Modern methods of preclinical anticancer drug screening using test systems based on cell cultures

Preclinical screening of medicinal drugs for novel anti-cancer treatments faces a problem of a rational approach to primary screening of substances with antitumor activity. Low correlation between in vitro and in vivo studies with clinical trials remains a serious issue. Choosing the right tumor model at the in vitro testing stage reduces the financial and time costs of finding and testing promising antitumor agents. In the light of the growing prevalence of cancer, it is urgently important to develop new approaches to screening of anticancer drugs, as well as to increase the pace of creation, development, and testing of new antitumor agents. Although the pharmaceutical industry uses mainly two-dimensional in vitro models, the field of preclinical screening needs more complex models, such as three-dimensional models, microfluidic systems, Boyden chamber, and models created using three-dimensional bioprinting. This review describes the above in vitro tumor models, including their use in research and features, in order to help researchers and clinicians from various fields of pharmacy, preclinical studies, and cell biology understand their prospects for screening potential antitumor drugs

Cell Culture Based in vitro Test Systems for Anticancer Drug Screening

© Copyright © 2020 Kitaeva, Rutland, Rizvanov and Solovyeva. The development of new high-tech systems for screening anticancer drugs is one of the main problems of preclinical screening. Poor correlation between preclinical in vitro and in vivo data with clinical trials remains a major concern. The choice of the correct tumor model at the stage of in vitro testing provides reduction in both financial and time costs during later stages due to the timely screening of ineffective agents. In view of the growing incidence of oncology, increasing the pace of the creation, development and testing of new antitumor agents, the improvement and expansion of new high-tech systems for preclinical in vitro screening is becoming very important. The pharmaceutical industry presently relies on several widely used in vitro models, including two-dimensional models, three-dimensional models, microfluidic systems, Boyden’s chamber and models created using 3D bioprinting. This review outlines and describes these tumor models including their use in research, in addition to their characteristics. This review therefore gives an insight into in vitro based testing which is of interest to researchers and clinicians from differing fields including pharmacy, preclinical studies and cell biology

Recent Advances in Experimental Dendritic Cell Vaccines for Cancer

The development of immunotherapeutic methods for the treatment of oncological diseases have made it possible to improve the effectiveness of standard therapies. There was no breakthrough after first using of personalized therapeutic vaccines based on dendritic cells in clinical practice. A deeper study of the biology of dendritic cells, as well as the use of new approaches and agents for antigenic work, have made it possible to expand the field of application of dendritic cell (DC) vaccines and improve the indicators of cancer patients. In addition, the low toxicity of DC vaccines in clinical trials makes it possible to use promising predictions of their applicability in wider clinical practice. This review examines new approaches and recent advances of the DC vaccine in clinical trials

Tay-Sachs disease: Diagnostic, modeling and treatment approaches

© 2020, Human Stem Cell Institute. All rights reserved. Tay-Sachs disease (OMIM 272800) belongs to the group of autosomal-recessive disorders, caused by β-hexosaminidase A (HexA) enzyme deficiency, resulting in GM2-ganglioside accumu-lation in nervous and other tissues of the body. Enzyme deficiency is caused by various mutations in HEXA gene. Clinical symptom severity depends on residual HexA enzymatic activity associated with some mutations. Currently, there is no effective treatment for Tay-Sachs disease. There are clinical reports of substrate reduction therapy, bone marrow or umbilical cord blood transplanta-tion. However, the therapeutic efficacy of these methods remains insufficient to prevent aggravation of neurological symptoms in Tay-Sachs disease patients. Encouraging results were obtained using gene therapy to deliver wild-type genes encoding the α and β subunits of HexA. This review discusses the therapeutic strategies in Tay-Sachs disease treatment, as well as diagnostic methods and existing animal models to evaluate the effectiveness of new approaches for Tay-Sachs disease therapy

Current trends in cancer immunotherapy

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. The search for an effective drug to treat oncological diseases, which have become the main scourge of mankind, has generated a lot of methods for studying this affliction. It has also become a serious challenge for scientists and clinicians who have needed to invent new ways of overcoming the problems encountered during treatments, and have also made important discoveries pertaining to fundamental issues relating to the emergence and development of malignant neoplasms. Understanding the basics of the human immune system interactions with tumor cells has enabled new cancer immunotherapy strategies. The initial successes observed in immunotherapy led to new methods of treating cancer and attracted the attention of the scientific and clinical communities due to the prospects of these methods. Nevertheless, there are still many problems that prevent immunotherapy from calling itself an effective drug in the fight against malignant neoplasms. This review examines the current state of affairs for each immunotherapy method, the effectiveness of the strategies under study, as well as possible ways to overcome the problems that have arisen and increase their therapeutic potentials

Molecular Aspects and Future Perspectives of Cytokine-Based Anti-cancer Immunotherapy

© Copyright © 2020 Chulpanova, Kitaeva, Green, Rizvanov and Solovyeva. Cytokine-based immunotherapy is a promising field in the cancer treatment, since cytokines, as proteins of the immune system, are able to modulate the host immune response toward cancer cell, as well as directly induce tumor cell death. Since a low dose monotherapy with some cytokines has no significant therapeutic results and a high dose treatment leads to a number of side effects caused by the pleiotropic effect of cytokines, the problem of understanding the influence of cytokines on the immune cells involved in the pro- and anti-tumor immune response remains a pressing one. Immune system cells carry CD makers on their surface which can be used to identify various populations of cells of the immune system that play different roles in pro- and anti-tumor immune responses. This review discusses the functions and specific CD markers of various immune cell populations which are reported to participate in the regulation of the immune response against the tumor. The results of research studies and clinical trials investigating the effect of cytokine therapy on the regulation of immune cell populations and their surface markers are also discussed. Current trends in the development of cancer immunotherapy, as well as the role of cytokines in combination with other therapeutic agents, are also discussed

Mouse tumor models for advanced cancer immunotherapy

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Recent advances in the development of new methods of cancer immunotherapy require the production of complex cancer animal models that reliably reflect the complexity of the tumor and its microenvironment. Mice are good animals to create tumor models because they are low cost, have a short reproductive cycle, exhibit high tumor growth rates, and can be easily genetically modified. However, the obvious problem of these models is the high failure rate observed in human clinical trials after promising results obtained in mouse models. In order to increase the reliability of the results obtained in mice, the tumor model should reflect the heterogeneity of the tumor, contain components of the tumor microenvironment, in particular immune cells, to which the action of immunotherapeutic drugs are directed. This review discusses the current immunocompetent and immunocompromised mouse models of human tumors that are used to evaluate the effectiveness of immunotherapeutic agents, in particular chimeric antigen receptor (CAR) T-cells and immune checkpoint inhibitors

Contribution of multipotent mesenchymal stromal cells in the tumor microenvironment and carcinogenesis

Carcinogenesis is a complex and dynamic process, an important part of which is the formation of the tumor microenvironment, which is an integral part of malignant tumors and plays an important role in their progression. To maintain the growth and development of a tumor, constant contact and cross exchange of various trophic factors and cytokines with the cell of microenvironment, such as endothelial, immune, stromal cells, are essential. Multipotent mesenchymal stromal cells are an integral component of the tumor microenvironment, but their role in carcinogenesis is highly controversial. It has been described that multipotent mesenchymal stromal cells are able to stimulate tumor growth by differentiation into tumor-associated fibroblasts, immunosuppression, stimulation of angiogenesis, participation in the epithelial-mesenchymal transition, inhibition of apoptosis, and maintenance of the metastatic potential of the tumor. However, other studies show that multipotent mesenchymal stromal cells suppress tumor growth by increasing inflammatory infiltration, inhibiting angiogenesis, suppressing WNT and AKT signals, and by directly inducing apoptosis of tumor cells. This review discusses the role of multipotent mesenchymal stromal cells in carcinogenesis, as well as the mechanisms responsible for the pro- and antitumor effects of multipotent mesenchymal stromal cells

Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

© Copyright © 2020 Shaimardanova, Chulpanova, Solovyeva, Mullagulova, Kitaeva, Allegrucci and Rizvanov. Metachromatic leukodystrophy is a lysosomal storage disease, which is characterized by damage of the myelin sheath that covers most of nerve fibers of the central and peripheral nervous systems. The disease occurs due to a deficiency of the lysosomal enzyme arylsulfatase A (ARSA) or its sphingolipid activator protein B (SapB) and it clinically manifests as progressive motor and cognitive deficiency. ARSA and SapB protein deficiency are caused by mutations in the ARSA and PSAP genes, respectively. The severity of clinical course in metachromatic leukodystrophy is determined by the residual ARSA activity, depending on the type of mutation. Currently, there is no effective treatment for this disease. Clinical cases of bone marrow or cord blood transplantation have been reported, however the therapeutic effectiveness of these methods remains insufficient to prevent aggravation of neurological disorders. Encouraging results have been obtained using gene therapy for delivering the wild-type ARSA gene using vectors based on various serotypes of adeno-associated viruses, as well as using mesenchymal stem cells and combined gene-cell therapy. This review discusses therapeutic strategies for the treatment of metachromatic leukodystrophy, as well as diagnostic methods and modeling of this pathology in animals to evaluate the effectiveness of new therapies

Inflammatory Bowel Disease-Associated Changes in the Gut: Focus on Kazan Patients

Background: Several studies have highlighted the role of host-microbiome interactions in the pathogenesis of inflammatory bowel disease (IBD), resulting in an increasing amount of data mainly focusing on Western patients. Because of the increasing prevalence of IBD in newly industrialized countries such as those in Asia, the Middle East, and South America, there is mounting interest in elucidating the gut microbiota of these populations. We present a comprehensive analysis of several IBD-related biomarkers and gut microbiota profiles and functions of a unique population of patients with IBD and healthy patients from Kazan (Republic of Tatarstan, Russia). Methods: Blood and fecal IBD biomarkers, serum cytokines, and fecal short-chain fatty acid (SCFA) content were profiled. Finally, fecal microbiota composition was analyzed by 16S and whole-genome shotgun sequencing. Results: Fecal microbiota whole-genome sequencing confirmed the presence of classic IBD dysbiotic features at the phylum level, with increased abundance of Proteobacteria, Actinobacteria, and Fusobacteria and decreased abundance of Firmicutes, Bacteroidetes, and Verrucomicrobia. At the genus level, the abundance of both fermentative (SCFA-producing and hydrogen (H2)-releasing) and hydrogenotrophic (H2-consuming) microbes was affected in patients with IBD. This imbalance was confirmed by the decreased abundance of SCFA species in the feces of patients with IBD and the change in anaerobic index, which mirrors the redox status of the intestine. Conclusions: Our analyses highlighted how IBD-related dysbiotic microbiota - which are generally mainly linked to SCFA imbalance - may affect other important metabolic pathways, such as H2 metabolism, that are critical for host physiology and disease development