Human epidermal growth factor receptor 2 (HER2) is overexpressed in numerous cancer cell types. Therapeutic antibodies and chimeric antigen receptors (CARs) against HER2 were developed to treat human tumors. The major limitation of anti-HER2 CAR-T lymphocyte therapy is attributable to the low HER2 expression in a wide range of normal tissues. Thus, side effects are caused by CAR lymphocyte "on-target off-tumor" reactions. We aimed to develop safer HER2-targeting CAR-based therapy. CAR constructs against HER2 tumor-associated antigen (TAA) for transient expression were delivered into target T and natural killer (NK) cells by an effective and safe non-viral transfection method via nucleofection, excluding the risk of mutations associated with viral transduction. Different in vitro end-point and real-time assays of the CAR lymphocyte antitumor cytotoxicity and in vivo human HER2-positive tumor xenograft mice model proved potent cytotoxic activity of the generated CAR-T-NK cells. Our data suggest transient expression of anti-HER2 CARs in plasmid vectors by human lymphocytes as a safer treatment for HER2-positive human cancers. We also conducted preliminary investigations to elucidate if fucosylated chondroitin sulfate may be used as a possible agent to decrease excessive cytokine production without negative impact on the CAR lymphocyte antitumor effect.

The immunosuppression and inhibition of hematopoiesis are considered to be reasons for the development of complications after intensive chemotherapy and allogeneic hematopoietic stem cell transplantation. Chondroitin sulfate (CS), isolated from the fish Salmo salar, and fucosylated chondroitin sulfate (FCS), isolated from the sea cucumber Apostichopus japonicus, were studied for their roles as stimulators of hematopoiesis in a model of cyclophosphamide-induced immunosuppression in mice. The recombinant protein r G-CSF was applied as a reference. The studied polysaccharides were shown to stimulate the release of white and red blood cells, as well as platelets from bone marrow in immunosuppressed mice, while r G-CSF was only responsible for the significant increase in the level of leucocytes. The analysis of different populations of leucocytes in blood indicated that r G-CSF mainly stimulated the production of neutrophils, whereas in the cases of the studied saccharides, increases in the levels of monocytes, lymphocytes and neutrophils were observed. The normalization of the level of the pro-inflammatory cytokine IL-6 in the serum and the recovery of cell populations in the spleen were observed in immunosuppressed mice following treatment with the polysaccharides. An increase in the proliferative activity of hematopoietic cells CD34(+)CD45(+) was observed following ex vivo polysaccharide exposure. Further study on related oligosaccharides regarding their potential as promising drugs in the complex prophylaxis and therapy of hematopoiesis inhibition after intensive chemotherapy and allogeneic hematopoietic stem cell transplantation seems to be warranted.

In this study, we studied the changes in the binding of pea lectin to the lymphocytes of mice against the background of the growth of ovarian carcinoma CaO1 and Ehrlich ascites carcinoma. It was revealed that during tumor growth, the appearance in the peripheral blood of experimental animals of two populations of lymphocytes was observed. In the first population of lymphocytes, the level of binding to lectins does not differ from the level of binding of lectins to lymphocytes of animals without a tumor. In the second lymphocyte population, the lectin binding level is lower. It is suggested that this phenomenon is associated with the elimination of lymphocytes, which are able to have an antitumor effect. At the same time, the surface structure of lymphocytes, which are responsible for anti-infective immunity, does not change.

Immunosuppression derived after cytostatics application in cancer chemotherapy is considered as an adverse side effect that leads to deterioration of quality of life and risk of infectious diseases. A linear sulfated (1→3)-α-l-fucan M-Fuc prepared by chemical modification of a fucoidan isolated from the brown seaweed Chordaria flagelliformis, along with two structurally related synthetic sulfated oligosaccharides, were studied as stimulators of hematopoiesis on a model of cyclophosphamide immunosuppression in mice. Recombinant granulocyte colony-stimulating factor (r G-CSF), which is currently applied in medicine to treat low blood neutrophils, was used as a reference. Polysaccharide M-Fuc and sulfated difucoside DS did not demonstrate significant effect, while sulfated octasaccharide OS showed higher activity than r G-CSF, causing pronounced neutropoiesis stimulation. In addition, production of erythrocytes and platelets was enhanced after the octasaccharide administration. The assessment of populations of cells in blood and bone marrow of mice revealed the difference in mechanisms of action of OS and r G-CSF.

In the current work was inspected the impact of phytogenic lectins extracted from the Pisum sativum and Ricinus seeds at proliferative activity of peripheral blood mononuclear cells of healthy donors. Identified that phytogenic lectins Pisum sativum and Ricinus in small concentration (from 5 to 15 ?g/ml) possess the mitogenetic effect.

Purpose. Investigation of the effect of the Metronizatol on the biological effect of Doxirubicin.Materials and methods. The studies were performed in the CBA/Lac males and C57Bl/6 females mice grafted with melanoma B16 and mucinous ovarian cancer CaO‑1. Metronidazole and Doxorubicin were used in the work. The antitumor effect was assessed by tumor volume and inhibition of tumor growth.Results. The data obtained indicate that Metronidazole used in oncologic practice for the treatment and prevention of infectious complications, and as a radiosensitizer, can enhance the antitumor effect of Doxorubicin, but this effect is accompanied by a significant increase of the cytostatic toxicity. These effects are leveled by increasing the interval between injections of Metronidazole and Doxorubicin up to 4 hours.Conclusion. The enhancement of the antitumor activity of Doxorubicin under the influence of Metronidazole depends on the interval between the administration of these drugs. When Metronidazole is used in cancer patients, the possibility of enhancing the toxic effect of cytostatics should be considered when they are simultaneously exposed. Patients receiving chemotherapy should be administered antitumor drugs no earlier than 4 hours after exposure to Metronidazole.

Quantitative Regulation of Melanoma Growth in the Host by Tumor-Specific Serpins in Blood Serum is a Main Reason for Inefficient Tumor Treatment 511 chemotherapy and ILS of animals was observed.Nine days after transplantation, tumor cells were integrated into the host.Then a molecular growth program for the tumor was set on.This program of tumor growth determines the life span of tumor-bearing animals.Therefore, a dependence between the number of killed tumor cells by chemotherapy and ILS of animals is not observed in advanced tumors. Acceleration of tumor growth after removal of primary tumorIt is a well-known phenomenon that metastatic growth is boosted after removal of the primary tumor.We addressed the question, whether growth of metastases in mice with removed primary tumor really leads to a decrease of average life span.Therefore, we performed the following experiment.Mice with implanted В16 melanoma were used in the experiment.The conditions of tumor implantation are described above.All animals were divided into three groups.The first group contained control animals.In the second group, the tumor was removed 24 hours after injection of tumor cells.In the third group, the tumor was removed 9 days after implantation of the tumor.In figure 3, the results of the influence of removal of the primary tumor on average life span of mice are shown.The average life span of mice in the control group was 39.3 ± 2.4 days, in mice which received treatment 24 hours after tumor inoculation more than 70 days (p<0.05vs control), and in mice where the tumors were removed 9 days later 38.3 ± 2.9 days (p<0.5 vs control).In the last group, in animals metastatic growth in lungs was observed.1.After transplantation of tumor cells they were integrated into the host.2. As a result of this integration, a program of tumor growth was activated in the host.3.This program restored eliminated cells so that the average life span of animals did not change. How to referenceIn order to correctly reference this scholarly work, feel free to copy and paste the following:

Comparative study of cytokeratin-positive (CK+) cells, isolated from bone marrow and lymph node micrometastases in patients with lung and esophageal cancer, was performed using the methods of immunocytochemistry and immunomagnetic separation. It was found that immunocytochemical analysis permitted the detection of CK+ cells in the smears of bone marrow of oncologic patients. All the samples of bone marrow with immunocytochemically demonstrated CK+ cells, contained also the cellular complexes marked by magnetic spheres. The method of positive immunomagnetic separation has some advantages for the intraoperative diagnosis. However, when either method was applied, among CK+ cells in bone marrow and lymph nodes some false-positive, questionable cellular forms and hemopoietic cells expressing epithelial markers were found. Theses results suggest that for verification of micrometastases in these organs, an additional study using the standard staining of the slides, is required.

The impact of surgical treatment of Ehrlich's carcinoma on animals' survival was studied. Tumour removal on posttransplantation day 30 was shown to cause no increases in the longevity of the animals operated on as compared with those non-operated on (mean longevity was 59.9 and 62.2 days, respectively). The death causes of the animals operated on were metastases and relapses. On day 7 after transplantation, cyclophosphanum therapy of Ehrlich's carcinoma failed to prolong the animals' life. While 24 hours after tumour transplantation the longevity increased from 61.8 to 93.4 days. No therapeutical effects were shown to be associated with the influence of humoral factors of the host body on tumor growth. It was shown that the lack of these humoral factors resulted in interrupting tumor growth.

Approximately a 1.6-fold increase in the antitumor action of doxorubicin used in combination with artificial hyperglycemia was shown on mice C57B1/6 with hemocytoblastosis La. Artificial hyperglycemia was found to change the doxorubicin pharmacokinetics in the experimental animals evident from increased in antibiotic half-life to 42.3 min against 26.5 min in the controls, the apparent initial concentration of doxorubicin being increased 1.6 times. Accumulation of doxorubicin in the bone marrow cells of the mice did not change with artificial hyperglycemia. It was suggested that the increase in the therapeutic effect of doxorubicin used in combination with artificial hyperglycemia was associated with changes in drug pharmacokinetics.

The concentration of reactive cyclophosphamide metabolites (CP) and the time of their circulation in blood plasma of mice increase during artificial hyperglycemia (HG). Intensification of the antitumor CP activity against a background of HG in C57Bl/6 mice with hemocytoblastosis La may be a result of changes in the drug pharmacokinetics. An inhibitory action of HG on the CP-metabolizing system of the liver monooxygenases is shown.

The influence of unithiol and thymidine treatment on the acute toxicity and therapeutic effect of adriamycin in hemoblastosis La was studied in CBA and C57B1 mice. Unithiol and thymidine were shown to markedly decrease the toxicity of different doses of adriamycin which resulted in a lower mortality and longer survival of the animals. When unithiol and thymidine were administered in combination, their antitoxic effect was added. Since unithiol and thymidine administration does not diminish the therapeutic effect of various doses of adriamycin, unithiol may be recommended for clinical use to decrease adriamycin toxicity in cancer patients.

The effect of unitiol treatment on the toxicity of dactinomycin, 5-fluorouracil, bleomycetin and vincristine was studied in CBA mice. Unitiol treatment was shown to decrease the acute toxicity of dactinomycin and involves a lower loss of body weight. Also, it reduced dactinomycin hemotoxicity which was assessed on the basis of leukocyte count in peripheral blood. Conversely, unitiol potentiated the acute toxic effect of 5-fluorouracil, bleomycetin and vincristine which was matched by body weight loss following treatment with cytostatic drugs. The results point to a wide range of the biological effects of unitiol.

It was shown in male CBA mice that toxic doses (15 and 20 mg/kg) of adriamycin (AD) inhibited the activity of nonspecific liver oxidases and noticeably increased the duration of the animals' sleep after injection of hexenal which is a substrate of this enzymatic system. The inhibitory effect of AD remained unchanged in the course of 9 days of the experiment. The nontoxic dose of AD (5 mg/kg) inhibited the activity of the enzymatic system on the 2nd--3rd days after the injection of the drug. Meanwhile the activity of the enzymatic system returned to the level seen in intact animals by days 5--6. The toxic action of AD declined on activation of nonspecific liver oxidases with phenobarbital and rose as a result of administering the inhibitor SKF 525-A. The authors discuss whether it is possible to use the data obtained for clinical application of AD.