GENETIC PREDICTORS OF TOXIC EFFECTS OF METHOTREXATE IN CANCER PATIENTS.

Today, methotrexate (MTX) is used in combination with other medicines to treat a wide range of malignancies. Despite its proven high efficacy, MTX often causes serious side effects, which may result in the need to reduce the dose of MTX or discontinue the drug altogether. This, in turn, can provoke the development of MTX resistance and cancer progression. Predicting the risk of MTX-induced toxicity is currently difficult due to the variability of pharmacokinetics and pharmacodynamics in different patients, so the scientific literature is intensively searching for potential biomarkers. Based on the data available in the current literature, we analyzed the relationship between variants in the genes encoding the key components of MTX intracellular metabolism and the MTX-induced side effects and drug response. According to the results of our work, the most studied variants are those of the SLC19A1 gene, which encodes the reduced folate carrier protein 1, and the MTHFR gene, which encodes the enzyme methylenetetrahydrofolate reductase. Studies of the effect of methylation of the promoter regions of genes on the therapeutic effect of MTX are also very promising. In conclusion, the study of molecular genetic markers of MTX toxicity is extremely relevant and necessary because it can help to avoid the effect of multidrug resistance and improve the quality of life and survival of patients.

[Evaluation of systemic involving of the connective tissue in children with different localisation of isolated abnormal chords of the left ventricle (ACLV)].

Evaluation of the systemic involving of the connective tissue (SICT) under the new Ghent nosology (2010) showed that in children with isolated ACLV born to parents exposed to the Chernobyl disaster, its expression is associated with their location and quantity. The degree of systemic involvement of connective tissue is confirmed by the results of the analysis of features echostructure of isolated ACLV (the presence of thickening and calcification), echomorphometry, assessment of systolic (hypokinetic organization of the central hemodynamics), and the relaxation functions of the heart (initiation of diastolic dysfunction). High level of SICT (score greater than 5) indicates systemic damage to the body and particularly the heart, which requires dynamic monitoring and preventive measures. Found that the diagnostic and monitoring of children with isolated ACLV may be based on registration of systemic involvement of connective tissue with the calculation of points under the new Ghent nosology of 2010.

[The activity of enzymes of energy supply of cells in prognosis of effectiveness of auxiliary reproductive technologies].

The comparative analysis was applied to activity of such enzymes of energy supply of cells as succinate dehydrogenase and alpha-glycerophosphate dehydrogenase in women with fertility disorders and effectiveness of results of application of auxiliary reproductive technologies. The examination was passed by two groups of female patients. The main group included women with barrenness (50 patients) referred to carrying out auxiliary reproductive technologies. The auxiliary reproductive technologies resulted in pregnancy in 21 female patients (group 1a) and no pregnancy occurred in 29 female patients (group 1b). The control group consisted of non pregnant women of comparative age and having children (20 female patients). The cytochemical detection of activity of enzymes was implemented according the R.P. Nartsissov technique. The count of granules of diformazan was made by microscopical technique. Then, the mean cytochemical coefficient was calculated. The study established a reliable decrease of activity of succinate dehydrogenase and alpha-glycerophosphate dehydrogenase in lymphocytes of peripheral blood in women with barrenness as compared with normal conditions. In female patients from group 1b activity of alpha-glycerophosphate dehydrogenase was reliably lower than in group 1a (with effective attempt of auxiliary reproductive technologies).

[Autonomic homeostasis of children born to parents irradiated in the result of the Chernobyl catastrophe with isolated abnormal chords of the left ventricle].

156 children of the main group (were born to parents irradiated in the result of Chernobyl disaster), in which according to Doppler echocardiography isolated abnormal chords of the left ventricle (AHLV) identified, 44 children of control group and 50 children of referent group were involved in the study Analysis of indicators of operational regulation of heart rate in children of primary group indicate the existence of autonomic dysregulation, which has the maximum expression in children with a threshold number of isolated abnormal chords. Evidence of autonomic dysregulation in children born to parents irradiated in the result of the Chernobyl disaster with isolated AHLV requires primary and secondary prevention to reduce the frequency of unfavourable clinical course.

[Analysis of structural and functional indices of the children hearts with isolated abnormal chords of the left ventricle and who were born to parents irradiated during the Chernobyl accident].

156 children of the main group, born to parents irradiated in the result of Chernobyl disaster have been involved in the study. These children were identified with isolated abnormal chords of the left ventricle (AHLV) according the results of Doppler echocardiography. 39 practically healthy children and 24 children of the nosology control group have also been observed. Threshold quantity of AHLV were determined in 33 children, main group, (subgroup Ia), sub-threshold--in 123 children (subgroup I(B)). The children of the control group with threshold quantity of AHLV were found with decreased adaptation capacity of the cardio-vascular system through shifts in dynamics and energetics of the heart contraction. Reduction in systolic output, systolic and heart indices justify hypokinetic type of organization of central hemodynamics, which can be considered an early sign of tension of functional capabilities of the heart and blood vessels. This subgroup of children was found to have changes of transmitral blood flow indicating the initiation of the heart's diastolic dysfunction. Almost 1/3 of children with subthreshold number of AHLV were also revealed to have signs of initiation of the heart's diastolic dysfunction.

[Abnormal chords of the left ventricle].

The analysis of literature data has showed that evaluation of prognostic significance of abnormal chords of the left ventricle (ACLV) is ambiguous. It remains an open question on the participation of ACLV in the pathogenesis of cardiovascular disease. Obviously, the prognosis of ACLV is determined not so much by the fact of its existence, as degree of connective tissue dysplasia, the number and topic of anomalous chords, the presence of hemodynamic and/or arrhythmic complications. Identification and verification of the anomalous intracavitary structures are important, because they often serve as potential sources of echodiagnostic mistakes, for they can mask more important pathological findings.

[System of collection and dynamic processing of information for predicting population genetics]. / Systema zboru ta dynamichnoï obrobky informatsiï dlia prognozuvannia genetychnykh protsesiv u populiatsiï liudyny.

Creation has come to be necessary in Ukraine of a system for collection, dynamic supply and processing of information about genetical processes. Such a system as that described above is submitted by the authors. The basis of the system is a module in which, by using special units and connections between them, a collection, storing, and processing of information about genetic pathological processes in the time-related course is to be carried on together with prognostication thereof in the population of the country as a whole or in each region taken separately.

[Effects of ionizing radiation and xenobiotics on the spermatogenic epithelium of laboratory animals]. / Vliianie ioniziruiushchego izlucheniia i ksenobiotikov na spermatogennyi épitelii laboratornykh zhivotnykh.

Intact BALB/c and CBA mice differ in the overall cellularity of the spermatogenous epithelium, in the number of normal and pathological multinuclear cells. Exposure to small-dose radiation (0.25 and 1 Gy) causes profound changes in the spermatogenous epithelium in BALB/c mice. Then the increase in the abnormal forms of multinuclear and uninuclear cells leads to the disintegration and elimination of such cells, which affects the overall cellularity of the spermatogenous epithelium. A reduction in the proportion of multicellular cells, a compensatory-and-protective response that promotes the maintenance of the size of sex cells at the level optimal for fertilization. Upon small-dose exposure of rats to sixvalent chromium, there is a decrease in the whole population of germinitive cells and an increase in the multinuclear spermatocytes and spermatids. The rise in multinuclear cells is indicative of retarded cell maturation and differentiation at some stages of spermatogenesis, which reduces the number of spermatogenous cells.

[An approach to genetic monitoring via a genetic registry]. / Pidkhid do henetychnoho monitorynhu cherez henetychnyi reiestr.

The analysis of the selective excerpt of the children with the inherited disorders has been made on the basis of the Kiev Medical Genetic Center, where the regional anonymous syndromological computer register has been organized. Register's file during 1993-96 has the information about 883 families that has a genetically ill proband. Genetic syndrome has been diagnosed in 78.02% (105 nosological points). The information taken from the register has allowed for the first time to distinguish the inherited pathology from the acquired one, so the new mutation from 30.23% out of all registered inherited disease. The necessity of the creation of the National Genetic Register in the Ukraine and the new conception of the two-stage genetical monitoring of the population has been proved.

[Genetic or ecogenetic consequences of the Chernobyl accident? (facts and hypotheses)]. / Henetychni chy ekohenetychni naslidky Chornobyl's'koï avariï? (fakty ta hipotezy).

The results of investigations indicated the necessity of genetic monitoring in population using the data of family examination in medical genetic centres. Indices of the frequency of developmental abnormalities in newborns are not suitable for monitoring because they do not permit to differentiate between new mutations and inherited ones. The dissemination of these abnormalities among newborns in Kiev mostly coincides with the same index in other European regions and is lower than in Canada and West Australia. According to the data of Kiev regional medical genetics centre, about 80% of developmental abnormalities occur as a result of inherited mutations but not new ones. Under the conditions of environmental pollution, ecogenetic consequences assume a new importance.

[The effect of low and sublethal doses of ionizing radiation on the function of the spermatogenic epithelium and the yield of dominant lethal mutations in different strains of mice]. / Vliianie malykh i subletal'nykh doz ioniziruiushchego izlucheniia na sostoianie spermatogennogo épiteliia i vykhod dominantnykh letal'nykh mutatsii u myshei raznykh linii.

There was a 30% increase in spermatozoids with microheads and a 3-fold increase in "young" spermatozoids at later times after irradiation of BALB/c mice a dose of 1.0 Gy. With radiation doses of 0.1-1.0 Gy, BALB/c and CBA mice (which differ in viability of spermatogenous cells, the number of Sertoli cells and total embryonal death rate) exhibited a significant increase in the preimplantation death at the stage of spermatogonia and stem cells. The results obtained indicate reduction of the fertilizing capacity of sperm which is probably realized as dominant lethal mutations.

[cGMP-binding centers in photoreceptor membranes]. / cGMP-sviazyvaiushchie tsentry v fotoretseptornykh membranakh.

The binding of cGMP by structural components of bovine rod outer segments was studied. The discs and plasma membranes were shown to contain two types of the specific binding sites for cGMP which are distinct from cyclic GMP phosphodiesterase. The sites have a "high" and "low" (Kd = 0.1 divided by 0.35 and 1.5 divided by 2.0 X 10(-6) M respectively) affinity for cGMP. They belong to membraneous integral proteins presumably associated with phospholipids. Their affinity for cGMP is controlled by GTP and calmodulin.

[Interaction of leucine with the plasma membranes of catfish taste buds]. / Vzaimodeistvie leitsina s plazmaticheskimi membranami vkusovykh lukovits karlikovogo somika.

The binding of L-[3H]leucine by the plasma membranes from the catfish Ictalurus nebulosus taste organ was studied. The two types of specific binding centers for amino acid with high (KD = 2,5 X 10(-10) M) and low (KD = 1,04 X 10(-9) M) affinities were found. Concentrations of high and low affinity centers were 11,85 nmol/mg and 26 nmol/mg respectively. The structural rearrangement of the surface layer of the chemoreceptor membrane was revealed by spin label technique using 5-doxylstearic acid at leucine concentrations 10(-4)-10(-9) M.

[Effect of the state of the lipid phase of the membrane on the effectiveness of photochemical modification of erythrocyte acetylcholinesterase]. / Vliianie sostoianiia lipidnoi fazymembrany na éffektivnost' fotokhimicheskoi modifikatsii éritrotsitarnoi atsetilkholinésterazy.

Modification of the lipid phase structure of the erythrocyte membrane by phospholipases A2, C and D as well as the partial depletion of cholesterol was shown to be accompanied by the change of the acetylcholinesterase (AChE) UV-sensitivity. The ability of UV-light to change the catalytic properties (Km) of the membrane-bound AChE not observed for free AChE (constant value of Km) and known as the phenomenon of photochemical allotopy, is retained in the cholesterol depleted membranes and disappears after an enzymatic treatment of the membranes by phospholipases. The possible non-photochemical influence of the membrane lipid phase in response to UV-damage of membrane-bound AChE is discussed.

[Influence of UV-light on erythrocyte membrane structure and catalytic behaviour of membrane acetylcholine esterase]. / Vliianie UF-sveta na strukturu membran zritrotsitov i na kataliticheskie svoistva membrannoi atsetilkholinzsterazy.

UV-light is shown to induce the structural transitions in the erythrocyte membrane described by S-shape curves in plots of the structural response versus the irradiation dose. In contrast to the free acetylcholine esterase (AChE) UV-light acts on the membrane enzyme as a mixed inhibitor (simultaneous change in Vmax and Km). The modification of the environment structure of residual enzyme is suggested to be the main reason of this phenomenon. The effect is under the control of membrane integrity and disappears after its desintegration. Membrane AChE treated ultrasonically both prior to and after irradiation is inactivated without a Km change. The data obtained show the influence of erythrocyte membrane structure on the catalytic behaviour of membrane-bound AChE.