumors.

Medical radiography examinations and carcinogenic effects. / Medicinskie rentgenologicheskie issledovanija i kancerogennye jeffekty.

The purpose of the review was the synthesis of the literature data and the results of our radiobiological (biodosimetric) research on the development of radiation-associated tumors as a result of medical radiography (X-ray) diagnostic. Medical X-ray examinations contribute the most to the excess of radiation exposure of the population, much of which is subject to examination to diagnose the underlying disease, the dynamic observation of the patient during treatment, the research of related deseases, and preventative examinations. The review provides arguments for the necessity of developing a more balanced indication for preventative radiological examination of the population in the aftermath of radio-ecological crisis caused by the Chornobyl accident, taking into account the likelihood of radiation carcinogenesis. The problems and tasks of biological (cytogenetic) dosimetry in radiology are formulated.

Destabilization of human cell genome under the combined effect of radiation and ascorbic acid.

UNLABELLED: The aim of this study was to investigate peculiarities of ascorbic acid effect on radiation-induced chromosomal aberrations frequency and range in the cultured peripheral blood lymphocytes (PBL) of healthy donors and cancer patients depending on doses of radiation and drug, as well as cells radiosensitivity (in vitro). METHODS: Test system of human PBL, metaphase analysis of chromosomal aberrations. Cells were cultivated according to the standard procedures with some modifications. PBL culture was exposed to x-ray radiation in G0- and G2-phases of cell cycle. Immediately after the irradiation the culture was treated with ascorbic acid in concentrations of 20.0-80.0 µg/ml of blood. RESULTS: Cell culture irradiation in low dose (0.3 Gy) and treatment with ascorbic acid in therapeutic concentration (20.0 µg/ml of blood) resulted in radioprotective effect, decreasing overall chromosome aberrations frequency as opposed to radiation effects. It has been established that post-irradiation effect of ascorbic acid upon the PBL culture in concentrations of 40.0 and 80.0 µg/ml, which exceeding therapeutic concentration value 2 and 4 times correspondingly, increased overall chromosome aberrations frequency 1.4 times compared with irradiation effect in a low dose (0.3 Gy). This bears evidence of ascorbic acid co-mutagenic activity in the range of concentrations exceeding therapeutic values. The peak of mitotic activity inhibition was observed at 2.0 Gy irradiation dose. Addition ascorbic acid in therapeutic concentration increased radiation effect this number ≈ 2 times (exceeding even intact control value). Compared with G0-phase, co-mutagenic effect of ascorbic acid in G2-phase appears earlier, starting with dose of 1.0 Gy. In the blood lymphocytes of cancer patients, the level of genetic damage was increased 1.7 times after combined treatment with low dose irradiation and ascorbic acid in comparison with irradiation alone which suggest the co-mutagenic instead of radioprotective effect of ascorbic acid. CONCLUSIONS: Genome destabilization enhancement of irradiated in vitro human somatic cells under ascorbic acid effect is due to its co-mutagenic properties. The formation of co-mutagenic effects of ascorbic acid depend on its concentration, irradiation dose and the efficiency of repair processes. Co-mutagenes may pose high carcinogenic hazard at low (above background) radiation levels.