The review presents modern ideas about the origin of tumor vessels and the features of their morphology. The various approaches to the classification of tumor vessel types and to the assessment of their clinical and prognostic significance are described. Also, the main problems associated with the use of angiogenesis blockers in the treatment of malignancies and their possible solutions are reflected in the review.

The concept of vasculogenic mimicry (VM) was introduced to describe the unique ability of highly aggressive tumor cells to form capillary-like structures and matrix-rich patterned network in three-dimensional culture that mimic embryonic vasculogenic network. VM has been reported in several aggressive tumors including ovaries, breast, liver, lung cancer, sarcoma, glioblastoma. It is worth to note, that VM in melanocyte-originated tumors is the most studied. Although much attention has been focused on factors that stimulate or suppress vascular channel formation by tumor cells, the molecular mechanisms underlying this phenomenon remain enigmatic. This review will focus on molecular determinants and key signaling pathways involved in tumor VM. The exploration of drugs targeted at molecular signaling pathways in VM is a field of challenges and hopes. The research on VM will increase our knowledge of the molecular events causing aggressive tumor cells to gain plasticity resulting in their ability to mimic vasculature. To date, little functional data exist that show how tumor cell-lined channels contribute to the overall survival of the tumor. However, even among researches who have questioned the concept of VM as a crucial circulatory system, there is generally a consensus that the prognostic significance of PAS-positive patterns is valid.

Modern research in the field of chondroitin sulfate chemical composition is considered. Clinical efficiency and safety are shown to depend on the nature and quality of the raw material used, ways of its technological processing and the degree of purification. The composition of chemical compounds (CC) variable is stated to represent the mixture of 2 main isomeric forms: chondroitin 4-sulfate and chondroitin 6-sulfate. In the animal tissue chondroitin 4-sulfate dominates, the content of which is 70 %; the content of chondroitin 6-sulfate is 30 %. The cartilages of sharks and other hydrobionts have got low content of chondroitin 4-sulfate (10 %) and chondroitin 6-sulfate 80 %. Complex polymeric structure and instability of CC composition make the problem of drug standardization on its basis complicated. The impurities encountered in substances are considered. The impurities are divided into several groups: related impurities, technological or mechanical ones uncharacteristic of CC. Comparative analysis of requirements for raw material from the point of view of normative documentation of different countries is carried out and their considerable difference is detected. It has been shown that for raising pharmacological activity the producer of drugs must take into account all the parameters of CC including the structural composition, molecular weight and presence of impurities.

Introduction . High prostate cancer (PC) incidence rates testify to importance of research into genesis of the given disease and means of its prevention. The item of oncogenic human papillomaviruses (HPVs) participance in PC origination is still being the subject of debates. If association of PC with HPV is proven prophylaxis of the given disease becomes possible by means of inoculating boys with the vaccines made for cervical cancer (CC) prevention.
Objective: to test whether prostate tissues surgically removed from PC patients harbor oncogen E7 of HPV18 – the second most common HPV type responsible for CC.
Materials and methods . The study was carried out on prostate glands of 17 PC patients surgically treated in N.N. Blokhin National Medical Research Center of Oncology. Detection of HPV18 oncogen E7 was done by polymerase chain reaction. To elevate polymerase chain reaction sensitivity DNA was isolated from homogeneous cell populations collected by means of microdissections from cryopreserved PC specimens.
Results . Amplification products corresponding to HPV18 oncogen E7 were registered in tests from 2 PC patients.
Conclusion . HPV18 oncogen E7 was detected in surgically removed prostate tissues of 2 PC patients. In the aggregate with our previous result (7 HPV16-positive PC cases in the same group of 17 patients) the given result enables one to presume participance of oncogenic HPVs in PC genesis. The problem deserves further study.

Introduction . Insulin-like growth factors (IGF) are one of the widely studied factors in oncology. For tumors with a high expression level of IGF typical postoperative relapse, they are invasive and give distant metastases. There are also data on the participation of IGF in the emergence of resistance to anticancer drugs. The mechanisms that determine the influence of insulin-like growth factors on the progression of a number of malignant neoplasms remain undisclosed and carrying out fundamental research in this direction is relevant. Objective: to study the role of IGF type 1 (IGF-1) in multiple myeloma (MM).
Materials and methods . 26 samples of bone marrow aspirates received from 26 patients – 14 men and 12 women – were studied in the work. All patients were diagnosed with stage III ММ. The age of patients ranged from 52 to 72 years. From the obtained bone marrow aspirates, using centrifugation in the Ficoll gradient, a mononuclear fraction of bone marrow cells containing plasma cells was obtained. Then we carried out the procedure of extracting RNA and using polymerase chain reaction with reverse transcription, we studied the expression of mRNA of the genes of IGF-1 and MDR1/ABCB1.
Results . The paper analyzes the overall survival (OS) of patients with MM depending on the expression of the gene IGF-1. It is shown that for patients with MM who have a high level of IGF-1 expression, a decrease in OS is characteristic and, conversely, with a weak expression of IGF-1 or in the absence of its expression, an increase in OS is observed. Studies of expression of IGF-1 gene and MDR1/ABCB1 gene responsible for the occurrence of multiple drug resistance showed that these genes are co-expressed in patients with MM. Conclusion . The obtained results indicate that the high level of IGF-1 gene expression may be a poor prognostic factor in ММ. IGF-1 may participate in regulation of the mechanisms of emergence of multiple drug resistance in patients with MM.

Background . Multiple myeloma (MM) is a malignant lymphoproliferative B-cell disease characterization by clonal proliferation of plasma cells in the bone marrow and beyond its borders. Currently, a wide range of cytogenetic anomalies and molecular-biological parameters are studied as prognostic factors.
Objective: a comparative study of the frequency, features and clinical significance of chromosomal abnormalities in MM by conventional cytogenetic and fluorescent in situ hybridization (FISH) methods.
Materials and methods . 77 patients with MM, which admitted in N.N. Blokhin National Medical Research Center of Oncology, were included in the study from 2016 to 2017.
Results . Chromosomal alterations were detected only in one case (1/77) by conventional cytogenetic method G-banding. However cytogenetic aberrations were revealed in 26 % of cases (20/77) using FISH. Deletions of different regions of chromosomes, indicating the possible presence of a hypodiploid clone or loss of some regions, were found in one patient in the second FISH analysis after 6 months. In the cohort of patients with chromosomal abnormalities (n = 20) a partial trisomy 11q, a deletion of the region q32 of the chromosome 14, a translocation t(4;14)(p16;q32) and IGHV gene rearrangement were determined in 30 % (6/20) as sole anomalies. Two or more cytogenetic aberrations were identified in the remaining 14 patients. Our study confirms that chromosomal abnormalities are more likely detected at later stages of MM (IA и IIA – 0 %, IIIA и IIIВ – 27 and 47 % respectively).
Conclusion . FISH allows to detect chromosomal changes in tumor plasma cells regardless of the mitosis phase. In MM, it becomes particularly important in connection with low proliferative activity of plasma cells. Additionally, in the fourth of MM patients in the study submicroscopic chromosomal aberrations were discovered using FISH. The improvement of the probe panel and the widespread use of locus specific FISH don’t replace G-banding that allows to see damages of all chromosomes at once.

Objective: to study drugs ingavirin and thymogen as activators of signal TLR and RLR reactions in a sensitive cell model of THP-1 monocytes and blood cells of donors.
Materials and methods . Investigated drugs ingavirin (imidazolylethanamide pentanedioic acid – 6-[2-(1H-imidazol-4-yl)ethylami- no]-5-oxohexanoic acid; Valenta Pharmaceutics, Russia) and thymogen (alpha-glutamyl-tryptophan; Cytomed, Russia), registered in Russia as medicines. The expression of TLR/RLR receptor genes was determined under the action of ingavirin 50–300 μg/ml and thymogen 0.1–5 μg/ml (24 h, 37 °C) using quantitative RT-PCR. The level of fluid cytokines was determined using ELISA kits (Vec- tor-Best, Russia) in the culture fluid. Transfection of small inhibitory RNA (siRNA) MAVS was performed using the reagent Lipofect- amine 2000 (Invitrogen). The immunophenotype of the THP-1 cell line was determined by flow cytometry with labeled monoclonal antibodies FITC CD14 and PE CD34 (BD Biosciences) on a FACSCanto II instrument (Becton Dickinson).
Results . For the first time, it has been shown that ingavirin (imidazolylethanamide) and thymogen (dipeptide Glu-Trp) preparations are activators of the immune TLR/RLR receptors and their signaling factors genes in the cultures of monocytic leukemia THP-1 and blood of healthy donors. In these cellular systems, ingavirin and thymogen preparations elicited similar immune responses and stimulated the expression of genes: endosomal TLR3/7/8/9 receptors, RIG1/MDA5 cytoplasmic sensors and NFκB1 and MAVS signaling factors. Induced cells secrete inflammatory cytokines of TNF-α and IL1-β. Ingavirin in THP-1 cell culture monocytes caused a decrease in CD34+ blast cells. Activation the genes of MAVS and co-receptor B2M of the main histocompatibility complex (MHCII) by ingavirin were interrelated. Transfection of siRNA MAVS reduced the level of homologous mRNA MAVS and heterologous mRNA B2M. Conclusion . The results obtained suggest that the antiviral and immunomodulating properties of the drugs ingavirin and thymogen are associated with the activation of a group of TLR/RLR signaling pathways of the innate and adaptive immunity and the differentiation of hematopoietic cell precursors.

Introduction . Noncoding RNA of XIST gene (X inactivation-specific transcript) initiates inactivation of one of X chromosomes in cells of female organism. Further stages of this process include chromatin epigenetic modifications leading to the inhibition of the most genes on X chromosome. Recently the data were obtained that tumor suppressor BRCA1 is associated with inactive X chromosome (Xi) participating in XIST RNA localization on Xi and influencing XIST RNA expression.
Objective: to reveal the role of BRCA1 in XIST RNA expression.
Materials and methods . The objects of the study were mutant breast cancer cell lines (BRCA1–/–): HCC1395, HCC1937, SUM149PT, and, as controls – cell lines containing wild type of BRCA1 gene (BRCA1+/+): IMR90 и 293T. Method of reverse transcription coupled with polymerase chain reaction (RT-PCR) was used for the analysis of XIST RNA expression.
Results . In the clone of doxycycline-inducible HCC1937 breast cancer cell line XIST RNA expression was observed upon BRCA1 induction. In HCC1395, HCC1937 and SUM149PT breast cancer cell lines containing mutant BRCA1 gene (BRCA1–/–) and nonfunctional BRCA1 protein the absence of XIST RNA expression was observed using RT-PCR. This observation indicates the indispensable role of functional BRCA1 protein in XIST RNA expression.
Conclusion . Altogether, the data obtained in this study confirm the role of BRCA1 in the expression of noncoding inhibiting XIST RNA and suggest the involvement of BRCA1 in the inhibition of gene expression on Xi.

Introduction . Currently, the study of the neurotoxic properties of new drugs is an indispensable step towards the promotion of the medicine to clinical practice. The original antitumor drug anthrafuran (LCTA-2034), obtained in Gause Institute of New Antibiotics, has demonstrated high activity against transplantable mice tumors. Previous studies have shown that the drug in high doses causes brain tissues damage.
Objective: a pilot investigation of anthrafuran neurotoxicity.
Materials and methods . The study was carried out on 52 female outbred rats. The suspension of drug in water for injection was administrated per os at a single maximum tolerated dose of 170 mg/kg. The testing was performed on “open field” setting 1, 4 and 8 h and repeated on day 1 and 30 post treatment.
Results . It was found that the administration of the drug reduced both motor (covered distance, average speed) and research (the number of rearings, contacts with the “burrow”) activity as compared to control. These effects were manifested to the greatest extent 4 h post treatment. A day later, when rats re-visit “open field”, the parameters under study increased in this group, while in the control group these indicators decreased.
Conclusion . Anthrafuran exhibits a reversible inhibitory effect on the motor and research activity of rats.

Introduction . The appearance of high-quality and effective generics can significantly reduce the cost of health care for the drug supply of the population of Russia. According to expert estimates, the cost of treatment of cancer patients with generics of domestic can be 30– 40 % cheaper as compared to the original drugs. In Russia the pharmaceutical production company “Ozon” created by the domestic analogue of the original anticancer drug hydrea – hydroxycarbamide.
Objective: comparative study of chronic toxicity of the drug hydroxycarbamide (“Ozon”, Russia) and registered reference drug hydrea (Corden Pharma Latina S. p. A., Italy) on rats.
Materials and methods . A comparative study of the toxicity of drugs was carried out on 70 non-inbred white male rats weighing 220– 250 g obtained from the accredited laboratory animal nursery of LLC “Krolinfo”. Both drugs were administered in parallel daily orally 5-fold in 3 doses. As a solvent, 1 % starch paste was used. Doses were calculated according to the literature data on the basis of maximum tolerated dose. Standard methods of evaluation of chronic toxicity of drugs in rats were used.
Results . The obtained data on chronic toxicity of the compared forms of the domestic drug hydroxycarbamide and the reference drug hydrea do not differ significantly in terms of quantitative and qualitative toxicity (lethality, biomarkers of toxicity, morphometry of organs). Conclusion . The compared generic and commercial preparations are practically equitoxic by 5 times oral administration to rats.

Introduction . In the lyophilization technology, the freezing stage plays a key role in determining the time of primary sublimation, secondary desorption, and often the appearance of the lyophilisate. The duration of lyophilization is related to the composition and freezing conditions through the parameter resistance to mass transfer, which depends on the size of ice crystals.
Objective: to select temperature regimes of thermal cycling (“annealing”) to obtain the most vapor-permeable sublimation layer, calculate the value of resistance to mass transfer of water and select the most optimal lyophilization mode for preparing lyophilisate GK-2 for preparing solutions for injections.
Materials and methods . Substance: GK-2 (hexamethyleneamide bis-(N-monosuccinyl-L-glutamyl-L-lysine)) (V.V. Zakusov Research Institute of Pharmacology, Russia); excipients intended for parenteral use: lyoprotector – sucrose (CompriSugar®) (CristalUnion, France), cryoprotector – polyethylene glycol 4000 (PEG, macrogol) (Polyglykol® 4000, Panreac, Spain). Edwards EF-6 Lyophilic Dryer (Italy); microscope Nikon Eclipse E200; digital camera Nikon DS-Ri2; confocal microscope LEXT OLS 4100. Various freezing, lyophilization, direct optical microscopy in a cold chamber, laser microscopy and mathematical formulas were used to determine the values of resistance to mass transfer of water vapor from model lyophilisates.
Results . This article discusses the possibilities of optimizing the freezing stage and, accordingly, the entire lyophilization cycle by introducing an intermediate thermal cycling stage, provides calculations of the mass transfer coefficient of the composition under different freezing conditions and ice crystal sizes.
Conclusion . A simplified equation for calculating the coefficient of resistance to mass transfer for model solutions of GK-2 based on the correlation dependence was determined. The selection of freezing and “annealing” modes was carried out on the basis of the most important indicators, such as productivity and time of lyophilization.

Background . Test “Dissolution” is one of the main methods for quality evaluation of solid dosage drug forms, which enables characterization of the drug both in technological and biopharmacological aspects. The test may be also used for comparative studies of drugs bioavailability in vitro. Objective . Development of the “Dissolution” test for the drug Secoisolariciresinol, capsules 100 mg.
Materials and methods . The study used: Secoisolariciresinol, capsules 100 mg; hydrochloric acid (c. p.); Twin-80 (Polysorbate LAUROPAN T/80, Italy); purified water (рН 6.5); 0.1 М and 0.2 М solutions of hydrochloric acid; phosphate buffer solution (рН 6.8). Equipment and devices: dissolution tester ERWEKA, series 700, type – paddle mixer (ERWEKA, Germany); recording spectrophotometer Cary-100 (Varian, USA); рН-meter HANNA рН 211 (Hanna Instruments, Germany); analytical balances Sartorius 2405 (Sartorius AG, Germany).
Results . Methodology for performing the “Dissolution” test for the drug Secoisolariciresinol, capsules 100 mg was developed according to Russian State Pharmacopoeia (XIV) requirements for solid dosage drug forms.
Conclusions . Optimal conditions were chosen for performing the study “Dissolution” for capsules containing 100 mg of secoisolariciresinol. Analytical methodology was designed for quantitative assessment of secoisolariciresinol release from capsules, which enables accurate control of pharmaceutical substance content in different dissolution media. Methodology for the “Dissolution” test of the drug Secoisolariciresinol, capsules 100 mg was developed on the base of the obtained experimental data.