In preparing the review, articles on the functioning of the reverse transcriptase enzyme of endogenous repeat sequences LINE1, the mechanisms of action and antitumor activity of viral reverse transcriptase inhibitors. Articles available in the biomedical literature information databases SciVerse Scopus, PubMed, Web of Science, Russian Science Citation
Index (RSCI) were analyzed. The review used information from 140 publications, of which 95 and 39 were published, respectively, over the last ten and three years, 2 articles present the results of clinical studies, and 45 articles refer to results demonstrating the anticancer properties of the studied compounds in various models in vitro and in vivo.

   Aim. Based on data on the functional properties of the reverse transcriptase enzyme of endogenous repeat sequences LINE1 (long interspersed nuclear elements 1), analyze the potential use of viral reverse transcriptase inhibitors in oncology, presenting their classification and main mechanisms of action.

   About 98 % of the human genome consists of repetitive sequences, most of which are represented by mobil genetic elements, the activation of which leads to increased genome instability. These include long (LINE) and short (SINE) interspersed nuclear element repeated DNA sequences interspersed nuclear elements, respectively, which occupy about 45 % of the human genome. Increased expression levels of these sequences in the genome have been identified in many forms of malignant neoplasms. Their transposition occurs due to the expression of LINE1-encoded reverse transcriptase, which
is homologous to viral reverse transcriptase. To date, reverse transcriptase inhibitors of viruses of nucleoside and non-nucleoside structure have been developed and are successfully used in the clinic. These drugs demonstrate an inhibitory effect on both LINE1 reverse transcriptase and telomerase, which provides the tumor cell with the ability to overcome replicative senescence. Due to these properties, these compounds are expected to exhibit both their own antitumor activity and increase the sensitivity of tumor cells to the therapy of malignant neoplasms, which is experimentally confirmed in models of malignant tumors in vitro and in vivo. Use of reverse transcriptase inhibitors in combination therapy seems advisable both to prevent further genome rearrangements caused by LINE1 and to suppress the survival of tumor cells by inhibiting telomerase activity.

   Breast, prostate, lung as well as colorectal carcinomas belong to leading positions in the world cancer incidence and mortality rankings. They make up about 40 % of newly diagnosed cancers. Connection of these cancers with oncogenic human papilloma viruses (HPVs) is being examined intensively, however it remains subject for discussion. Basing on case-control meta-analyses data were examined on oncogenic HPV detection in clinical samples of breast, prostate, lung and colorectal carcinomas. Findings on HPV genome activities were summarized. The results available prove to oncogenic HPVs as risk factors of the four enumerated above carcinomas.

   Gastric cancer if the 5^th most common oncological disease in the world and one of the leading causes of death associated with this pathology. In clinical practice, the Lauren classification is widely used for gastric cancer characterization, but it does not provide accurate information on tumor progression and does not allow to select the optimal therapeutic approach. More modern tumor typologies, for example proposed by the The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG), are based on profiling of molecular changes in the tumor genome. Currently, several new classifications exist dividing gastric cancer into groups depending on response to different treatment, for example, checkpoint inhibitors or therapy based on activity of pathological pathways associated with immunity, DNA repair, oncogenic and stromal signatures. The proposed typologies improve diagnosis and treatment of this pathology. The review describes currently available classifications of gastric tumors and considers their practical potential.

   The aim of this review is to summarize current understandings of the genetic risk factors for the development of breast cancer (BC), evaluate the role of germline mutations and single nucleotide polymorphisms associated with the disease, based on genome-wide association studies (GWAS) and other associative studies.

   The search for relevant sources was conducted in PubMed, Medline, Cochrane Library, eLIBRARY, and the NHGRI-EBI Catalog of GWAS. The analysis includes works published from January 2007 to December 2022. A total of 197 sources focused on the role of genetic factors in the development of BC were found. Search queries included data on associations of various molecular-genetic markers – germline mutations, and single nucleotide polymorphisms – with the formation of BC. From this body of work, 45 studies were included in the current review. The inclusion criterion for the analysis was
the presence of GWAS data and associative studies conducted among patients with representative samples with the necessary power. Additionally, results characterizing the clinical-pathological significance (association with molecular subtypes of BC, therapy features, disease prognosis) of BC genetic factors were evaluated. Excluded from the analysis were data from associative studies of candidate genes for malignant breast neoplasms that are morphologically not carcinomas, performed on small (non-representative) patient samples and control groups. Mutations in genes with high and moderate penetrance (BRCA1/2, CHEK2, PALB2, etc.) are associated with the onset of BC in 5 % of cases. Among families with two or more members affected by BC, their share reaches only 30–40 %. GWAS data revealed the role of more than 180 polymorphic loci associated with BC, which determine a heritability rate of about 18 %. According to twin studies, this rate is 1.7 times higher, reaching 31 %. Meanwhile, the contribution of environmental factors is no more than 16 %. The proportion of unidentified hereditary factors in BC formation is about 8 %. However, contemporary studies of associations of various candidate genes (ESR1/2, IGF1, EGFR, VEGF, TNFα, MMPs, etc.), whose signaling pathways regulate BC tumor progression, show their involvement in carcinogenesis. Thus, the unknown heritability in BC formation may reach 40 %. The proportion of germline mutations in major BC predisposition genes in the population is low. Genetic variations within the same gene (e.g., BRCA1) show ethnic or territorial diversity. Nevertheless, a significant portion of BC heritability is determined by various candidate genes, whose role in forming individual BC risk is demonstrated by GWAS. Substantial evidence on the involvement of key carcinogenesis-regulating genes in BC development is being accumulated. Each of the three considered groups of genetic factors has important clinical-pathological significance and can influence the course and prognosis of the disease.

   One of the promising directions in antitumor therapy is suicidal gene therapy based on the introduction of cytotoxic genes into tumor cells. Most often, these genes encode for enzymes of bacterial or viral origin, capable of direct or indirect killing of tumor cells. This review provides information about modern strategies for suicidal cancer gene therapy, discusses their advantages and disadvantages, and analyzes the properties of a potential candidate for creating a new highly effective suicidal system, combining the advantages of existing approaches.

   The sodium-dependent phosphate transporter NaPi2b is an integral membrane protein of the SLC34 phosphate transporter family and is an attractive target for precision therapy of several human diseases. Together with other members of this family, the NaPi2b transporter is involved in maintaining phosphate homeostasis in the mammalian body. The NaPi2b transporter gene (SLC34A2) has a broad expression pattern in healthy tissues, including small intestinal epithelial cells, where NaPi2b plays a major role in the absorption of dietary phosphate. NaPi2b transports one divalentorthophosphoric acid residue into cells along with three sodium ions. NaPi2b transport is regulated by dietary phosphate, pH, hormones, and vitamins including vitamin D, estrogen, glucocorticoids, and epidermal growth factor. The NaPi2b transporter exists in two isoforms – 689 and 690 amino acid residues. The molecular weight of NaPi2b depends on the degree of glycosylation and varies from 70 to 100 kDa. According to various sources, the transporter has from 6 to 12 transmembrane domains, 2 co-transport domains, a large extracellular localization domain, as well as N- and C-terminal domains that face the inside of the cell. Impaired NaPi2b function leads to the development of several diseases, including pulmonary alveolar microlithiasis and hyperphosphatemia, and pulmonary alveolar microlithiasis is known to be associated with mutations in the SLC34A2 gene encoding NaPi2b. High levels of NaPi2b have been found in several malignant tumors, including ovary, lung, breast, thyroid, colon, bladder, liver, stomach, kidney, and in gliomas. The tumor-specific conformation of the large extracellular domain of the NaPi2b transporter, mutations, and features of expression of the transporter gene in normal and pathological conditions show that NaPi2b is a promising target for the development of highly selective targeted drugs against it for the treatment of cancer and metabolic disorders.

   Introduction. Local hypermethylation of gene promoters and global genome hypomethylation are well-known manifestations of aberrant methylation associated with carcinogenesis. We investigated this phenomenon as a possible diagnostic marker for liquid biopsy of colorectal cancer using the original quantitative DNA melting analysis with hybridiza-
tion probes (qDMA-HP) method.

   Aim. To quantify the methylation of HIST1H4F promoter and LINE-1 transposon in circulating blood plasma DNA of colorectal cancer patients.

   Materials and methods. Bisulfite-treated DNA samples isolated from blood plasma of healthy donors and cancer patients were analyzed. HIST1H4F methylation was assessed by asymmetric polymerase chain reaction with hybridized probe and post-amplification melting of probe / amplicon hybrids. To test for repetitive and highly polymorphic LINE-1 sequences, asymmetric polymerase chain reaction with hybridized probe and SYBR Green intercalating dye was used, followed by melting of hybrids and analysis of multicomponent melt curves.

   Results. High diagnostic efficiency of LINE-1 and HIST1H4F methylation markers in liquid biopsy of colorectal cancer was demonstrated with the area under the ROC curve = 0.92, sensitivity – 100 %, specificity – 84 %. Cross validation supports this result. Hypermethylation of HIST1H4F and hypomethylation of LINE-1 are statistically significantly correlated (Spearman correlation coefficient r = 0.4; p = 0.01).

   Conclusion. The qDMA-HP is suitable for quantitative assessment of aberrant methylation of various clinically significant genes.

   Introduction. Lung and colorectal cancers are the most common cancer types, characterized by a poor prognosis. Tumor progression is also caused by the aberrant activity of intercellular signaling pathways, which can arise due to mutations in genes encoding their components. In particular, the oncogenic role of NOTCH1 receptor of Notch signaling pathway has been proven for various cancer types, including lung and colorectal cancers. In this research, we delved deeper into the importance of NOTCH1 receptor expression for the progression of these malignancies.

   Aim. To investigate the importance of NOTCH1 expression in maintaining the cancer stem cell (CSC) pool and phenotype of human lung and colon cancers.

   Materials and methods. Experiments were performed on previously obtained NOTCH1 knockdown cell lines of human lung A549 and colon HCT116 carcinomas. First of all, we studied the effect of NOTCH1 knockdown on the metastatic ability of A549 cells and the tumorigenicity of A549 and HCT116 cells when injected to immunodeficient BALB/c nu/nu mice. Next, we carried out in vitro tests to determine CSC pool and phenotype in tumor cell culture: cytofluorimetric analysis of ABC-transporters activity to exclude dye to the external environment and analysis of colony formation in a semi-liquid medium. In conclusion, we assessed the proportion of cells in the culture producing the CSC marker – CD133 using flow cytometry and the expression level of some genes associated with CSC phenotype (NANOG, POU5F1, SOX2) using real-time polymerase chain reaction.

   Results. NOTCH1 knockdown decreased the number of experimental animals with metastases, the number of formed metastatic foci and increased in the minimum cell inoculation dose. The activity of ABC-transporters, the ability for unattached growth, the proportion of CD133-positive cells in culture, and the expression of genes associated with maintaining of CSC pool and phenotype decreased under NOTCH1 knockdown in both cell lines.

   Conclusion. NOTCH1 expression is important for maintaining CSC pool and phenotype of human lung and colon carcinomas. The obtained data may be valuable in the development of anticancer therapies.

   Aim. To determin the clinical and biological features of neuroblastoma in patients over 10 years old.

   Materials and methods. Patients with a histologically verified diagnosis of neuroblastoma / ganglioneuroblastoma established over the age of 10 years were retrospectively selected. Molecular genetic tests included fluorescence in situ hybridization (FISH), multiplex ligation-dependent amplification (MLPA) and targeted next generation sequencing of tumor-derived DNA. The described cohort included 11 adolescents with histologically verified neuroblastoma / ganglioneuroblastoma with a median age of 160 months (124–173 months) at diagnosis and 1 patient aged 41 years (clinical data is missing). All adolescents were treated according to the neuroblastoma treatment protocol NB-2004. The median follow-up time for patients (n = 11) was 32 months (8–68 months).

   Results. MYCN gene amplification was detected by FISH in 17 %; deletion of 1p and 11q – in 20 and 22.2 % of cases, respectively. Deletions of 1p and 3p (80 % cases each), 11q (67 % cases), 4p (56 % cases), and gain 17q (62.5 % cases) were frequently detected in tumors (n = 9) by MLPA. ATRX gene aberrations was found in 91.6 % (11 / 12). In the most cases (10 / 11; 90 %), ATRX gene deletions of varying length were detected. Missense substitutions p.V1678F, p.N2125I and nonsense mutation p.S213* were detected in 3 / 11 (27.3 %) patients. Moreover, in 2 patients, oncogenic nucleotide substitutions were identified in combination with ATRX gene deletion entire and monosomy X. Oncogenic genetic variants in components of the RAS-RAF-MEK (BRAF, NRAS, ALK) and p53 (ATM, TP53) pathways were detected in 58 % (7 / 12) of cases. No adverse events were observed when ALK inhibitors were added to first-line therapy in neuroblastomas harboring activating ALK mutations.

   Conclusion. The clinical aggressiveness of adolescent / adult NB may be explained by the replicative immortalization of cells through alternative lengthening of telomeres, which is highlighted by ATRX aberrations. Special therapeutic recommendations should be elaborated for the treatment of patients in this age group, where special attention should be paid to the use of molecularly targeted therapy.

Introduction. It has been established that the presence of homologous recombination deficiency in a breast tumor is associated with the effectiveness of treatment. But despite the high chemosensitivity of the tumor to DNA-damaging agents, complete pathological responses to treatment are very rare. And this process may be based on a change in the somatic status of BRCA1, that is, a reversion and return of the wild-type allele occurs and the DNA repair function is restored.

Aim. To evaluate changes in the presence of chromosomal aberrations and the expression profile of the main genes of homologous recombination in cell models of breast cancer under the influence of cisplatin and docetaxel.

Materials and methods. The study was conducted on breast cancer tumor cell cultures: MCF-7, MDA-MB-231 and MDA-MB-468. A cell model of drug resistance was obtained for two drugs: cisplatin and docetaxel. RNA and DNA were isolated from cell suspension using the RNeasy Plus Mini Kit and QIAamp DNA Mini Kit (Qiagen, Germany), respectively. The expression level of homologous recombination genes was assessed using reverse transcription polymerase chain reaction. To assess the presence of chromosomal aberrations, microarray analysis was performed on DNA chips.

Results. Restoration of normal copy number for the BRCA1, CDK12, CHEK1 and RAD51D genes in MCF-7 under the influence of cisplatin was shown. For BRCA2 and PALB2, amplifications were detected. A statistically significant increase in the expression of the BRCA1 (p = 0.04), BRCA2 (p = 0.02), PALB2 (p = 0.01) and RAD51D (p = 0.05) genes was also shown. MDAMB-231 shows that all identified loci with deletions, where the BRCA2, BARD1, CHEK2, PALB2 and RAD54L genes are localized, are restored to normal copy number by cisplatin. The appearance of amplifications was registered for BRCA1, BRIP1, FANCL, RAD51B, PARP1. A similar result was shown for docetaxel. An increase in the expression level is typical for the genes BRCA1 (p = 0.02), BRCA2 (p = 0.02), CHEK2 (p = 0.05), FANCL (p = 0.04), PALB2 (p = 0.05), RAD51C (p = 0.02), PARP1 (p = 0.02), which corresponds to the appearance of amplifications. In the MDA-MB-468 cell culture, an increase in the copy number of only the BRCA1 gene is observed. The effect of docetaxel has no effect on this cell culture. The level of BRCA1 expression increases in direct proportion to the duration of drug action.

Conclusion. Thus, the study showed that under the influence of cisplatin, reversion of not only homologous recombination gene mutations, but also other disorders can occur.

   Introduction. Microtubules are highly dynamic polymers of α, β-tubulin dimers involves in a broad spectrum of the processes, such as intracellular transport and cell proliferation. This makes them an attractive molecular target for anti-cancer therapies. Substances that affect the dynamic state of tubulin microtubules are known as the mitotic poisons that are effective
and widely used in the chemotherapy of various tumors. Mitotic poisons are able to interfere with polymerization (stabilization) or depolymerization of tubulin, which in turn leads to the arrest of cells in the M-phase (named as a mitotic catastrophe) and their subsequent death via activation of apoptotic mechanisms. However, the effectiveness of MP-based therapies is gradually decreasing over the time due to development of multiple drug resistance mechanisms in cancer cells. Thus, development of novel compounds selectively targeting tubulin and effectively overcoming multiple drug
resistance phenotype in cancer is an urgent need in current oncology.

   Aim. To examine the cytotoxic and antitumor activities of several pyrrole-containing heterocyclic compounds (EPC-91, EPC-92 and PCA-93) against cancer cell lines with epithelial and mesenchymal origin, including those with multiple drug resistance phenotype.

   Materials and methods. Studies were performed on parental human cancer cell lines – triple-negative breast cancer HCC1806, gastrointestinal stromal tumor GIST T-1, osteosarcoma SaOS-2, – sensitive to chemotherapy (paclitaxel, doxorubicin) and their resistant sublines (HCC1806 Tx-R, GIST T-1 Tx-R, SaOS-2 Dox-R), as well as on murine colorectal adenocarcinoma cell line Colon-26, exhibiting primary resistance to the aforementioned chemotherapeutic agents.

   Results. The cytotoxic activities of EPC-91 and PCA-93 were due to their abilities to depolymerize tubulin. The results of immunofluorescence microscopy and Western blotting indicated that the compounds disrupt assembly of tubulin microtubules and prevent polymerization of α-tubulin in cancer cells. Inhibition of tubulin polymerizations led to significant increase
in number of round-shaped and phospho-histone 3 (e. g. mitotic) cells, followed by their death through apoptosis. PCA-93 also exhibited potent anti-tumor effect against Colon-26 cells due to its anti-proliferative and proapoptotic activities.

   Conclusion. The data shown here illustrates potent cytotoxic activities of EPC-91 and PCA-93 against multiple cancer cell lines in vitro including those with multiple drug resistance phenotype. Similarly, PCA-93 was found to be highly effective against Colon-26 cell in vivo, thereby illustrating the attractive platform for the development of novel pyrrole-based agents exhibiting potent anti-tumor activities.