Gold(iii) complexes containing (non)protonated oligopyridines—unexpected results in cancer drug research Kseniya A. Koshenskova, Elena E. Bardina, Eugeniya V. Makotchenko, Viktoria Yu. Kharlamova, Igor V. Mironov, et al. New Journal of Chemistry, 2025 Two novel gold(iii) complexes with doubly protonated forms of phenanthrolines, (neocH2)[AuCl4]·Cl (1) and (1,7-phenH2)[AuCl4]·NO3 (2), were synthesized using the phenanthrolines.
MelCher5k/BRAF+ subcutaneous human melanoma xenograft with CD20 expression I. N. Mikhaylova, H. M. Treshalina, S. Sh. Karshieva, D. A. Khochenkov, N. V. Andronova, et al. Uspehi Molekularnoj Onkologii, 2025 Introduction. Metastatic melanoma of the skin (mMC) is characterized by an extremely unfavorable prognosis of survival. Significant remission of mMK is associated with the use of vemurafenib, which blocks the proliferation of cells with a mutation in the BRAF gene. However, after its cancellation, relapse develops rapidly, determining the need for continued treatment. The search for another therapeutic target in the primary mMC led to a small subpopulation of stem-like CD20 antigen-expressing cells. Pilot clinical trials of CD20-blocking rituxibam did not yield the desired result, which we interpreted as a lack of control of CD20 expression in recurrent cells, which is available only in vivo in an adequate human model of recurrent mMK / BRAF+ with high CD20 expression.Aim. To create an in vivo model of recurrent human mMC / BRAF+ with control of the representation of a subpopulation of cells with CD20 expression.Materials and methods. Vemurafenib (Roche, Switzerland), human melanoma cell culture MelCher5k / BRAF+, male Balb / c nude immunodeficient mice weighing 20–23 g breeding and maintenance at the N. N. Blokhin National Medical Research Center of Oncology were used. Mice with a transplanted tumor (n = 12) were divided into 2 groups: without the drug (control) and with the drug (vemurafenib). A comparative assessment of the growth dynamics of tumor nodes in the groups was carried out according to the volume ratio using the standard T / C (treatment / control) criterion, expressed as a percentage. The dynamics of the expression of S100, CD20, and CD45 markers was evaluated by flow cytofluorometry before the start of vemurafenib administration and at the end of follow-up.Results. According to the data obtained, in mice with MelCher5k / BRAF+ treated with vemurafenib from days 7 to 21, tumor reduction was observed from day 10 with complete remission by day 20. Relapses with the development of a tumor node at the implantation site (renewed growth of melanoma cells) occurred on day 28 (a week after drug withdrawal), and then the tumor progressed rapidly over the course of 34–41 days. In mice treated with vemurafenib, the proportion of CD20+ cells in the new focus was 35 %, which was 1.82 times higher than the proportion of CD20+ cells in the tumor of mice not treated with this drug (19 %). At the same time, the cells of the newly emerged tumor expressed the melanoma marker S100+ and did not express CD45.Conclusion. Thus, in vivo, using the MelCher5k / BRAF+ model, it was shown that in a recurrent tumor node developing after the use of vemurafenib, the proportion of stem-like cells expressing CD20 significantly increases. These data suggest that it is advisable to use the model to evaluate the clinical prospects of CD20-targeted agents capable of prolonging remission after vemurafenib withdrawal in patients with recurrent melanoma.
Preclinical characteristics of siRNA duplexes as targeted adjuvants in malignant growth H. N. Treshalina, G. B. Smirnova, A. Yu. Kuzevanova, S. Sh. Karshieva, M. V. Kiselevskiy, et al. Rossijskij Bioterapevticeskij Zurnal, 2025 Background. Small or short double-stranded interfering RNAs (siRNAs, small interfering RNAs) 20–25 nucleotides long are known to be able to target block uncontrolled malignant proliferation. As target genes, apoptosis inhibitors are considered, including the cellular glycoprotein CD47 (cluster of differentiation 47), and genes of the replicative complex that regulate the cell cycle in the S phase. This determines the relevance of the study in tumor models of siRNAs aimed at these targets as adjuvants.Aim. To evaluate the antiproliferative effects of novel siRNAs as adjuvants for immune-/chemotherapy in human colorectal and renal cancer models.Materials and methods. SiRNA/antiCD47 and two-component siRNA antiMSM4/antiLIVIN were developed at the Research Centre for Medical Genetics and studied in lipid dispersion for intravenous (IV) administration. Preclinical models – subcutaneous xenographs of RTK-8 colon cancer and human kidney cancer Rpoch-1/CD47, Balb/c nude mice were obtained from the N.N. Blokhin National Medical Research Center of Oncology. In the adjuvant mode, siRNA/antiCD47 was studied in combination with activated human macrophages (AM), siRNA antiMSM4/antiLIVIN (1:1) – with cyclic-dependent cytostatic oxaliplatin (OXP). Administration regimens are justified earlier. Efficacy parameters and criteria (treatment/control (T/C) ≤42 %), tolerability of effects and statistical analysis at p <0.05 are standard for experimental cancer therapy. Laboratory manipulations are regulated by the current recommendations of the Ministry of Health of the Russia.Results. The siRNA/anti-CD47 + AM regimen was practically ineffective at Rpoch-1/CD47, T/C = 45 % (p >0.05). The antiMCM4/antiLIVIN + 24 h siRNA regimen on an OXP-insensitive RTK-8 showed a significant adjuvant effect against cytostatic, T/C = 33–21 % versus T/Cmin = 49 % (p ≤0.05). Both combinations were tolerable.Conclusion. Preclinical study showed the controversy of the assumption about the possibility of adjuvant use of siRNA/antiCD47 with AM and the promise of antiMSM4/antiLIVIN siRNA on low-sensitivity to cycle-dependent OXR in human colon cancer with the possibility of cell cycle synchronization.
OPPORTUNITIES for CORRECTION of IMMUNOSUPPRESSION in PATIENTS with COVID-19 Mikhail V. Kiselevskiy, H. M. Treshalina, I. N. Mikhailova, D. V. Martirosyan, I. V. Manina, et al. Russian Journal of Infection and Immunity, 2022 Here, we review thematic publications in available literature sources of the databases PubMed, Scopus, Web of Science, eLibrary, 49 of which were dated of the years 19972022. Analysis of such reports is aimed at assessing features of cytokine storm-induced hyperinflammatory reaction with signs of immunosuppression accompanied by pronounced lymphopenia and lowered count of CD4+T helpers during severe COVID-19. The prognostic factor for unfavorable prognosis was based on the marker of systemic inflammatory reaction correlating with the disease severity the soluble IL-2 receptor as well as the neutrophil-to-lymphocyte ratio and the lymphocyte subset imbalance. An immunosuppressive therapy of severe forms of COVID-19, aimed at weakening the inflammatory response, exacerbates immune dysfunction by suppressing the T cell function, mainly due to Th1 lymphocytes involved in recognizing and eliminating intracellular pathogens particularly viruses. Upon that, cell-mediated immunity becomes compromised that relies on cytotoxic T-lymphocytes, natural killer cells and macrophages. Timely and targeted immunocorrection is required to prevent or reduce the immunosuppression that accompanies a severe disease course and leads to serious and prolonged complications, as well as to association of secondary infections. In fight against the cytokine storm, it is important not to miss a time point of developing immunosuppressive condition that transitions into immunoparalysis as follows from recent publications covering the tactics of treating immune-mediated complications of coronavirus infection. The review discusses opportunities for immunosuppressive therapy along with glucocorticosteroids and monoclonal antibodies blocking IL-6 or cognate receptors. Studies using mesenchymal stem cells (MSCs) to reduce systemic inflammatory response at COVID-19 are outlined in the review. The use of antigen-specific Treg and their combinations with antagonists of tumor necrosis factor- (TNF), interferon- (IFN) as well as low-dose IL-2 in patients with SARS-CoV-2 infection were analyzed. The prognostic perspectives for CAR-T cells and CAR-NK cells technology have been considered as novel therapeutic approaches aimed at training effector cells to recognize the surface SARS-CoV-2 virus spike-like (S) protein. The feasibility of a therapeutic approach is also emphasized by comparatively analyzed of efficacy of using IL-7 or IL-15 during lymphopenia in patients with COVID-19. Here, side effects complicating immunocorrection come to the fore. Critical evaluation of corrected immunosuppressive conditions in patients with COVID-19 in the post-COVID-19 period by using low-dose IL-2 therapy revealed its ability to repair cellular immune response. As a result, a low-dose IL-2 therapy is recommended as a cytokine replacement therapy in such patients with COVID-19 during hyper-to-hypo-inflammatory phase transition in immune response.
Evaluation of Toxic Properties of New Glycopeptide Flavancin on Rats Michael I. Treshchalin, Vasilisa A. Polozkova, Elena I. Moiseenko, Helen M. Treshalina, Andrey E. Shchekotikhin, et al. Pharmaceuticals, 2022 Glycopeptide antibiotics have side effects that limit their clinical use. In view of this, the development of glycopeptides with improved chemotherapeutic properties remains the main direction in the search for new antibacterial drugs. The objective of this study was to evaluate the toxicological characteristics of new semi-synthetic glycopeptide flavancin. Acute and chronic toxicity of antibiotic was evaluated in Wistar rats. The medium lethal dose (LD50) and the maximum tolerated doses (MTD) were calculated by the method of Litchfield and Wilcoxon. In the chronic toxicity study, the treatment regimen consisted of 15 daily intraperitoneal injections using two dosage levels: 6 and 10 mg/kg/day. Total doses were equivalent to MTD or LD50 of flavancin, respectively. The study included assessment of the body weight, hematological parameters, blood biochemical parameters, urinalysis, and pathomorphological evaluation of the internal organs. The results of the study demonstrated that no clinical-laboratory signs of toxicity were found after 15 daily injections of flavancin at a total dose close to the MTD or LD50. The pathomorphological study did not reveal any lesions on the organ structure of animals after low-dose administration of flavancin. Thus, flavancin favorably differs in terms of toxicological properties from the glycopeptides currently used in the clinic.
Peptide antitumor vaccines targeting HER2/neu H. M. Treshalina, M. A. Baryshnikova, E. V. Neborak, V. S. Kosorukov Rossijskij Bioterapevticeskij Zurnal, 2022 Antitumor vaccines are aimed at correcting cellular immunity by overcoming immunological tolerance with eluding surveillance due to the specific presentation of tumor-associated or tumor-specific antigens to immunocompetent cells.The purpose of this review was to study modern strategies for the development of antitumor vaccines containing epitopes of HER2/neu receptors acting as tumor-associated antigens. Approaches to the creation of such vaccines are classified by targeting the T-cell link or B-cells by the choice and length of the epitopes used or by the use of specific adjuvants.The review provides information on this topic, obtained from more than 50 publications of the last 20 years, found in the most significant sources of citation. The text is categorized for the convenience of perception by scientists of different specialties and is completed with a brief conclusion with an emphasis on development prospects. The results of clinical studies of vaccines with an analysis of the immunological features of the results of immunotherapy, mainly breast cancer with HER2/neu expression, are considered. Vaccines targeting different histocompatibility complexes are compared. The review traces the evolution of vaccine preparations from the simplest containing short peptide sequences to complex combined systems, including viral vectors. Attention is paid to various methodological approaches used in the development of such drugs: from computer design and phage display in experiments in vitro/in vivo. The emphasis is placed on the problem of a personalized approach to vaccination of an oncological patient associated with a mutation process occurring inside tumors and leading to the appearance of unique tumor-associated antigens. The participation of complement system components in antibody-mediated lysis of tumor cells induced by the presented vaccines is discussed.Thus, the review introduces readers to the existing directions of creating immune drugs designed to suppress the development of the tumor process by activating the body’s own immune forces and the prospect of their development.
Subchronic toxicity study of oral anthrafuran on rabbits Michael I. Treshchalin, Helen M. Treshalina, Vasilisa A. Golibrodo, Andrey E. Shchekotikhin, Eleonora R. Pereverzeva Pharmaceuticals, 2021 A new antitumor multi-target drug anthrafuran, with cellular targets such as topoisomerase I/II and some protein kinases, was obtained in Gause Institute of New Antibiotics and was demonstrated to have a reliable specific effect on different murine and human tumor models by oral administration. In this study, we focused on the evaluation of subchronic toxicity of oral anthrafuran drug formulation (AF) on Chinchilla rabbits. The absence of any changes in the condition or behavior of animals was shown for oral anthrafuran. Changes with reversible and dose-dependent hepato- and nephrotoxicity at low doses, as well as hemato- and gastrointestinal toxicity at high doses, were confirmed pathomorphologically. The identified toxic properties are extremely valuable, since oral anthrafuran does not have the limiting cardio- and myelotoxicity. Anthrafuran with 2 mg/kg/day or 6 mg/kg/day doses was administrated orally over 15 days. Investigations include assessment of the body weight, hematological and serum biochemical parameters and urinalysis, electrocardiography and pathomorphological evaluation of the internal organs. Quantitative data were processed statistically with Student’s t-Test, p < 0.05. Revealed during the subchronic study were the favorable toxicological properties of oral anthrafuran as opposed to clinical anthracyclines, oral idarubicin, or parenteral doxorubicin, which allows it to be considered promising for further research.
Analysis of cancer-testis antigens as potential markers for dissemination of primary human skin melanoma I. N. Mikhaylova, H. M. Treshalina, I. A. Utyashev, M. V. Kiselevsky, A. A. Lushnikova, et al. Siberian Journal of Oncology, 2021 Purpose of the study: to analyze characteristics of cancer-testis antigens (Ctas) as potential biomarkers for dissemination of primary human skin melanoma (sm).Material and Methods. Recent publications from Pubmed, scopus and elibrary databases were analyzed for the available appropriate literature review. In total, 176 papers reported the description of Ctas and encoding genes and their potential for prognosis of primary sm dissemination. The authors included 52 of them in the given review.Results. Two sections of the paper comprise clinically significant characteristics of Ctas and their genes, including overexpression, which is selective for the heterogeneous tumor cell populations and mediated by humoral and/or cellular immune reactions; the association of tumor process and activation of Cta genes by demethylation of promotor sites, which is correlated with tumor progression; and the conditions required for effective immunotherapy involving Ctas and/or their genes.Conclusion. At present, there are no standards or clinical recommendations for the Cta-based prognosis of the early dissemination of primary skin melanoma. Therefore, it is important to study and analyze the Cta and encoding gene characteristics that reveal the connection between primary sm progression and tumor genesis including the role of circulating tumor cells (ctc), similar to stem cells, which have epithelial-mesenchymal transition (emt) phenotype, for clinical diagnostics of early sm dissemination. As a result of the study, the following Ctas could be considered as significant biomarkers of the early sm dissemination: mage-a1, mage-a4 and ny-eso-1, which expression correlates with the clinical pathological description of the disease progression, as well as with the relapse-free period and overall survival of the patients; magea3, which expression correlates with spag5 activation and Cd8+ t-cell abundance; ssx, a marker for stem cell migration including identification of the cells with emt and/or ctcs; and prame, signaling marker for dissemination of the uveal melanoma.
Experimental evaluation of anticancer efficiency and acute toxicity of anthrafuran for oral administration Andrey E. Shchekotikhin, Helen M. Treshalina, Michael I. Treshchalin, Eleonora R. Pereverzeva, Helen B. Isakova, et al. Pharmaceuticals, 2020 The new antitumor agent anthrafuran has demonstrated a consistent effect in murine tumor models when administered parenterally due to the simultaneous inhibition of multiple cellular targets such as topoisomerases I/II and protein kinases. In this study, we assessed the anticancer efficiency and acute toxicity of anthrafuran administered orally. The action of anthrafuran was studied on transplanted tumor models which included P388 leukemia, Ca755 mammary adenocarcinoma, LLC lung carcinoma, and T47D human breast cancer xenografts on Balb/c nude mice. A significant antitumor efficacy of oral anthrafuran was revealed for all tested tumor models as follows: T/Cmax = 219% for P388, TGImax = 91% for Ca755, TGImax = 84% with CRmax = 54% for LLC, and T/C = 38% for T47D. The optimal treatment schedule of orally administered anthrafuran was 70–100 mg/kg given daily for five days. The LD50 value of orally administered anthrafuran (306.7 mg/kg) in mice was six times higher than that for i.p. administration (52.5 mg/kg). The rates of antitumor efficacy and acute toxicity indicate the high potential for further research on anthrafuran as a new original oral anticancer multitarget agent with an expected satisfactory tolerability and bioavailability.
Dynamics of tumor growth under the action of the new nano-ferrimagnetic nanoembosyl with transarterial introduction Yelena Treshchalina, M. Lkunina, K. Makovetskaya, A. Stanzhevskiy Voprosy Onkologii, 2020 Introduction. For the treatment of primary inoperable and metastatic solid human tumors with local regional arterial blood flow, a minimally invasive embolization method is used, which causes a decrease in the growth rate and size of the malignancy (cytoreduction), local side effects of which depend on the viscosity of the embolizing agent. Nanostructured ferro- and ferrimagnetics (ferrites) allow selectively achieving not only cytoreduction, but also full effect by following the embolization of magnetic hyperthermia (MHT). Material and methods. The study of a new original embolizing nano-ferrimagnetic nanoembosil with low viscosity was performed with intra-arterial (i.a.) administration to anesthetized animals with intramuscular (i.m.) developed tumors (PC1 and VX2). This allowed us to evaluate its effectiveness using adequate criteria and the method of variation statistics (Fisher-Student’s criterion «t» in the environment of the IBM SPSS 21 package) and statistically significant differences at p≤0.05. Results and discussion. It is shown that nanoembosil in doses of 0.1 and 0.2 ml for rats and 1.5 ml for rabbits is dose-dependent, and in the case of VX2 it is statistically significant (p=0.001) for a long time in 2-6 times inhibits the rate of tumor growth without side effects with long-term stabilization and cytoreduction by 50-65%. Structural analogs of nanoembosil in the practice of medicine there. Conclusion. Thus, nanoembosil can be considered an original effective agent for selective arterial embolization and it is recommended to continue its preclinical study in therapeutic and preoperative modes. Good tolerance of i.a. administration of nanoembosil in the studied doses with no local side effects opens the possibility of studying the possibility of studying it as a thermo-sensitive nanomaterial for low-frequency MHT.
