The antitumor activity of the N-glycoside derivative indolo[2,3-a]carbazole LCS-1269 with a polysaccharide from Helianthus tuberosus L. as an adjuvant agent was studied on a model of Lewis epidermoid lung carcinoma in mice of F1 hybrids (C57Bl/6 × DBA/2). The antitumor effect was assessed by inhibition of tumor growth in treated animals in comparison with controls. As a result, it was found that the therapeutic effect of the combination was higher and longer than in monotherapy, with a decrease in tumor growth of Lewis lung carcinoma by 53–64

The Lewis model of epidermoid carcinoma that developed in the lungs of F1(C57Bl/6 × DBA/2) hybrid mice has been used while investigating antitumor activity of the N-glycoside derivative indolo[2,3-a]carbazole (LCS-1269) with a polysaccharide from Helianthus tuberosus L. as an adjuvant agent. The antitumor effect of LCS-1269 together with the polysaccharide was evaluated by the inhibition of tumor growth in treated ani mals in comparison to the control group. As a result, it was found that combination of LCS-1269 with the polysaccharide from Helianthus tuberosus L. provided more pronounced therapeutic and longer-lasting effect than monotherapy showing a 53–64% decrease in growth of Lewis lung carcinoma for up to a 28-day obser vation period. Polysaccharide supplementation led to an increase in the number of blood cells leukocytes, lymphocytes and phagocytes responsible for antitumor immunity. The chemotherapy in combination with LCS-1269 and polysaccharide had a pronounced sustained antitumor effect on Lewis lung carcinoma in the peripheral blood system of mice in presence of a temporarily increased level of neutrophils and monocytes by the 12th day of tumor development. Apparently, the tested compounds stimulated proliferation of neutrophils and monocytes of certain phenotypes with antitumor activity at an earlier stage of Lewis lung carcinoma de velopment.

Introduction. Improving the efficacy of chemotherapy is a non-trivial task of modern oncology. Its successful solution requires knowledge in many fields, including physiology, pathology, clinical oncology, pharmacology and others. The search for small molecules that selectively kill tumor cells led to the accidental discovery of erastin.Text. Erastin is a unique molecule that has a quinazoline fragment in its structure. Not so long ago it became known that the antitumour effect of this compound is due to the induction of ferroptosis – an iron-dependent form of cell death caused by lipid peroxidation. Erastin is able to induce ferroptosis through various biochemical pathways, including blocking of cystine-glutamate transport channel of cell membrane and potential-dependent anion channel of mitochondria, as well as activation of p53 protein.Conclusion. Pharmacological induction of ferroptosis by erastin and its analogues represents a promising direction in cancer chemotherapy. In addition, erastin and its analogues are able to increase sensitivity to chemotherapy and radiation therapy, which allows us to talk about the possibility of their use in the combined treatment of malignant neoplasms.

Objective: In recent years, significant progress has been achieved in the treatment of patients with colorectal cancer, but in most cases, treatment is accompanied by the development of drug resistance. Recently discovered iron-dependent cell death, ferroptosis, provides promising therapeutic targets that might aid in reducing the recurrence rates. Methods: Derivatives of 3-hydroxyquinazoline were obtained by chemical synthesis and have a purity of at least 95

Background. Increasing the solubility of new pharmacologically active substances is one of the main tasks of pharmacy. It becomes even more relevant in the field of creating dosage forms for difficult-to-solubilise substances with a new mechanism of action, as in the case of 3-hydroxyquinazoline derivatives, which have shown in vivo experiments the ability to activate tumour cell death by ferroptosis. This includes OVF-009 – an original domestic substance. Due to the solubility of this compound in oils, the technology of its solubilisation using modified castor oil (Kolliphor® ELP, BASF, Germany), approved for parenteral use, was proposed. Aim. To create a model dosage form for a new hydrophobic quinazoline derivative in order to further evaluate the spectrum of its antitumour activity in in vivo experiments. Materials and methods. OVF-009, Kolliphor® ELP, 95 % ethanol, Kollidon 17 PF (BASF, Germany), sodium hydroxide, phosphate buffer, water for injection; spontaneous micelle formation, ultrasound, potentiometry, dynamic light scattering, electrophoretic method, viscometry method, etc. Results. The main properties of micelle-forming solubiliser Kolliphor® ELP and its aqueous solutions were considered; 10 model solutions OVF-009 based only on Kolliphor® ELP and with addition of ethanol and Kollidon 17PF in different concentrations were obtained; the quality of the obtained compositions was evaluated by parameters – appearance, solution transparency, pH, stability over time and tolerability by laboratory animals. As a result, two formulations prepared on phosphate buffer were chosen: formulation No 5, which contains 10 % Kolliphor® ELP and additionally 10 % polyvinylpyrrolidone, and formulation No 8, in which in addition to the main solubiliser 10 % ethanol and 16 % polyvinylpyrrolidone were added. Both formulations have neutral pH, can be stored for 24 h and are tolerated by laboratory animals. Conclusion. The selected model compositions for solubilisation of the substance OVF-009 on the basis of Kolliphor® ELP allowed to provide the concentration of the active substance in the solution suitable for further biological experiments on animals.

Introduction. Early malignant tumor detection programs have significantly increased the survival rate of breast cancer patients but the results of drug therapy for this pathology are not always highly effective. Recently discovered iron-dependent cell death, ferroptosis, makes it a promising therapeutic target to reduce the recurrence rates. Objective – to study the induction of ferroptosis in breast cancer cells MCF-7 by quinazoline derivatives synthesized at the Research Institute of Experimental Diagnostics and Therapy of Tumors of the N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia and to evaluate its antitumor activity on transplanted breast carcinoma Ca-755. Materials and methods. Derivatives of 3-hydroxyquinazoline were obtained by chemical synthesis and have a purity of at least 95 %. In this study 2D cultivation of MCF7 cells, phase-contrast and fluorescence microscopy, and a model of experimental growth of breast carcinoma Ca-755 in female hybrids of immunocompetent mice F1 (C57Bl/6 × DBA/2) were used. Results. Five derivatives of 3-hydroxyquinazoline, analogues of erastine, were studied in this work. The ferroptotic cell death was identified by the level of lipid peroxidation at the concentrations of 1/3 and 1/5 IC 50 . The level of lipid peroxidation induced by compound 3 was comparable with the activity of erastin in MCF7 cells at both 1/3 and 1/5 of IC 50 , the activity of the other four quinazoline derivatives was 50–70 % of the activity of erastin. In in vivo experiments at a dose of 30 mg/kg the antitumor efficacy of the compound 3 was higher than that of erastin at the same dose. Conclusion. The data obtained suggest that quinazoline derivative 3 might be considered as a promissisng antitumor agent to treat breast cancer.

Background. Expression evaluation of somatostatin receptors (SSTRs) in tumor cells is necessary for the reasonable use of therapy directed at such receptors.Aim. The affinity determination of the original analogue of somatostatin cyphetrylin for SSTRs of transplanted mice mammary adenocarcinoma Ca-755.Materials and methods. Cyphetrylin was synthesized in the Chemical Synthesis Laboratory of the Research Institute of Experimental Diagnostics and Therapy of Tumors, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia. Cyphetrylin in tablet form was administered orally at a therapeutic dose of 10 mg/kg for 7 days to female F1 (C57Bl/6 × DBA/2) tumor-grafted Ca-755 mice. Animals of the control group were not administreted with сyphetrylin. Tumor tissue samples were obtained from animals on the 9th and 14th days after Ca-755 transplantation and sent for immunohistochemical study, which was performed on serial paraffin sections by the immunoperoxidase method using primary antibodies to various types of SSTRs.Results. The high frequency of positive expression of SSTR1, SSTR2, and SSTR5 (in 80, 100 and 100 % of tumor samples, respectively) was shown in tumor samples of the control group animals. As a result of cyphetrylin introduction in tumor samples obtained on the 9th day after Ca-755 inoculation, a change in the tumor receptor status was found towards a decrease in the level of expression of SSTR2 (80 % of samples) and SSTR5 (80 % of samples); SSTR1 expression did not change (80 % of samples). Compared to the controlled, in tumor samples after cyphetrylin administration, obtained on day 14 from Ca-755 transplantation, a decrease in the expression level of SSTR2 (80 % of samples), SSTR1 and SSTR5 (60 % of samples for SSTR each type) was noted, due to cyphetrylin binding to SSTRs of tumor cells. The receptors SSTR3 and SSTR4 did not show a high level of expression in the studied Ca-755 tumor samples.Immunohistochemical staining of Ca-755 cells with antibodies to SSTRs showed a tendency to reduction of antigen-positive cells number from 15–50 % in control to 10–40 % on day 9 after Ca-755 transplantation and 10–30 % on day 14 after Ca-755 transplantation.Conclusion. The data obtained indicates the presence in mice transplanted mammary adenocarcinoma Ca-755 of SSTR1, SSTR2 and SSTR5 high level expression due to the binding to which the direct cyphetrylin antitumor effect is realized.

Introduction. The main cause of clinical progression of tumor under the conditions of treatment is the resistance. Reactivate apoptosis in resistant to chemotherapy cells is impossible, the tumor grows into an irreversible growth phase. Recently published data on the ability of ferroptosis inducers to induce the death of resistant cells opens up new possibilities for improving the effectiveness of antitumor therapy.The purpose of the study – assessment of the mechanism of ferroptosis induction of the synthesized analogue of erastin OVN‑002 on Mel Z melanoma cells and investigation of its antitumor activity on transplanatated B‑16 melanoma of mice.Materials and methods. In this study 2D cultivation of metastatic Mel Z melanoma cells, phase‑contrast and fluorescence microscopy, and a model of experimental growth of B‑16 melanoma in female hybrids of immu‑ nocompetent mice F1 (C57Bl/6 × DBA / 2) were used. The antitumor effect was evaluated by measurement of tumor growth inhibition (TGI, %) and increase of life span of the treated animals as compared to the control ones.Results. The cytotoxic activity of OVN‑002 was equal to the activity of erastin on metastatic melanoma cells Mel Z: 744 ± 20 and 719 ± 20 a. u., respectively. OVN‑002 at a dose 50 mg / kg reduced the growth of experimental melanoma B‑16 about 81 % (TGI 81–57 %, p <0.05). The effect was stable up to 7th day, while erastin showed only a direct antitumor effect (TGI 65 %, p <0.05).Conclusion. The data obtained suggest that OVN‑002 might be considered as a novel antitumor agent.

We studied specific antitumor activity of a liposomal drug based on tetra-3-phenylthiophthalocyanine aluminum hydroxide (lipophthalocyan) intended for photodynamic therapy. The optimal dose and protocol for photodynamic therapy with lipophthalocyan were chosen in experiments on mice: single intravenous dose of 6 mg/kg with a 5-h interval between administration and laser exposure and irradiation energy density of 400 J/cm2. A wide spectrum antitumor activity of lipophthalocyan was demonstrated in vivo for various transplantable mouse tumors (Lewis lung epidermoid carcinoma, S37 sarcoma, and colon adenocarcinoma AKATOL). The results show the possibility of using lipophthalocyan for photodynamic therapy of tumors of surface localization (skin and mucosa tumors).

Introduction. The search for new antineoplastic agents in a series of indolo[2,3-a]-carbazole derivatives is an urgent and promising direction, since compounds with antitumor activity have been found in this class. In the chemical fusion laboratory, N.N. Blokhin National Medical Research Center оf the Ministry of Health of Russia has developed an original and effective method for the synthesis of glycosides of indolo[2,3-a]-pyrrolo[3,4-c]carbazoles, which makes it possible to synthesize derivatives of N-glycosides of indolo[2,3-a]carbazoles with different substituents in the heterocyclic parts including at the maleimide nitrogen atom and with different carbohydrate residues.The purpose of the study – the primary assessment of the antitumor activity of new derivatives of indolocarbazoles with a carbohydrate residue xylose in models of tumor growth mice.Materials and methods. The compounds studied at transplanted tumors of mice: the Lewis epidermoid carcinoma (LLC), colon cancer ACATOL, cervical cancer RSHM-5, breast adenocarcinoma CA-755. Studies were performed on immunocompetent mice: males and females of BDF1 hybrids (C57Bl/6 × DBA/2), females CBA/Lac and Balb/c. Compound solutions were prepared ex tempore and administered to the mice intraperitoneally at a dose of 60 mg/kg daily for five days. The antitumor effect was evaluated as to of tumor growth inhibition and increase of life span of the treated animals as compared with the control ones.Results. Eight compounds studied, containing D-xylose as a carbohydrate component and various substituents at the maleimide nitrogen atom, showed different degrees of antitumor activity. Two derivatives have been identified: N-[5,7-dioxo-12-(β-D-xylopyranosyl)-indole[2,3-a]pyrrolo[3,4-c]carbazol-6-il]benzamide (compound 4) and N-[5,7-dioxo-12-(β-D-xylopyranosyl)-5,7,12,13-tetrahydro-6H-indole[2,3-a]pyrrolo[3,4-c]carbazole-6-il]pyridin-2-carboxamide (compound 8), which showed high antitumor activity on 4 solid tumors of mice with a duration of effect of 12 days or more. The most pronounced antitumor effect was obtained in compounds 4 and 8 in RSHM-5 and Ca-755, tumor growth inhibition was amounted, respectively: in RSHM-5 – 68–82 % and 80–72 %; for Ca-755 – 57–62 % and 86–68 % (p <0.05).Conclusion. For further research, we chose the compound (N-[5,7-dioxo-12-(β-D-xilopiranosil)-5,7,12,13-tetrahydro-6H-indole[2,3-a] pyrrolo[3,4-c]carbazol-6-il]pyridin-2-carboxamide).

We studied cytotoxic activity of new tetranitrosyl NO-generating binuclear iron—sulfur [Fe—S] complexes containing different ligands in the molecule against tumor cells in vitro. Cytotoxic activity of the most active complex with cysteamine (CysAm) was compared with that of antitumor drug cisplatin. Caspase activation and morphological changes in cells were visualized by fluorescence microscopy. Fluorescence of active caspases 3 and 7 and changes in nuclear DNA in cells in the presence of CyAm were detected by using fluorochrome-labeled inhibitor of caspases (FLICA) and Hoechst and propidium iodide reagents. Similar cytotoxic activities of CyAm and cisplatin were demonstrated in various human tumor cell lines of different histogenesis. Therefore, a new class of NO-donating [Fe—S] complexes can provide the base of potential drugs for chemotherapy with a new mechanism of action.

The present work is devoted to the study of pharmacokinetics of infrared photosensitizer (PS) based on hydroxyaluminium tetra‑3‑phenylthiophthalocyanine in a sterically stabilized liposomal form. The study was carried out on adult female mice. The PS was administered once intravenously at a dose of 6 mg / kg. Evaluation of the PS accumulation dynamics in the mice tissues and organs was performed at time intervals from 5 minutes to 7 days using spectral‑fluorescent method. The maximum accumulation of the PS photoactive form was recorded in lungs (32 µg / g in the interval of 5–30 minutes after introduction), liver (20.8 µg / g in the interval of 4–24 hours after introduction) and spleen (28 µg / g 4 hours after introduction). At the same time, by the end of the observation period (7 days after administration), trace amounts of the PS photoactive form were still detected in the liver and the spleen at a calculated concentration of 0.5‑1 µg / g. The PS accumulated the least in muscles and skin. The fluorescent signal from the PS accumulated in skin was detectable almost immediately, and its concentration remained at the same level (1.2‑1.5 µg / g) for up to 3 days of observation. In the muscles, the concentration of the PS reached 1.5 µg / g 15 minutes after administration, and then gradually decreased until 0.25 µg / g at 24 hours. Data on the pharmacokinetics of PS in blood, basic organs and tissues of animals were obtained, pharmacokinetic parameters were calculated. 7 days after the administration, the PS concentration in the skin and muscles was below the detection limit. The studies confrmed that PEGylation of the PS liposomal form slows down the process of its capture by reticulo‑endothelial system. It was shown that the PS circulates in blood and organs of mice for a long time and it completely distributes only when 4 hours pass after administration.

We performed an in vivo comparative study of activity of three substances of the nitrosourea group produced in Russia. All substances demonstrated high antitumor activity against various solid and leukemic tumors. Aranosa significantly enhanced life duration in mice with leukemia (by 65-194%) and inhibited the growth of solid tumors (by 49-99.6%). Lisomustine and ormustine showed higher activity than aranose. Single administration of lisomustine increased life span of mice (by 22-114%) and resulted in cure of all animals in four models: lymphoblastic leukemia L-1210, lymphocytic leukemia P-388, Lewis lung carcinoma, and cervical cancer RShM-5. After ormustine treatment, full recovery was observed only in groups with lymphocytic leukemia P-388 and cervical cancer RShM-5. These findings attest to higher activity of lisomustine in the studied models.

The present work is devoted to the study of pharmacokinetics of infrared photosensitizer (PS) based on hydroxyaluminium tetra‑3‑phenylthiophthalocyanine in a sterically stabilized liposomal form. The study was carried out on adult female mice. The PS was administered once intravenously at a dose of 6 mg / kg. Evaluation of the PS accumulation dynamics in the mice tissues and organs was performed at time intervals from 5 minutes to 7 days using spectral‑fluorescent method. The maximum accumulation of the PS photoactive form was recorded in lungs (32 µg / g in the interval of 5–30 minutes after introduction), liver (20.8 µg / g in the interval of 4–24 hours after introduction) and spleen (28 µg / g 4 hours after introduction). At the same time, by the end of the observation period (7 days after administration), trace amounts of the PS photoactive form were still detected in the liver and the spleen at a calculated concentration of 0.5‑1 µg / g. The PS accumulated the least in muscles and skin. The fluorescent signal from the PS accumulated in skin was detectable almost immediately, and its concentration remained at the same level (1.2‑1.5 µg / g) for up to 3 days of observation. In the muscles, the concentration of the PS reached 1.5 µg / g 15 minutes after administration, and then gradually decreased until 0.25 µg / g at 24 hours. Data on the pharmacokinetics of PS in blood, basic organs and tissues of animals were obtained, pharmacokinetic parameters were calculated. 7 days after the administration, the PS concentration in the skin and muscles was below the detection limit. The studies confrmed that PEGylation of the PS liposomal form slows down the process of its capture by reticulo‑endothelial system. It was shown that the PS circulates in blood and organs of mice for a long time and it completely distributes only when 4 hours pass after administration.

The paper discusses the possible mechanisms of antitumor action of indolocarbazole derivatives. Here we present a data that show interaction drugs based on indolocarbazole derivatives with several intracellular targets and consequently activation different pathways of cell death. Also we present results of our studies on the mechanisms of antitumor action of compounds LCS-1006 and LCS-1208 synthesized in the N.N. Blokhin Russian Cancer Research Center, Ministry of Health of Russia.

Представлены результаты изучения противоопухолевой активности отечественного аналога соматостатина цифетрилина на экспериментальных опухолях животных. Выявлен максимальный противоопухолевый эффект цифетрилина в дозе 10 мг/кг на перевиваемой модели рака шейки матки РШМ5 непосредственно после окончания применения препарата (торможение роста опухоли, ТРО = 86 %). Показано, что цифетрилин в дозе 120 мг/кг способствовал увеличению продолжительность жизни (УПЖ) животных с аденокарциномой Са755 на 59 % (ТРО = 86 %). Препарат подавлял рост аденокарциномы толстой кишки АКАТОЛ в течение 9 дней: ТРО = 79 % и 62 % в 1-й и 9-й день наблюдения, соответственно, а меланомы В16 — в течение 17 дней, ТРО = 77 – 62 %. Установлено, что режим ежедневного перорального введения препарата в течение 5 дней является наиболее эффективным: на РШМ5 эффект цифетрилина оставался статистически достоверным (ТРО = 54 %) до 22-го дня наблюдения, а на Са755, АКАТОЛе и меланоме В16 — на протяжении 14 дней (ТРО 82, 58 и 59 %, соответственно). Показаны высокая противоопухолевая эффективность цифетрилина в отношении развившейся опухоли РШМ5 (ТРО = 79 – 76 %), а также антиметастатическая эффективность препарата (61 % торможения роста метастазов) в комбинации с хирургическим удалением опухоли.

Introduction . The report considers the prospect of rational approach to the new anticancer agents creation based on indolocarbazole derivatives.Objective . To conduct a comparative study of 12 domestic N-glycosides, indolo[2,3-a]pirrolo[2,3-a]carbazole derivatives in the course of “structure – activity” bond analysis.Materials and methods . The investigation of influence of 12 carbohydrate – containing indolocarbazoles, synthesized in N. N. Blokhin Russian Cancer Research Center of the Ministry of Health of Russia, performed on models of solid transplantable mouse tumors: lung Lewis epidermoid carcinoma and B16 melanoma. The antitumor effect was assessed by Lewis epidermoid carcinoma and B16 melanoma tumor growth inhibition (TGI %) criterion.Results . A variety of indolocarbazoles modifications allowed revealing the dependence of their antitumor properties on the structure of both, the aglycone and the glycoside residue. Imino-nitrogen interchange of atoms in upper heterocycle influences on indocarbazole derivatives antitumor activity change. During a comparative study of 12 N-glycosides indolocarbazole derivatives on lung Lewis epidermoid carcinoma and B16 melanoma models, 8 derivatives showed antitumor activity.Conclusion . The formulated concepts on the modification features in indolocarbazole derivatives structure can be used for more active compounds creation with greater action selectivity.